# Patent

## Title
Therapeutic compositions for treatment of ocular inflammatory disorders

## Abstract

The invention comprises a composition with means to inhibit the function of the inflammatory cytokine IL-17 and methods for using this composition to treat IL-17-mediated ocular inflammatory disorders. The invention also discloses devices for delivering this composition to the eye.

## Background
RELATED APPLICATIONS
This application is a national stage application, filed under 35 U.S.C. §371, of International Application No. PCT/US2009/000114, filed Jan. 9, 2009, which claims the benefit of provisional application U.S. Ser. No. 61/010,566, filed Jan. 9, 2008, the contents of which are incorporated by reference in their entireties.
FIELD OF THE INVENTION
This invention relates generally to the field of ophthalmology.
BACKGROUND OF THE INVENTION
Ocular surface inflammatory disorders are one of the major causes of visual impairments. Dry Eye Syndrome (DES), which is also known as keratoconjunctivitis sicca, is a predominant ocular surface inflammatory disorder. Current knowledge of the etiology and pathogenesis of ocular surface inflammatory disorders remains inadequate and current treatments provide only temporary and incomplete symptomatic relief.
SUMMARY OF THE INVENTION
The invention comprises a method for inhibiting or reducing the severity of an IL-17-mediated ocular surface inflammatory disorder by locally administering to an eye of a subject a composition that inhibits an activity of an inflammatory interleukin-17 cytokine such as binding of an inflammatory IL-17 cytokine to an IL-17 receptor or other elements of proinflammatory signaling pathways. The claimed compositions and methods fulfill a need for a treatment of an IL-17-mediated ocular surface inflammatory disorders that not only completely addresses the symptoms of this condition, but also affects the underlying biological mechanism. The ability of the methods described herein to target molecular signaling pathways that lead to ocular surface inflammatory disorders provides a long-term solution for treating these common, yet, complex conditions.
In a preferred embodiment, the composition of the claimed invention inhibits the activity of IL-17A or IL-17F. Alternatively, the composition of the claimed invention inhibits the activity of IL-17A and IL-17F. In another preferred embodiment the composition of the claimed invention inhibits the activity of IL-17RA or IL-17RC. Alternatively, the composition of the claimed invention inhibits the activity of IL-17RA a IL-17-mediated ocular surface inflammatory disorders of the invention comprise penetrating keratoplasty, corneal transplantation, lamellar or partial thickness transplantation, selective endothelial transplantation, corneal neovascularization, keratoprosthesis surgery, corneal ocular surface inflammatory conditions, conjunctival scarring disorders, autoimmune conditions, Pemphigoid syndrome, Stevens-Johnson syndrome, allergy, severe allergic (atopic) eye disease, conjunctivitis, and microbial keratitis. IL-17-mediated ocular surface inflammatory disorders comprise severe allergic (atopic) eye disease. Preferably, IL-17-mediated ocular surface inflammatory disorders do not comprise uveitis, intraocular conditions, or inflammation of interior tissues of the eye.
In one preferred embodiment of the invention, the IL-17-mediated ocular surface inflammatory disorder is Dry Eye Syndrome (DES). Synonyms and related disorders of DES include, but are not limited to, keratoconjunctivitis sicca (KCS), Sjögren syndrome (SS), Sjögren syndrome associated keratoconjunctivitis sicca, non-Sjögren syndrome associated keratoconjunctivitis sicca, keratitis sicca, sicca syndrome, xerophthalmia, tear film disorder, decreased tear production, aqueous tear deficiency (ATD), meibomian gland dysfunction (MGD), and evaporative loss. The subject is identified as suffering from DES or a related disorder by detecting a sign or symptom selected from the group consisting of dry, scratchy, stingy, itchy, burning or pressured sensations, irritation, pain, redness, inflammation, discharge, and excessive eye watering. Alternatively, a subject is identified as suffering from DES or a related disorder if their tear composition is insufficient for proper eye tissue lubrication. The method of therapy inhibits or reduces the severity of at least one of these signs or symptoms.
Dry eye is a multifactorial disorder of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability, with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface (emp MA. Report of the National Eye Institute/Industry Workshop on clinical trials in dry eyes. CLAO J 1995; 21:221-2). For a more detailed definition, see The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop. Ocular Surface. 2007 April; 5(2):75-92, herein incorporated by reference. The method of therapy inhibits or reduces the severity of at least one of these signs or symptoms.
The method comprises administration of a compound that inhibits binding of an inflammatory IL-17 cytokine to the IL-17 receptor complex. Preferred formulations are in the form of a solid, a paste, an ointment, a gel, a liquid, an aerosol, a mist, a polymer, a contact lens, a film, an emulsion, or a suspension. The formulations are administered topically, e.g., the composition is delivered and directly contacts the eye. The composition is present at a concentration of 0.01-50% (weight/volume). For example, the inhibitory composition is present at concentrations of 1% (weight/volume), 10% (weight/volume), 20% (weight/volume), 25% (weight/volume), 30% (weight/volume), 40% (weight/volume), 50% (weight/volume), or any percentage point in between. The method does not involve systemic administration or planned substantial dissemination of the composition to non-ocular tissue.
Optionally, the composition further contains a pharmaceutically-acceptable carrier. Exemplary pharmaceutical carriers include, but are not limited to, compounds selected from the group consisting of a physiological acceptable salt, poloxamer analogs with carbopol, carbopol/hydroxypropyl methyl cellulose (HPMC), carbopol-methyl cellulose, a mucolytic agent, carboxymethylcellulose (CMC), hyaluronic acid, cyclodextrin, and petroleum. In one embodiment, the mucolytic agent is N-acetyl cysteine.
All polynucleotides and polypeptides of the invention are purified and/or isolated. As used herein, an “isolated” or “purified” nucleic acid molecule, polynucleotide, polypeptide, or protein, is substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. Purified compounds are at least 60% by weight (dry weight) the compound of interest. Preferably, the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight the compound of interest. Purity is measured by any appropriate standard method, for example, by column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis.
A method for inhibiting or reducing the severity of Dry Eye Syndrome is also carried out by locally administering to an eye of a subject a composition comprising a polynucleotide, a polypeptide, an antibody, a compound, or a small molecule that inhibits or modifies the transcription, transcript stability, translation, modification, localization, secretion, or function of a polynucleotide or polypeptide encoding an inflammatory interleukin-17 cytokine or any component of the IL-17 receptor complex.
The composition may comprise a neutralizing or function-blocking antibody against IL-17 and/or a receptor complex. The neutralizing or function-blocking antibody against IL-17 may be a reformulated or humanized derivative of or bind to the epitope of human IL-17 affinity purified polyclonal antibody (Catalog #AF-317-NA, R&D Systems), human IL-17 allophycocyanin monoclonal antibody (clone 41802) (Catalog #IC3171A, R&D Systems), human IL-17 biotinylated affinity purified polyclonal antibody (Catalog #BAF317, R&D Systems), human IL-17 monoclonal antibody (clone 41802) (Catalog #MAB3171, R&D Systems), human IL-17 monoclonal antibody (clone 41809) (Catalog #MAB317, R&D Systems), human IL-17 phycoerythrin monoclonal antibody (clone 41802) (Catalog #IC3171P, R&D Systems), mouse IL-17 affinity purified polyclonal antibody (Catalog #AF-421-NA, R&D Systems), mouse IL-17 biotinylated affinity purified polyclonal antibody (Catalog #BAF421, R&D Systems), mouse IL-17 monoclonal antibody (clone 50101) (Catalog #MAB721, R&D Systems), or mouse IL-17 monoclonal antibody (clone 50104) (Catalog #MAB421, R&D Systems). Preferably, the neutralizing or function-blocking antibody against IL-17 may be a reformulated or humanized derivative of or bind to the epitope of monoclonal anti-human IL-17 antibody, (Clone: 41809, Catalog #MAB317, R&D Systems), anti-human IL-17 antibody, polyclonal raised in Goat, (Catalog #AF-317-NA, R&D Systems), or recombinant human IL-17 R/Fc chimera (Catalog #177-IR, R&D Systems).
The neutralizing or function-blocking antibody against an IL-17 receptor (IL-17R) may be a reformulated or humanized derivative of or bind to the epitope of human IL-17R affinity purified polyclonal antibody (Catalog #AF177, R&D Systems), human IL-17R allophycocyanin monoclonal antibody (clone 133617) (Catalog #FAB177A, R&D Systems), human IL-17R biotinylated affinity purified polyclonal antibody (Catalog #BAF177, R&D Systems), human IL-17R fluorescein monoclonal antibody (clone 133617) (Catalog #FAB177F, R&D Systems), human IL-17R monoclonal antibody (clone 133617) (Catalog #MAB177, R&D Systems), human IL-17R monoclonal antibody (clone 133621) (Catalog #MAB1771, R&D Systems), human IL-17R phycoerythrin monoclonal antibody (clone 133617) (Catalog #FAB177P, R&D Systems), mouse IL-17R affinity purified polyclonal antibody (Catalog #AF448A, R&D Systems), mouse IL-17R biotinylated affinity purified polyclonal antibody (Catalog #BAF448, R&D Systems), or mouse IL-17R monoclonal antibody (clone 105828) (Catalog #MAB448, R&D Systems).
The neutralizing or function-blocking antibody against an IL-17 may be a reformulated or humanized derivative of, or bind to the epitope of, one or more formats of mouse anti-IL-17A (SKU #s including but not limited to, 7172, 7173, 7175, 7177, 8171, 7371, 7971, and 7370, eBioscience) or mouse anti-IL-17F (SKU #s including, but not limited to, 7471 and 8471, eBioscience). The neutralizing or function-blocking antibody against an IL-17 may be a reformulated or humanized derivative of one or more formats of human anti-IL-17A (SKU #s including, but not limited to, 7178, 7179, 8179, 7176, 7976, and 7876 or human anti-IL-17F SKU #s including, but not limited to, 8479, eBioscience). Preferably, the neutralizing or function-blocking antibody against an IL-17 may be a reformulated or humanized derivative of, or bind to the epitope of functional grade purified anti-human IL-17A antibody (Clone: eBio64CAP17, Catalog #16-7178. eBioscience).
Alternatively, the composition may comprise an intrabody that binds to the IL-17 receptor complex or any synthetic intermediate of IL-17 or the IL-17 receptor complex. The composition may alternatively, or in addition, comprise a soluble fragment of the IL-17 receptor complex which binds IL-17.
Exemplary polypeptides include, but are not limited to, fusion and/or chimeric proteins capable of disrupting IL-17 function. Moreover, the composition comprises morpholino antisense oligonucleotides, microRNAs (miRNAs), short hairpin RNA (shRNA), or short interfering RNA (siRNA) to silence gene expression.
Contemplated function-blocking antibodies targeted against an IL-17 cytokine or an IL-17 receptor are monoclonal or polyclonal. The contemplated antibody binds to one or more sequences within an IL-17 or IL-17 receptor polypeptide. The antibody is alternatively an intrabody. In some embodiments, the antibody comprises a single chain, a humanized, a recombinant, or a chimeric antibody. One or more compounds are directly or indirectly conjugated onto this antibody.
Antagonists of IL-17 and/or its receptor complex are administered either simultaneously or sequentially with a secondary composition comprising one or more of the following: an antibiotic, an immunosuppressive composition, an anti-inflammatory composition, a growth factor, a steroid, a chemokine, or a chemokine receptor.
The composition comprises microRNA molecules adapted for topical administration to ocular or adnexal tissues in order to silence gene expression. Exemplary miRNAs that bind to human IL-17R include, but are not limited to, miR-24 (SEQ ID NO:33), miR-378 (SEQ ID NO:34), and let-7g (SEQ ID NO:35).
Small molecules are organic or inorganic. Exemplary organic small molecules include, but are not limited to, aliphatic hydrocarbons, alcohols, aldehydes, ketones, organic acids, esters, mono- and disaccharides, aromatic hydrocarbons, amino acids, and lipids. Exemplary inorganic small molecules comprise trace minerals, ions, free radicals, and metabolites. Alternatively, small molecule inhibitors can be synthetically engineered to consist of a fragment, or small portion, or a longer amino acid chain to fill a binding pocket of an enzyme. Typically small molecules are less than one kilodalton.
In one embodiment of the invention, the composition comprises one or more antibiotic compositions to be used in combination with an antagonist of IL-17 function. The antibiotic and IL-17 antagonist compositions are administered simultaneously or sequentially. Exemplary antibiotic compositions used for combination-therapy with antagonists of IL-17 function include but are not limited to, amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, teicoplanin, vancomycin, azithromycin, clarithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, amoxicillin, ampicillin, azlocillin, carbenicillin, clozacillin, dicloxacillin, flucozacillin, mezlocillin, nafcillin, penicillin, piperacillin, ticarcillin, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, oflazacin, trovafloxacin, mafenide, sulfacetamide, sulfamethizole, sulfasalazine, sulfisoxazole, tetracycline, trimethoprim, cotrimoxazole, demeclocycline, soxycycline, minocycline, doxycycline, oxytetracycline, or tetracycline.
The composition comprises an antagonist of an IL-17 cytokine or an IL-17 receptor complex, administered simultaneously or sequentially with a second immunosuppressive composition. The composition comprising an IL-17 or IL-17R antagonist is administered topically. The second immunosuppressive composition is administered topically or systemically.
The immunosuppressive compound comprises cyclosporin A or analogs thereof a concentration of 0.05-4.0% (mg/ml). Alternatively, or in addition, the immunosuppressive composition comprises a glucocorticoid, a cytostatic agent, an alkylating agent (nitrogen mustards/cyclophosphamide, nitrosoureas, platinum compounds), an antimetabolic agent (methotrexate, any folic acid analog, azathioprine, mercaptopurine, any purine analog, any pyrimidine analog, any inhibitor of protein synthesis), a cytotoxic antibiotic (dactinomycin, an anthracycline, mitomycin C, bleomycin, mithramycin), a polyclonal antibody (Atgam®, Thympglobuline®, any antibody against the antilymphocyte or antithymocyte antigens), a monoclonal antibody (OKT3®, any antibody against the T-cell receptor, any antibody against IL-2, basiliximab/Simulect®, declizumab/Zenapax®), Tacrolimus/PrografTM/FK506, Sirolimus/RapamuneTM/Rapamycin, interferon beta, interferon gamma, an opioid, a TNFα binding protein, mycophenolate, or FTY720.
The composition comprises a polynucleotide, a polypeptide, an antibody, or a small molecule that binds or modifies the function of IL-17 or IL-17R administered topically with a pharmaceutically appropriate carrier. Delivery methods for polynucleotide compositions include, but are not limited to, liposomes, receptor-mediated delivery systems, naked DNA, and engineered viral vectors such as herpes viruses, retroviruses, adenoviruses and adeno-associated viruses, among others. Polynucleotide compositions are administered topically with a pharmaceutically acceptable liquid carrier, e.g., a liquid carrier, which is aqueous or partly aqueous. Alternatively, polynucleotide sequences within the composition are associated with a liposome (e.g., a cationic or anionic liposome).
A number of methods have been developed for delivering short DNA or RNA sequences into cells; e.g., polynucleotide molecules can be contacted directly onto the tissue site, or modified polynucleotide molecules, designed to specifically target desired cell types (e.g., sequences linked to peptides or antibodies that specifically bind receptors or antigens expressed on the target cell surface).
A preferred approach uses a recombinant DNA construct in which the short polynucleotide sequence is placed under the control of a strong polymerase III or polymerase II promoter. The use of such a construct will result in the transcription of sufficient amounts of polynucleotide that will form complementary base pairs with the endogenous transcripts of nucleic acids of the invention and thereby prevent translation of endogenous mRNA transcripts. The invention encompasses the construction of a short polynucleotide using the complementary strand as a template. For example, a vector can be introduced in vivo such that it is taken up by a cell and directs the transcription of an interfering RNA or precursor to a double stranded RNA molecule. Alternatively, the template for the short polynucleotide transcript is placed under the transcriptional control of a cell-type specific promoter or other regulatory element. Thus, diffusion or absorption of a topically administered composition beyond the intended ocular target tissue does not cause deleterious or systemic side effects. The vector remains episomal or becomes chromosomally integrated, as long as it can be transcribed to produce the desired polynucleotide.
Vectors are constructed by recombinant DNA technology methods standard in the art. Vectors can be plasmid, viral, or others known in the art, used for replication and expression in mammalian cells. Expression of the sequence encoding the short polynucleotide can be placed under the control of any promoter known in the art to act in mammalian, preferably human cells. Promoters are inducible or constitutive. Exemplary promoters include, but are not limited to: the SV40 early promoter region (Bernoist et al., Nature 290:304, 1981); the promoter contained in the 3′ long terminal repeat of Rous sarcoma virus (Yamamoto et al., Cell, 22:787-797, 1988); the herpes thymidine kinase promoter (Wagner et al., Proc. Natl. Acad. Sci. USA, 78:1441, 1981); or the regulatory sequences of the metallothionein gene (Brinster et al., Nature, 296:39, 1988).
Polypeptide compositions are associated with liposomes alone or in combination with receptor-mediated delivery systems, to enable transport across the plasma membrane. Polypeptide compositions are soluble or membrane-bound. An exemplary receptor-mediated delivery system involves fusion of a low-density or very-low-density lipoprotein containing particle or vesicle to the low-density lipoprotein (LDL) receptor (LDLR) as observed with Hepatitis C Virus (HCV) infection and HCV-mediated drug delivery methods.
Compositions comprise one or more extracellular or intracellular antibodies, also called intrabodies, raised against IL-17 or an IL-17 receptor complex. Extracellular antibodies are topically administered with a pharmacologically appropriate aqueous or non-aqueous carrier. Sequences encoding intracellular antibodies are subcloned into a viral or mammalian expression vector, packed in a lipophilic device to facilitate transport across the plasma membrane, and topically administered to eye tissue with a pharmacologically appropriate aqueous or non-aqueous carrier. Once inside the plasma membrane, host cell machinery transcribes, translates, and processes the intrabody code to generate an intracellular function-blocking antibody targeted against IL-17 or an IL-17 receptor complex. In the case of secreted molecules, intracellular antibodies prevent post-translational modification or secretion of the target protein. In the case of membrane-bound molecules, intracellular antibodies prevent intracellular signaling events upon receptor engagement by IL-17 cytokines.
The composition comprises an antagonist of IL-17 and/or an IL-17 receptor complex function in combination with other inhibitory elements. Antagonists of IL-17 and/or an IL-17 receptor complex and other inhibitory elements are administered simultaneously or sequentially. In one embodiment, the composition comprises an antagonist of IL-17 and/or IL-17 receptor function and an antagonist of tumor necrosis factor alpha (TNFα). Exemplary functional blockers of TNFα include, but are not limited to, recombinant and/or soluble TNFα receptors, monoclonal antibodies, and small molecule antagonists and/or inverse agonists. One or more commercially-available TNF-α blocking agents are reformulated for topical administration in this embodiment. Exemplary commercial TNF-α blocking agents used for reformulation include, but are not limited to, etanerept/Embrel, infliximab/Remicade, and adalimumab/Humira. Alternatively, the composition comprises an antagonist of IL-17 and/or IL-17 receptor function and antagonist(s) of one or more interleukin cytokines. Exemplary cytokines include, but are not limited to, IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12, IL-18, and IL-23. In another embodiment, the composition comprises an antagonist of IL-17 and/or IL-17 receptor function and antagonist(s) of one or more member(s) of the vascular epithelial growth factor (VEGF) family composed of growth factors and receptors (VEGFR). Exemplary members include, but are not limited to, VEGF-A, VEGF-C, VEGFR-2, and VEGFR-3. In another embodiment, the composition comprises an antagonist of IL-17 and/or IL-17 receptor function and an antagonist of interferon-gamma. In another embodiment, the composition comprises an antagonist of IL-17 and/or IL-17 receptor function and antagonist(s) of one or more chemokines and their receptors. Exemplary chemokines and receptors comprised by the composition of this embodiment include, but are not limited to, chemokine (C-C motif) receptor 1 (CCR1), chemokine (C-C motif) receptor 2 (CCR2), chemokine (C-C motif) receptor 5 (CCR5), chemokine (C-C motif) receptor 7 (CCR7), and chemokine (C-X-C motif) receptor 3 (CXCR3).
In embodiments wherein the composition comprises an antagonist of IL-17 and/or IL-17 receptor function and a second composition, the respective doses of the IL-17 antagonist to the second composition is a ratio between 1:10 and 10:1 (mass/weight). Alternatively, the ratio is 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or 9:1.
The invention also comprises a contact lens device consisting of a composition that inhibits an activity of an inflammatory interleukin-17 cytokine and a pharmaceutically compatible polymer. This composition also comprises a combination of antagonists of IL-17 or IL-17 receptor function as well as secondary compositions. For example, the composition is incorporated into or coated onto said lens. The composition is either chemically bound or physically entrapped by the contact lens polymer. The contact lens is either hydrophobic or hydrophilic.
The invention comprises a drug-delivery device consisting of a composition that inhibits an activity of an inflammatory interleukin-1 cytokine and a pharmaceutically compatible polymer. This composition also comprises a combination of antagonists of IL-17 or IL-17 receptor function as well as secondary compositions. For example, the composition is incorporated into or coated onto said polymer. The composition is either chemically bound or physically entrapped by the polymer. The polymer is either hydrophobic or hydrophilic. The polymer device comprises multiple physical arrangements. Exemplary physical forms of the polymer device include, but are not limited to, a film, a scaffold, a chamber, a sphere, a microsphere, a stent, or other structure. The polymer device has internal and external surfaces. The device has one or more internal chambers. These chambers contain one or more compositions. The device contains polymers of one or more chemically-differentiable monomers. The subunits or monomers of the device polymerize in vitro or in vivo.
The invention comprises a device comprising a polymer and a bioactive composition incorporated into or onto said polymer, wherein said bioactive composition inhibits an activity of an inflammatory interleukin-17 cytokine, and wherein said device is implanted or injected into an ocular surface tissue, an adnexal tissue in contact with an ocular surface tissue, a fluid-filled ocular or adnexal cavity, or an ocular or adnexal cavity.
Exemplary mucoadhesive polyanionic natural or semi-synthetic polymers from which the device is formed include, but are not limited to, polygalacturonic acid, hyaluronic acid, carboxymethylamylose, carboxymethylchitin, chondroitin sulfate, heparin sulfate, and mesoglycan. In one embodiment, the device comprises a biocompatible polymer matrix that may optionally be biodegradable in whole or in part. A hydrogel is one example of a suitable polymer matrix material. Examples of materials which can form hydrogels include polylactic acid, polyglycolic acid, PLGA polymers, alginates and alginate derivatives, gelatin, collagen, agarose, natural and synthetic polysaccharides, polyamino acids such as polypeptides particularly poly(lysine), polyesters such as polyhydroxybutyrate and poly-.epsilon.-caprolactone, polyanhydrides; polyphosphazines, poly(vinyl alcohols), poly(alkylene oxides) particularly poly(ethylene oxides), poly(allylamines)(PAM), poly(acrylates), modified styrene polymers such as poly(4-aminomethylstyrene), pluronic polyols, polyoxamers, poly(uronic acids), poly(vinylpyrrolidone) and copolymers of the above, including graft copolymers. In another embodiment, the scaffolds may be fabricated from a variety of synthetic polymers and naturally-occurring polymers such as, but not limited to, collagen, fibrin, hyaluronic acid, agarose, and laminin-rich gels.
One preferred material for the hydrogel is alginate or modified alginate material. Alginate molecules are comprised of (1-4)-linked β-D-mannuronic acid (M units) and α L-guluronic acid (G units) monomers which vary in proportion and sequential distribution along the polymer chain. Alginate polysaccharides are polyelectrolyte systems which have a strong affinity for divalent cations (e.g. Ca+2, Mg+2, Ba+2) and form stable hydrogels when exposed to these molecules. See Martinsen A., et al., Biotech. & Bioeng., 33 (1989) 79-89.
An embodiment of the invention utilizes an alginate or other polysaccharide of a lower molecular weight, preferably of size which, after dissolution, is at the renal threshold for clearance by humans. Polymeric devices are located topically or subcutaneously, though very superficially, wherein either a composition chemically bound or physically entrapped by the polymeric device or the device itself, degrades and must be cleared from the body. For a biodegradable polymeric device, it is preferred that the alginate or polysaccharide is reduced to a molecular weight of 1000 to 80,000 daltons, more preferably 1000 to 60,000 daltons, particularly preferably 1000 to 50,000 daltons. It is also useful to use an alginate material of high guluronate content since the guluronate units, as opposed to the mannuronate units, provide sites for ionic crosslinking through divalent cations to gel the polymer.
Internal and external surfaces optionally contain pores. Pores are either created prior to administration into a subject or result from the inclusion of pore-forming agents within the device that perforate surfaces upon administration to a subject. Exemplary pore forming agents include, but are not limited to, water soluble compounds such as inorganic salts and sugars. Pore forming agents are added as particulates and comprise between one and thirty percent (weight/weight of polymer). Pore size is sufficient for diffusion of proteins but not large enough cell migration into or out of the device.
The device is administered topically, subconjunctively, or in the episcleral space, subcutaneously, or intraductally. Specifically, the device is placed on or just below the surface if an ocular tissue. Alternatively, the device is placed inside a tear duct or gland. The composition incorporated into or onto the polymer is released or diffuses from the device.
The invention comprises a composition with variable physical and chemical forms; however, the composition is topically administered and contacts an eye directly. The composition is administered as a solid, a paste, an ointment, a gel, a liquid, an aerosol, a mist, a polymer, a film, an emulsion, or a suspension. Furthermore, the composition is incorporated into or coated onto a contact lens or drug delivery device, from which one or more molecules diffuse away from the lens or device or are released in a temporally-controlled manner. In this embodiment, the contact lens composition either remains on the ocular surface, e.g. if the lens is required for vision correction, or the contact lens dissolves as a function of time simultaneously releasing the composition into closely juxtaposed tissues. Similarly, the drug delivery device is optionally biodegradable or permanent in various embodiments.
In one preferred embodiment, the invention comprises a composition with means to inhibit the transcription, transcript stability, translation, modification, localization, secretion, or receptor binding of IL-17. In one preferred embodiment, the composition is capable of binding to one or more regions of an IL-17 mRNA transcript or the IL-17 polypeptide. Alternatively, the composition is capable of binding to one or more regions of an IL-17 mRNA transcript or an IL-17 polypeptide selected from the group consisting of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. In another preferred embodiment, the composition is capable of binding to one or more regions of an IL-17A mRNA transcript or the IL-17F polypeptide.
The composition comprises an antagonist or inverse agonist of a receptor for IL-17. IL-17 receptors comprise IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE. Preferably IL-17RA and IL-17RC are targeted by an antagonist or inverse agonist. In this embodiment an antagonist is defined as a binding partner, or ligand, of an IL-17R that inhibits the function of an agonist, IL-17, or inverse agonist by blocking its binding to the receptor. An inverse agonist is defined as a molecule which binds to the same IL-17R binding-site as an agonist, for instance, IL-17, but exerts the opposite pharmacological effect. The composition contains a polynucleotide, a polypeptide, an antibody, a compound, or a small molecule that binds to a region of an IL-17R mRNA or polypeptide.
In another preferred embodiment, the composition comprises a human recombinant IL-17R antagonist either in pure form, or as a component of a mixture. The human recombinant IL-17R antagonist is combined with balanced saline, carboxymethylcellulose (CMC), or hyaluronic acid (HA), or other vehicles prior to the composition contacting the ocular surface. Within these mixtures, the human recombinant IL-17R antagonist comprises at least 0.1%, 2.0%, 2.5%, 5%, 10% or at most 50% of the total volume administered. Purified is defined as the antagonist in the absence of unrelated polynucleotides, polypeptides, cellular organelles, or lipids. Purified defines a degree of sterility that is safe for administration to a human subject, e.g. lacking infectious or toxic agents.
The invention provides a method of restoring or augmenting regulatory T-cell-mediated immune suppression in a subject with an IL-17-mediated ocular disease including administering to the subject a composition that inhibits an activity of an inflammatory interleukin-17 cytokine, restoring or augmenting regulatory T-cell-mediated immune suppression. Alternatively, or in addition, the invention also provides a method of restoring or augmenting regulatory T-cell-mediated immune suppression in a subject with dry eye including administering to the subject a composition that inhibits an activity of an inflammatory interleukin-17 cytokine, thereby restoring or augmenting regulatory T-cell-mediated immune suppression. Alternatively, the subject has an ocular disorder.
Furthermore, the invention provides a method of reducing Th17 cell abundance in an ocular, adnexal, or lymph tissue of a subject in need thereof including administering to the subject a composition that inhibits an activity of an inflammatory interleukin-17 cytokine. For example, a method of decreasing or inhibiting secretion of lymphangiogenesis-specific growth factors in an ocular or adnexal tissue of a subject with dry eye is carried out by administering to the subject a composition that inhibits an activity of an inflammatory interleukin-17 cytokine, thereby inhibiting lymphangiogenesis. In certain embodiments of the invention, the lymphangiogenesis-specific growth factors are VEGF-C, VEGF-D, a VEGF receptor, or a combination thereof. Moreover, the invention provides a method of decreasing or inhibiting secretion of lymphangiogenesis-specific growth factors in an ocular or adnexal tissue of a subject with an IL-17-mediated ocular disease including administering to the subject a composition that inhibits an activity of an inflammatory interleukin-17 cytokine, thereby inhibiting lymphangiogenesis.
Furthermore, the invention provides a method of reducing macrophage and monocyte cell abundance or concentration in an ocular, adnexal, or lymph tissue of a subject in need thereof including administering to the subject a composition that inhibits an activity of an inflammatory interleukin-17 cytokine.
A method of reducing pathogenic immune cell abundance in an ocular, adnexal, or lymph tissue of a subject in need thereof includes administering to the subject a composition that inhibits an activity of an inflammatory interleukin-17 cytokine. As used herein, the term “pathogenic immune cell” is meant to describe any immune cell that exacerbates, induces, reduces the time to onset, or prolongs the appearance a sign or symptom of an ocular disease. Pathogenic immune cells in this context antagonize or decrease an IL-17 inhibiting activity of compositions of the invention.
Pathogenic lymphatic vessel growth in an ocular, or adnexal tissue of a subject is inhibited or reduced by administering to the subject a composition that inhibits an activity of an inflammatory interleukin-17 cytokine. Pathogenic lymphatic vessel growth encompasses lymphatic vessel growth that exacerbates, induces, reduces the time to onset, or prolongs the appearance a sign or symptom of an ocular disease. Moreover, pathogenic lymphatic vessel growth antagonizes or decreases an IL-17 inhibiting activity of compositions of the invention. Alternatively, or in addition, pathogenic lymphatic vessel growth occurs prior to, simultaneously with, or following the presentation of an IL-17-mediated ocular disease. Pathogenic lymphatic vessel growth includes the ability of lymphatic vessels to expand within or to invade corneal tissue or describes the potential and/or actual growth, expansion, elaboration, splitting, or remodeling of lymphatic vessels either within a corneal tissue or from a non-corneal tissue (such as the adjacent limbus) into corneal tissue. Alternatively, or in addition, pathogenic lymphatic vessel growth permits or induces the transport of immune cells, which encompasses the unidirectional or bidirectional movement or deposition of an immune cell between a corneal tissue and a non-corneal tissue, preferably, a lymph node or other sites in the lymphoid compartment. Exemplary immune cells is include, but are not limited to, T cells, B cells, dendritic cells, macrophages, monocytes, and natural killer (NK) cells.
The invention also provides a method for reducing corneal nerve damage in a subject in need thereof, including the steps of: (a) identifying a subject with corneal nerve damage; and (b) locally administering to the cornea of the subject a composition that inhibits an activity of an inflammatory interleukin-17 cytokine, thereby enhancing corneal nerve regeneration, reducing the development of abnormalities in nerve morphology, and reducing corneal nerve damage.
In certain embodiments of the above method, the subject is identified as having corneal nerve damage or loss that results from a congenital defect, disease, trauma, medical or surgical procedure. Alternatively, or in additional, the subject is identified as having corneal nerve damage or loss that results from neurotrophic keratitis, herpes simplex, zoster keratitis, diabetes mellitus, trigeminal nerve damage, orbital or head surgery, head trauma, aneurysm, intracranial neurologic disease, keratorefractive procedures, photorefractive keratectomy (PRK), laser in situ keratomileusis (LASIK), congenital defect, ocular surface disease, dry eye syndrome, a non-ophthalmic disorder, a non-ophthalmic procedure, peripheral neuropathy, or diabetic neuropathy.
The invention provides a method for preventing corneal nerve damage in a subject in need thereof, including the steps of: (a) identifying the subject at risk of exposure to corneal nerve damage; and (b) locally administering to the cornea of the subject a composition that inhibits an activity of an inflammatory interleukin-17 cytokine prior to the exposure, thereby decreasing nerve degeneration, reducing the development of abnormalities in nerve morphology, and preventing damage corneal nerve damage.
For example, the subject is identified as being at risk of exposure to corneal nerve damage or loss that could result from disease, trauma, or a medical procedure. Alternatively, or in addition, the subject is identified as being at risk of exposure to corneal nerve damage or loss that could result from neurotrophic keratitis, herpes simplex, zoster keratitis, diabetes mellitus, trigeminal nerve damage, orbital or head surgery, head trauma, aneurysm, intracranial neurologic disease, keratorefractive procedures, photorefractive keratectomy (PRK), laser in situ keratomileusis (LASIK), ocular surface disease, dry eye syndrome, a non-ophthalmic disorder, a non-ophthalmic procedure, peripheral neuropathy, or diabetic neuropathy.
The above methods further include the step of identifying a subject with a sign or symptom of corneal nerve damage or loss. For example, a sign of corneal nerve damage or loss is a decrease of corneal innervation or sensation, a reduction in the number of nerve fibers or bundles innervating the cornea, death of neurons innervating the cornea, a decrease or loss of neurotransmitter release, a decrease or loss of nerve growth factor release, abnormal tearing reflexes, abnormal blink reflexes, abnormal nerve morphology, appearance of abnormal nerve sprouts, abnormal tortuosity, increased bead-like nerve formations, thinning of nerve fiber bundles, or thickening of nerve fiber bundles. For example, a symptom of corneal nerve damage or loss is abnormal tear production or dryness, abnormal blinking, and difficulty or loss of ability to focus, decreased or lost visual acuity, or decreased or lost corneal sensitivity.
Signs or symptoms of corneal damage or abnormal nerve morphology are detected, analyzed, examined, and evaluated using in vivo confocal microscopy (IVCM) of the central cornea or other imaging or diagnostic devices that allow for detection of corneal nerve damage. Exemplary devices for IVCM include, but are not limited to the Heidelberg Retina Tomograph 3 with the Rostock Cornea Module (HRT3/RCM) (Heidelberg Engineering GMBH) and the Confoscan 4 Confocal Microscope (Nidek, Inc.). In certain embodiments of the above methods, IVCM is used to detect, analyze, examine, and evaluate the form and number of nerve fibers in the various corneal layers, as well as to discriminate between parallel running, bifurcating, branching, and interconnecting nerve fiber bundles. Alternatively or in addition, IVCM is used to detect, analyze, examine, and evaluate changes in the total number of nerves, changes in the length of nerves, nerve density, the presence or absence of abnormal nerve sprouts, the presence or absence of abnormal nerve fiber tortuosity, changes in number or morphology of bead-like nerve formations, and thinning versus thickening of nerve fiber bundles. In one aspect of the methods of the invention, IVCM is used to detect, analyze, examine, and evaluate nerve regeneration. Alternatively, or in addition, IVCM is used to detect, analyze, examine, and evaluate nerve degeneration. For instance, IVCM has been used to show an average of 6-8 corneal nerve bundles per image within the subbasal area of healthy individuals and nerve regeneration in patients who experienced nerve damage as a result of photoreceptive keratectomy.
In certain preferred embodiments, the above methods are performed on a corneal tissue.
Publications, U.S. patents and applications, Genbank/NCBI accession numbers, and all other references cited herein, are hereby incorporated by reference.



BRIEF DESCRIPTION OF THE DRAWINGS
Table 1 is a summary of mRNAs comprised in the invention, their human target genes, amino acid sequences, and their sequence identifier numbers.
FIG. 1 is a series of graphs depicting flow cytometric dots demonstrating increased frequency of IL-17 producing CD4+ T cells in the draining lymph nodes of mice with DES compared to those of normal mice (p=0.03).
FIG. 2 is a graph showing the fold change in IL-17 expression in normal versus DES mice. Conjunctiva of mice with DES expresses approximately a 2.5-3 fold increase in IL-17 mRNA abundance compared to those of normal mice.
FIG. 3A-B is a pair of photographs of immunofluorescence showing that IL-17RAs are constitutively expressed on the epithelium of (A) cornea and (B) conjunctiva of both normal mice as well as mice with DES.
FIG. 4A is a schematic diagram of the experimental design for FIGS. 4B, 4C, and 4D.
FIG. 4B is a graph showing the CFS score on days 1-5 of either control or IL-17 Ab treated corneas. More than 50% reduction in the DES-clinical score was observed during induction as well as progression phase of the disease in mice treated with anti-IL-17 antibody compared to those treated with control antibody
FIG. 4C is a series of graphs depicting flow cytometric dots demonstrating that a decreased frequency of IL-17+CD4+ T cells was observed in the draining lymph nodes of anti-IL-17 antibody treated group as compared to those of the control-antibody treated group.
FIG. 4D is a graph of the fold change in IL-17 mRNA expression in the conjunctiva of normal versus either IL-17 or Control Ab-treated groups. Conjunctiva of mice treated with anti-IL-17 antibody showed decreased IL-17 mRNA expression than those of treated with control antibody.
FIG. 5 is the Oxford schema for grading corneal and conjunctival staining (see, Example 4).
FIG. 6 is an Ocular Surface Disease Index (OSDI) 12-item questionnaire.
FIG. 7 is a graph showing the results of an in vitro regulatory T cell (Treg) suppression assay using CD3 stimulated primed-T cells (isolated from the LN of dry eye mice) and Tregs (isolated from the LN of mice treated with anti-IL-17 or isotype antibodies). The data show a significant recovery in the suppressor potential of Tregs only in mice treated with anti-IL-17 antibody (i.p.) compared to those isolated from the isotype antibody treated groups (p=0.029). The suppressor potential of Tregs isolated from different groups is calculated in relation to the suppression potential of Tregs of normal mice, considered as 100%. The data suggest a reversal of regulatory-T cell (Treg) suppressor function by anti-IL-17 therapy.
FIG. 8A is a schematic diagram of the experimental design to study the effects of in vivo IL-17 blockade using topical application of anti-IL-17 antibody or isotype-antibody on clinical signs.
FIG. 8B is a graph showing corneal fluorescein staining (CFS) scores, a readout for the principal clinical sign of dry eye, in anti-IL-17 antibody-treated, isotype antibody-treated and untreated groups from Day 4 (base line) to Day 10.
FIG. 8C is a graph showing the percent change in CFS scores at Day 10 from baseline CFS scores (Day 4) in different groups. CFS scores are significantly lower in anti-IL-17 antibody-treated mice compared to isotype antibody-treated and untreated groups.
FIG. 9 is a pair of graphs showing that topical application of anti-IL-17 antibody reduces frequencies of pathogenic Th17 cells both in conjunctiva (Conj) (left) and the draining lymph nodes (LN) (right). Conjunctiva and the draining lymph nodes were harvested at day 10 (as shown in FIG. 8) from anti-IL-17 antibody and isotype antibody treated mice. Real-time PCR was performed to analyze mRNA expression levels of IL-17 (Th17 cells) and Foxp3 (Treg cells). Dotted line represents mRNA levels in normal controls.
FIG. 10A is a series of micrographs showing that topical application of anti-IL-17 antibody inhibits dry eye induced corneal lymphatic vessels via decreased secretion of lymphangiogenesis-specific growth factors, particularly VEGF-C and -D in dry eye corneas. Induction of new lymphatic vessels in dry eye corneas facilitate the migration of resident corneal antigen presenting cells to the draining lymph nodes which in turn induce generation of adaptive immunity to ocular surface. Representative micrographs of corneal whole mounts showing lymphatic vessels (LV) and blood vessels (BV) in different groups.
FIG. 10B is a graph showing that topical application of anti-IL-17 antibody inhibits dry eye induced corneal lymphatic vessels via decreased secretion of lymphangiogenesis-specific growth factors, particularly VEGF-C and -D in dry eye corneas. Induction of new lymphatic vessels in dry eye corneas facilitate the migration of resident corneal antigen presenting cells to the draining lymph nodes which in turn induce generation of adaptive immunity to ocular surface. Real-time PCR analysis of whole cornea showing mRNA levels of Interleukin-1 (IL1)-beta, IL1-alpha, and lymphatic vessel-specific growth factors VEGF-C and -D, and their cognate receptor, VEGFR-3. Dotted line represents mRNA levels in cornea of normal controls.
FIG. 11 is a series of micrographs and associated key showing that topical application of anti-IL-17 antibody maintains the normal phenotype of CD11b+ cells in cornea. Representative micrographs showing CD11b staining in corneas of different groups. Corneas of Anti-IL17-antibody treated group show that similar to normal cornea, majority of CD11b+ cells have phenotype of resident dendritic cells. However, corneas of Isotype-antibody treated group show that phenotype of majority of CD11b+ cells are similar to the infiltrating pathogenic macrophages/monocytes.
FIG. 12 is a series of micrographs showing that topical application of anti-IL-17 antibody prevents corneal nerve degeneration. Representative micrographs of corneal whole mount showing epithelial and sub-epithelial nerves (Tubulin-III, Red) in different groups. Patterns of nerves in the corneas of Anti-IL17-antibody treated group show similarity to those in the normal corneas, whereas corneas of Isotype-antibody treated group show loss of epithelial nerves.
FIG. 13 is a schematic representation of the vicious circle of epithelial disease to nerve damage. IL-17 mediates corneal epithelial cell and nerve damage. Nerve damage can in turn exacerbate epithelial disease by lower provision of trophic factors necessary for epithelial cell health. The resultant increased level of inflammation and IL-17 overexpression also leads to lymphatic vessel invasion or growth into the cornea and the activation of immune cells, allowing the immune cells easier access from the cornea to the lymphoid compartment where autoimmunity is generated and chronic diseases sustained.
FIG. 14A is a schematic diagram of the experiments performed to generate the data of FIG. 14B.
FIG. 14B is a graph of the fold change in mRNA levels of lymphangiogenesis growth factors, such as VEGF-A, VEGF-C, and VEGF-D, in human corneal epithelial cells treated with human-r-IL-17 (5 ng/ml).



DETAILED DESCRIPTION
Ocular Surface Inflammatory Disorders
DES is a predominant ocular surface inflammatory disorder, however, other disorders are contemplated. Exemplary contemplated ocular surface inflammatory disorders include, but are not limited to, penetrating keratoplasty (corneal transplantation), corneal neovascularization, allergy, conjunctivitis, and microbial keratitis. Contemplated disorders can be caused by autoimmune mechanisms, bone marrow transplant, surgery (general eye surgery, corneal transplantation, refractive surgery, LASIK), allergy, infection, trauma, injury, drug use, tear film abnormalities, contact lens use, neovascularization, tumor formation or growth, exposure to airborne or liquid irritants, hormonal variation, deprivation of essential fatty acids, and genetic predisposition.
Dry Eye Syndrome (DES):
DES and related diseases can be caused by autoimmune and environmental conditions as well as any activity that decreases the rate of blinking. Alternatively, DES and related diseases are caused by decreased tear production or a change in tear composition that results in inadequate lubrication of the eye. Contact lens use, eye surgery, and eye injury can induce DES. Finally, DES often occurs as a consequence of aging and hormonal changes.
Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability, with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface (emp MA. Report of the National Eye Institute/Industry Workshop on clinical trials in dry eyes. CLAO J 1995; 21:221-2). For a more detailed definition, see The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop. Ocular Surface. 2007 April; 5(2):75-92, herein incorporated by reference. The method of therapy inhibits or reduces the severity of at least one of these signs or symptoms.
Synonyms and related diseases of DES include, but are not limited to, keratoconjunctivitis sicca (KCS), Sjögren syndrome (SS), Sjögren syndrome associated keratoconjunctivitis sicca, non-Sjögren syndrome associated keratoconjunctivitis sicca, keratitis sicca, sicca syndrome, xerophthalmia, tear film disorder, decreased tear production, aqueous tear deficiency (ATD), meibomian gland dysfunction, and evaporative loss. The subject is identified as suffering from DES or a related disorder by detecting a sign or symptom selected from the group consisting of dry, scratchy, stingy, itchy, burning or pressured sensations, irritation, pain, redness, inflammation, discharge, and excessive eye watering. Alternatively, a subject is identified as suffering from DES or a related disorder if their tear composition is insufficient for proper eye tissue lubrication. The method of therapy inhibits or reduces the severity of at least one of these signs or symptoms.
Th17 Cells
T lymphocytes are circulating small white blood cells that play a central role in cell-mediated immunity. T helper cells (Th), also known as effector T cells, are one subgroup of T lymphocytes. Th17 cells are a recently-identified population of T helper cells that produce Interleukin-17 (IL-17) and have been shown to contribute to autoimmune conditions. Importantly, these cells have not been previously implicated in DES.
Determination of IL-17-Mediated Ocular Surface Inflammation
Exemplary tests used to determine the occurrence and severity of ocular surface inflammation include, but are not limited to, the following:
The Surface Disease Index (OSDI)
The Ocular Surface Disease Index (OSDI) is a 12-item questionnaire that provides a rapid assessment of the symptoms of ocular irritation consistent with ocular surface inflammatory disorders, including DES, and their impact on vision-related functioning (FIG. 6). The 12 items of the OSDI questionnaire are graded on a scale of 0 to 4, where 0 indicates none of the time; 1, some of the time; 2, half of the time; 3, most of the time; and 4, all of the time. The total OSDI score is then calculated on the basis of the following formula: OSDI=[(sum of scores for all questions answered)×100]/[(total number of questions answered)×4]. Thus, the OSDI is scored on a scale of 0 to 100, with higher scores representing greater disability. A negative change from baseline indicates an improvement in vision-related function and the ocular inflammatory disorders described herein. For the therapeutic method described herein, treatment is considered more effective than control (vehicle) as indicated by a mean change (decrease) from baseline for the OSDI of >10 units compared to control.
Therapeutic treatment is considered more effective than the vehicle as indicated by a mean change from baseline of average score (0-100) for the Ocular Surface Disease Index (OSDI) of >10 units better than vehicle.
Corneal and Conjunctival Staining
Corneal staining is a measure of epithelial disease, or break in the epithelial barrier of the ocular surface, typically seen with ocular surface inflammatory disorders such as DES, among others. Importantly, corneal staining can exist even without clinically evident dry eye, if there is significant lid disease, such as posterior blepharitis. Corneal staining is highly correlated with ocular discomfort in many, though not all patients; in general corneal staining is associated with high scores in the OSDI, as described above. For corneal fluorescein staining, saline-moistened fluorescein strips or 1% sodium fluorescein solution are used to stain the tear film. The entire cornea is then examined using slit-lamp evaluation with a yellow barrier filter (#12 Wratten) and cobalt blue illumination (staining is more intense when it is observed with a yellow filter). Staining is graded according to the Oxford Schema (FIG. 5).
Conjunctival staining is a measure of epithelial disease or break in the epithelial barrier of the ocular surface, typically seen with ocular surface inflammatory disorders such as DES, among others. Importantly, conjunctival staining, similar to corneal staining, can exist even without clinically evident dry eye, if there is significant lid disease, such as posterior blepharitis. Conjunctival staining can also correlate with symptoms of ocular irritation and high OSDI scores as described above. Conjunctival staining is performed under the slit-lamp using lissamine green. Saline-moistened strip or 1% lissamine green solution is used to stain the tear film, and interpalpebral conjunctival staining is evaluated more than 30 seconds, but less than 2 minutes, later. Using white light of moderate intensity, only the interpalpebral region of the nasal and temporal conjunctival staining is graded using the Oxford Schema (FIG. 5). The treatment described herein leads to decreases in ocular staining scores beyond what is observed with the vehicle alone.
Therapeutic treatment is considered more effective than vehicle as indicated by a mean change from baseline in average score (0-5 scale) for corneal and conjunctival staining of >1 unit better than vehicle, e.g. as detected using the Oxford Schema.
Schirmer Test
The Schirmer test is performed in the presence and in the absence of anesthesia by placing a narrow filter-paper strip (5×3 5 mm strip of Whatman #41 filter paper) in the inferior cul-de-sac. This test is conducted in a dimly lit room. The patient gently closes his/her eyes until five minutes have elapsed and the strips are removed. Because the tear front will continue advancing a few millimeters after it has been removed from the eyes, the tear front is marked with a ball-point pen at precisely five minutes. Aqueous tear production is measured by the length in millimeters that the strip wets during 5 minutes. Results of 10 mm or less for the Schirmer test without anesthesia and 5 mm or less for the Schirmer test with anesthesia are considered abnormal. A positive change from baseline indicates improvement of one or more symptoms of an ocular inflammatory disorder described herein.
Conjunctiva Hyperemia
Bulbar conjunctival hyperemia is graded as follows:
None (0): none
Mild (1): slight localized injection
Moderate (2): pink color, confined to palpebral or bulbar conjunctiva
Severe (3): red color of the palpebral and/or bulbar conjunctiva
Very Severe (4): marked dark redness of the palpebral and/or bulbar conjunctiva
The presence or absence of tarsal papillary hypertrophy is also noted.
Impression Cytology
Filter paper or other collection devices are used to collect cells and liquid samples from the ocular surface, tear ducts, or meibomian glands to be tested for the presence and/or abundance of an IL-17 cytokine, an IL-17 receptor, and/or a Th17 cell. The presence and/or abundance of RNA, DNA, or protein relating to an IL-17 cytokine or IL-17 receptor is determined by standard methods including, but not limited to, polymerase chain reaction (PCR), reverse transcriptase PCR (RT-PCR), gel electrophoresis, probe hybridization, antibody detection, in situ hybridization, Western blot, Northern Blot, Southern Blot, fluorescent microscopy, flow cytometry, enzyme-linked immunosorbant assay (ELISA), immunoprecipitation, gene chip analysis, protein chip analysis, cell culture methods, and cell sorting (see, Gulati A, Saccheti M, Bonini S, Dana R. Chemokine Receptor CCR5 Expression in Conjunctival Epithelium of Patients with Dry Eye Syndrome. Arch Ophthalmol 2006; 124: 710-716; Argueso P, Balaram M, Spurr-Michaud S, Keutmann H T, Dana M R, Gipson I K. Decreased levels of goblet cell mucin MUC5AC in tears of Sjögren's syndrome patients. Invest Ophthalmol Vis Sci. 2002; 43: 1004-1011. Sambrook, J., Fritsch, E. F., and Maniatis, T., Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory Press, NY, Vol. 1, 2, 3 (1989), herein incorporated by reference).
Corneal Structure
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, and as a result helps the eye to focus, accounting for approximately two-thirds of the eye's total optical power. The cornea has unmyelinated nerve endings sensitive to touch, temperature and chemicals; a touch of the cornea causes an involuntary reflex to close the eyelid. Because transparency is of prime importance the cornea does not have blood vessels; it receives nutrients via diffusion from the tear fluid at the outside and the aqueous humor at the inside and also from neurotrophins supplied by nerve fibers that innervate it. In humans, the cornea has a diameter of about 11.5 mm and a thickness of 0.5-0.6 mm in the center and 0.6-0.8 mm at the periphery.
Transparency, avascularity, the presence of highly immature resident immune cells, and immunologic privilege makes the cornea a unique tissue. Immune privilege is meant to describe certain sites in the body that are able to tolerate the introduction of an antigen without eliciting an inflammatory immune response. The cornea has no blood supply, but rather, the cornea it gets oxygen directly through the air and the tears that bathe it. The human cornea, like that of other primates, has five layers. From the anterior to posterior they are the corneal epithelium, Bowman's layer, the corneal stroma, Descemet's membrane, and the corneal endothelium. The corneal epithelium is a thin epithelial multicellular tissue layer, stratified squamous epithelium, of continuously regenerating cells, kept moist with tears. Irregularity or edema of the corneal epithelium disrupts the smoothness of the air-tear film interface, the most significant component of the total refractive power of the eye, thereby reducing visual acuity. Bowman's layer, also known as the anterior limiting membrane, is a condensed layer of irregularly-arranged collagen, about 8-14 microns thick, that protects the corneal stroma. The corneal stroma, also known as the substantia propria, is a thick and transparent middle layer, consisting of regularly-arranged collagen fibers along with sparsely populated keratocytes. The corneal stroma consists of approximately 200 layers of type I collagen fibrils. Ninety percent of the corneal thickness is composed of the stroma. Descemet's membrane, also known as the posterior limiting membrane, is a thin and acellular layer that serves as the modified basement membrane of the corneal endothelium. The corneal endothelium is a simple squamous or low cuboidal monolayer of mitochondria-rich cells responsible for regulating fluid and solute transport between the aqueous and corneal stromal compartments. The corneal endothelium is bathed by aqueous humor, not by blood or lymph, and has a very different origin, function, and appearance from vascular endothelia. Unlike the corneal epithelium, the cells of the endothelium do not regenerate. Instead, corneal endothelial cells expand or spread to compensate for dead cells which reduces the overall cell density of the endothelium and impacts fluid regulation.
The cornea is one of the most sensitive tissues of the body, it is densely innervated with sensory nerve fibers via the ophthalmic division of the trigeminal nerve by way of 70-80 long and short ciliary nerves. Nerves enter the cornea via three levels, scleral, episcleral and conjunctival. Most of the bundles subdivide and form a network in the stroma, from which fibers supply different regions of the cornea. Three exemplary networks are midstromal, subepithelial/Bowman's layer, and epithelium. Corneal nerves of the subepithelial layer converge and terminate near the apex of the cornea.
Corneal Innervation
The cornea is one of the most densely innervated tissues in the body and is abundantly supplied by different types of nerve fibers. Rabbit studies have revealed that the nerve density of the corneal epithelium is about 300-600 times as much as that of skin and 20-40 times that of the dental pulp. It is estimated that there are approximately 7000 sensory receptors per mm2 in the human corneal epithelium, implying that injuries to individual epithelial cells may be adequate to give a pain perception (Exp Eye Res 2003; 76:521-42).
Most corneal nerve fibers are sensory in origin and are derived from the ophthalmic branch of the trigeminal nerve. Nerve bundles enter the peripheral mid-stromal cornea in a radial fashion parallel to the corneal surface. Soon after entering the cornea, the main stromal bundles branch repeatedly and dichotomously into smaller fascicles that ascended into progressively more superficial layers of the stroma. Eventually the stromal nerve fibers turn abruptly 90°, penetrate Bowman's layer and proceed towards the corneal surface. After penetrating Bowman's layer, bundles divide and run parallel to the corneal surface between Bowman's layer and the basal epithelium, forming the subbasal nerve plexus. The density and number of nerves in the subbasal epithelial nerve plexus are significantly greater than the density and number of nerves in the remaining corneal layers. Subbasal fibers subsequently form branches that turn upward and enter the corneal epithelium between the basal cells to reach the wing cells, where they terminate (Invest Ophthalmol Vis Sci 1996; 37:476-88).
Corneal nerve fibers mediate not only sensation but also exert critical trophic influences on the corneal epithelium and play a vital role to the preservation of a healthy ocular surface. Corneal sensation is a key mechanism in preventing injury through the blink reflex and reflex tearing. Enhanced epithelial cell proliferation is mediated by neurotransmitters and nerve growth factors released from corneal nerve endings (Acta Ophthalmol Suppl 1989; 192:115-34). Dysfunction of corneal innervation produces a degenerative condition known as neurotrophic keratitis, which therefore renders the corneal surface vulnerable to occult injury and delayed healing of established corneal epithelial injuries. Most clinical cases of neurotrophic keratitis are caused by herpes simplex or zoster keratitis, diabetes mellitus, or by trigeminal nerve damage associated with orbital or head surgery, head trauma, aneurysms, or intracranial neurologic disease. Absent or reduced corneal sensation may be congenital in origin. Keratorefractive procedures such as photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) can sever stromal and subbasal corneal nerves plexus and produce a transient mild to severe neurotrophic dry eye.
Intact corneal innervation is also mandatory for tearing reflexes. Under normal physiological conditions, sensory nerves in the cornea transmit an afferent stimulation signal to the brain stem and then, after a series of interneurons, the efferent signal is transmitted to the lacrimal gland through the parasympathetic and sympathetic nerves that innervate the gland and drive tear production and secretion (Ocul Surf 2004; 2:76-91). Damage to this neural circuit interrupts the normal regulation of lacrimal gland secretion and causes dry eye disease. A reduction in neural drive from the cornea favors the occurrence of dry eye-associated ocular surface disease in two ways; first, by decreasing reflex-induced lacrimal secretion and by reducing the blink rate and, consequently, increasing evaporative loss; second, by decreasing the trophic factors to the epithelial layer. Damage to the sensory nerves in the ocular surface, particularly the cornea, as a consequence of refractive surgery and normal aging, prevents the normal reflex arc to the lacrimal gland and can result in decreased tear secretion and dry eye syndromes. Evidence for this mechanism comes from the clinical observation that dry eye syndrome frequently occurs after corneal refractive surgery. Clinical studies confirmed that tear production and secretion are reduced after LASIK surgery (Ophthalmology 2001; 108:1230-5). Hyposecretion of tears in dry eye may lead to pathologic alterations in corneal nerves and a decline in corneal sensitivity which subsequently perpetuate the dry eye state (Cornea 1996; 15:235-9).
Corneal Pathology
Ocular diseases that affect the corneal epithelium such as dry eye, exposure keratopathy, and other ocular surface diseases cause corneal nerve degeneration. On the other hand, normal neural drive is an essential requirement for corneal epithelium to heal and maintain its homeostasis. Therefore, corneal nerve alterations, either as a primary reason (refractive surgery) or just as the outcome of dryness and other corneal epithelial or ocular surface diseases, have crucial effects on the homeostasis of corneal epithelium, thus neatly contributing to the increase of the vicious circle of epithelial disease and nerve damage.
The Relationship Between Corneal Epithelial Disease and Corneal Nerve Damage
Ocular diseases that affect the corneal epithelium such as dry eye, exposure keratopathy, and other ocular surface diseases cause corneal nerve degeneration. On the other hand, normal neural drive and function are essential requirements for corneal epithelial healing and the maintenance of corneal homeostasis. Therefore, corneal nerve damage, either as a primary reason (inflicted by refractory surgery, herpetic eye disease, diabetes, or trigeminal nerve damage, e.g. fifth cranial nerve damage) or as a secondary outcome of dryness and other corneal epithelial or ocular surface diseases, can cause further damage to the corneal epithelium, thus contributing to the increase of the vicious circle of epithelial disease and nerve damage. In addition, IL-1 and corneal epithelial disease induce lymphatic vessel formation in the cornea. These lymphatic vessels are crucial for migration of resident and infiltrating antigen presenting cells and other immune cells, and drainage of corneal antigens, to the lymphoid compartment including draining lymph nodes and induction of adaptive immunity at the ocular surface, which ultimately leads to persistent and chronic ocular surface disease (see FIG. 13).
The Relationship Between Corneal Lymphatics and Inflammation
The normal human cornea has no lymphatic vessels. However in pathological conditions such as corneal epithelial disease, IL-17 induces lymphatic vessel formation in the cornea. These lymphatic vessels are crucial for migration of resident and infiltrating antigen presenting cells and other immune cells, and drainage of corneal antigens, to the lymphoid compartment including draining lymph nodes and induction of adaptive immunity against ocular surface, which ultimately leads to persistent and chronic ocular surface disease (see FIG. 13). In addition, corneal lymphatics play an important role in the induction of alloimmune response to corneal grafts in transplantations. The existence of corneal lymphatic vessels leads to increased rate of transplant rejections. Therapeutic inhibition of corneal lymphatics may thus enhance corneal transplant survival both in the high- and low-risk recipients.
Interleukin-17 (IL-17):
Interleukin-17 (IL-17) is a potent proinflammatory cytokine produced by a new lineage of CD4+ T cells (Th17). IL-17 signals through a heteromeric receptor complex composed of IL-17RA and IL-17RC. IL-17 has pleiotropic effects on several immune and non-immune cells, providing an association between T cell activation and the inflammatory response. Furthermore, IL-17 cooperates either additively or synergistically with other proinflammatory cytokines such as TNFα, IL1β or IL6, leading to amplification of inflammatory processes. IL-17, also known as IL-17A, is part of a larger family comprising 6 cytokines, referred to as IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. All members of this family share a common protein structure. Among these family members, IL-17A and IL-17F are most frequently expressed in immune cells. In alternative embodiments of the invention, one or more of these family members are targeted by antagonists to inhibit or modify their activity.
The invention comprises compositions with means to inhibit or modify the activity of human IL-17, defined as the ability of this protein to bind an IL-17 receptor. Compositions that comprise an inhibitor of human IL-17 function antagonize the activity of an IL-17 receptor. The composition comprises a polynucleotide, a polypeptide, an antibody, a compound, or a small molecule, or a fragment thereof, with means to inhibit or modify the transcription, transcript stability, translation, modification, localization, secretion, or function of a polynucleotide or polypeptide encoding human IL-17. In a preferred embodiment, the inhibitory composition binds to one or more region(s)/fragment(s) of IL-17 comprised by SEQ ID NO: 1 and SEQ ID NO: 2.
A fragment, in the case of these sequences and all others provided herein, is defined as a part of the whole that is less than the whole. Moreover, a fragment ranges in size from a single nucleotide or amino acid within a polynucleotide or polypeptide sequence to one fewer nucleotide or amino acid than the entire polynucleotide or polypeptide sequence. Finally, a fragment is defined as any portion of a complete polynucleotide or polypeptide sequence, which is intermediate between the extremes defined above.
Human IL-17 is encoded by the following mRNA sequence (NCBI Accession No. NM_002190, alternatively called IL-17A, and SEQ ID NO: 1): (For all mRNA transcripts incorporated into the present application, the initiator methionine, encoded by the codon “atg,” is bolded and capitalized to delineate the start of the coding region.)









1
gcaggcacaa actcatccat ccccagttga ttggaagaaa caacgATGac tcctgggaag



 


61
acctcattgg tgtcactgct actgctgctg agcctggagg ccatagtgaa ggcaggaatc


 


121
acaatcccac gaaatccagg atgcccaaat tctgaggaca agaacttccc ccggactgtg


 


181
atggtcaacc tgaacatcca taaccggaat accaatacca atcccaaaag gtcctcagat


 


241
tactacaacc gatccacctc accttggaat ctccaccgca atgaggaccc tgagagatat


 


301
ccctctgtga tctgggaggc aaagtgccgc cacttgggct gcatcaacgc tgatgggaac


 


361
gtggactacc acatgaactc tgtccccatc cagcaagaga tcctggtcct gcgcagggag


 


421
cctccacact gccccaactc cttccggctg gagaagatac tggtgtccgt gggctgcacc


 


481
tgtgtcaccc cgattgtcca ccatgtggcc taagagctct ggggagccca cactccccaa


 


541
agcagttaga ctatggagag ccgacccagc ccctcaggaa ccctcatcct tcaaagacag


 


601
cctcatttcg gactaaactc attagagttc ttaaggcagt ttgtccaatt aaagcttcag


 


661
aggtaacact tggccaagat atgagatctg aattaccttt ccctctttcc aagaaggaag


 


721
gtttgactga gtaccaattt gcttcttgtt tactttttta agggctttaa gttatttatg


 


781
tatttaatat gccctgagat aactttgggg tataagattc cattttaatg aattacctac


 


841
tttattttgt ttgtcttttt aaagaagata agattctggg cttgggaatt ttattattta


 


901
aaaggtaaaa cctgtattta tttgagctat ttaaggatct atttatgttt aagtatttag


 


961
aaaaaggtga aaaagcacta ttatcagttc tgcctaggta aatgtaagat agaattaaat


 


1021
ggcagtgcaa aatttctgag tctttacaac atacggatat agtatttcct cctctttgtt


 


1081
tttaaaagtt ataacatggc tgaaaagaaa gattaaacct actttcatat gtattaattt


 


1141
aaattttgca atttgttgag gttttacaag agatacagca agtctaactc tctgttccat


 


1201
taaaccctta taataaaatc cttctgtaat aataaagttt caaaagaaaa tgtttatttg


 


1261
ttctcattaa atgtatttta gcaaactcag ctcttcccta ttgggaagag ttatgcaaat


 


1321
tctcctataa gcaaaacaaa gcatgtcttt gagtaacaat gacctggaaa tacccaaaat


 


1381
tccaagttct cgatttcaca tgccttcaag actgaacacc gactaaggtt ttcatactat


 


1441
tagccaatgc tgtagacaga agcattttga taggaataga gcaaataaga taatggccct


 


1501
gaggaatggc atgtcattat taaagatcat atggggaaaa tgaaaccctc cccaaaatac


 


1561
aagaagttct gggaggagac attgtcttca gactacaatg tccagtttct cccctagact


 


1621
caggcttcct ttggagatta aggcccctca gagatcaaca gaccaacatt tttctcttcc


 


1681
tcaagcaaca ctcctagggc ctggcttctg tctgatcaag gcaccacaca acccagaaag


 


1741
gagctgatgg ggcagaacga actttaagta tgagaaaagt tcagcccaag taaaataaaa


 


1801
actcaatcac attcaattcc agagtagttt caagtttcac atcgtaacca ttttcgccc






Human IL-17 is encoded by the following amino acid sequence (NCBI Accession No. NM_002190, alternatively called IL-17A, and SEQ ID NO: 2):







MTPGKTSLVSLLLLLSLEAIVKAGITIPRNPGCPNSEDKNFPRTVMVNL


 


NIHNRNTNTNPKRSSDYYNRSTSPWNLHRNEDPERYPSVIWEAKCRHLG


 


CINADGNVDYHMNSVPIQQEILVLRREPPHCPNSFRLEKILVSVGCTCV


 


TPIVHHVA.






Human IL-17B is encoded by the following mRNA sequence (NCBI Accession No. NM_014443 and SEQ ID NO: 3):









1
tggggttcca ggcgggcagc agctgcaggc tgaccttgca gcttggcgga ATGgactggc



 


61
ctcacaacct gctgtttctt cttaccattt ccatcttcct ggggctgggc cagcccagga


 


121
gccccaaaag caagaggaag gggcaagggc ggcctgggcc cctggcccct ggccctcacc


 


181
aggtgccact ggacctggtg tcacggatga aaccgtatgc ccgcatggag gagtatgaga


 


241
ggaacatcga ggagatggtg gcccagctga ggaacagctc agagctggcc cagagaaagt


 


301
gtgaggtcaa cttgcagctg tggatgtcca acaagaggag cctgtctccc tggggctaca


 


361
gcatcaacca cgaccccagc cgtatccccg tggacctgcc ggaggcacgg tgcctgtgtc


 


421
tgggctgtgt gaaccccttc accatgcagg aggaccgcag catggtgagc gtgccggtgt


 


481
tcagccaggt tcctgtgcgc cgccgcctct gcccgccacc gccccgcaca gggccttgcc


 


541
gccagcgcgc agtcatggag accatcgctg tgggctgcac ctgcatcttc tgaatcacct


 


601
ggcccagaag ccaggccagc agcccgagac catcctcctt gcacctttgt gccaagaaag


 


661
gcctatgaaa agtaaacact gacttttgaa agcaaaaaaa aaaaaaaaaa a






Human IL-17B is encoded by the following amino acid sequence (NCBI Accession No. NM_014443 and SEQ ID NO: 4):







MDWPHNLLFLLTISIFLGLGQPRSPKSKRKGQGRPGPLAPGPHQVPLD


 


LVSRMKPYARMEEYERNIEEMVAQLRNSSELAQRKCEVNLQLWMSNKR


 


SLSPWGYSINHDPSRIPVDLPEARCLCLGCVNPFTMQEDRSMVSVPVF


 


SQVPVRRRLCPPPPRTGPCRQRAVMETIAVGCTCIF






Human IL-17C is encoded by the following mRNA sequence (NCBI Accession No. NM_013278 and SEQ ID NO: 5):









1
gccaggtgtg caggccgctc caagcccagc ctgccccgct gccgccacca tgacgctcct



 


61
ccccggcctc ctgtttctga cctggctgca cacatgcctg gcccaccatg acccctccct


 


121
cagggggcac ccccacagtc acggtacccc acactgctac tcggctgagg aactgcccct


 


181
cggccaggcc cccccacacc tgctggctcg aggtgccaag tgggggcagg ctttgcctgt


 


241
agccctggtg tccagcctgg aggcagcaag ccacaggggg aggcacgaga ggccctcagc


 


301
tacgacccag tgcccggtgc tgcggccgga ggaggtgttg gaggcagaca cccaccagcg


 


361
ctccatctca ccctggagat accgtgtgga cacggatgag gaccgctatc cacagaagct


 


421
ggccttcgcc gagtgcctgt gcagaggctg tatcgatgca cggacgggcc gcgagacagc


 


481
tgcgctcaac tccgtgcggc tgctccagag cctgctggtg ctgcgccgcc ggccctgctc


 


541
ccgcgacggc tcggggctcc ccacacctgg ggcctttgcc ttccacaccg agttcatcca


 


601
cgtccccgtc ggctgcacct gcgtgctgcc ccgttcagtg tgaccgccga ggccgtgggg


 


661
cccctagact ggacacgtgt gctccccaga gggcaccccc tatttatgtg tatttattgt


 


721
tatttatatg cctcccccaa cactaccctt ggggtctggg cattccccgt gtctggagga


 


781
cagcccccca ctgttctcct catctccagc ctcagtagtt gggggtagaa ggagctcagc


 


841
acctcttcca gcccttaaag ctgcagaaaa ggtgtcacac ggctgcctgt accttggctc


 


901
cctgtcctgc tcccggcttc ccttacccta tcactggcct caggcccccg caggctgcct


 


961
cttcccaacc tccttggaag tacccctgtt tcttaaacaa ttatttaagt gtacgtgtat


 


1021
tattaaactg atgaacacat ccccaaaa






Human IL-17C is encoded by the following amino acid sequence (NCBI Accession No. NM_013278 and SEQ ID NO: 6):







MTLLPGLLFLTWLHTCLAHHDPSLRGHPHSHGTPHCYSAEELPLGQAP


 


PHLLARGAKWGQALPVALVSSLEAASHRGRHERPSATTQCPVLRPEEV


 


LEADTHQRSISPWRYRVDTDEDRYPQKLAFAECLCRGCIDARTGRETA


 


ALNSVRLLQSLLVLRRRPCSRDGSGLPTPGAFAFHTEFIHVPVGCTCV


 


LPRSV






Human IL-17D is encoded by the following mRNA sequence (NCBI Accession No. NM_138284 and SEQ ID NO: 7):









1
aaaatgtttt cagctcctgg aggcgaaagg tgcagagtcg ctctgtgtcc gtgaggccgg



 


61
gcggcgacct cgctcagtcg gcttctcggt ccgagtcccc gggtctggAT Gctggtagcc


 


121
ggcttcctgc tggcgctgcc gccgagctgg gccgcgggcg ccccgagggc gggcaggcgc


 


181
cccgcgcggc cgcggggctg cgcggaccgg ccggaggagc tactggagca gctgtacggg


 


241
cgcctggcgg ccggcgtgct cagtgccttc caccacacgc tgcagctggg gccgcgtgag


 


301
caggcgcgca acgcgagctg cccggcaggg ggcaggcccg ccgaccgccg cttccggccg


 


361
cccaccaacc tgcgcagcgt gtcgccctgg gcctacagaa tctcctacga cccggcgagg


 


421
taccccaggt acctgcctga agcctactgc ctgtgccggg gctgcctgac cgggctgttc


 


481
ggcgaggagg acgtgcgctt ccgcagcgcc cctgtctaca tgcccaccgt cgtcctgcgc


 


541
cgcacccccg cctgcgccgg cggccgttcc gtctacaccg aggcctacgt caccatcccc


 


601
gtgggctgca cctgcgtccc cgagccggag aaggacgcag acagcatcaa ctccagcatc


 


661
gacaaacagg gcgccaagct cctgctgggc cccaacgacg cgcccgctgg cccctgaggc


 


721
cggtcctgcc ccgggaggtc tccccggccc gcatcccgag gcgcccaagc tggagccgcc


 


781
tggagggctc ggtcggcgac ctctgaagag agtgcaccga gcaaaccaag tgccggagca


 


841
ccagcgccgc ctttccatgg agactcgtaa gcagcttcat ctgacacggg catccctggc


 


901
ttgcttttag ctacaagcaa gcagcgtggc tggaagctga tgggaaacga cccggcacgg


 


961
gcatcctgtg tgcggcccgc atggagggtt tggaaaagtt cacggaggct ccctgaggag


 


1021
cctctcagat cggctgctgc gggtgcaggg cgtgactcac cgctgggtgc ttgccaaaga


 


1081
gatagggacg catatgcttt ttaaagcaat ctaaaaataa taataagtat agcgactata


 


1141
tacctacttt taaaatcaac tgttttgaat agaggcagag ctattttata ttatcaaatg


 


1201
agagctactc tgttacattt cttaacatat aaacatcgtt ttttacttct tctggtagaa


 


1261
ttttttaaag cataattgga atccttggat aaattttgta gctggtacac tctggcctgg


 


1321
gtctctgaat tcagcctgtc accgatggct gactgatgaa atggacacgt ctcatctgac


 


1381
ccactcttcc ttccactgaa ggtcttcacg ggcctccagg tggaccaaag ggatgcacag


 


1441
gcggctcgca tgccccaggg ccagctaaga gttccaaaga tctcagattt ggttttagtc


 


1501
atgaatacat aaacagtctc aaactcgcac aattttttcc cccttttgaa agccactggg


 


1561
gccaatttgt ggttaagagg tggtgagata agaagtggaa cgtgacatct ttgccagttg


 


1621
tcagaagaat ccaagcaggt attggcttag ttgtaagggc tttaggatca ggctgaatat


 


1681
gaggacaaag tgggccacgt tagcatctgc agagatcaat ctggaggctt ctgtttctgc


 


1741
attctgccac gagagctagg tccttgatct tttctttaga ttgaaagtct gtctctgaac


 


1801
acaattattt gtaaaagtta gtagttcttt tttaaatcat taaaagaggc ttgctgaagg


 


1861
aaaaaaaaaa aaa






Human IL-17D is encoded by the following amino acid sequence (NCBI Accession No. NM_138284 and SEQ ID NO: 8)







MLVAGFLLALPPSWAAGAPRAGRRPARPRGCADRPEELLEQLYGRLAA


 


GVLSAFHHTLQLGPREQARNASCPAGGRPADRRFRPPTNLRSVSPWAY


 


RISYDPARYPRYLPEAYCLCRGCLTGLFGEEDVRFRSAPVYMPTVVLR


 


RTPACAGGRSVYTEAYVTIPVGCTCVPEPEKDADSINSSIDKQGAKLL


 


LGPNDAPAGP






Human IL-17E is encoded by the following mRNA sequence (NCBI Accession No. AF305200 and SEQ ID NO: 9):









1
ggcttgctga aaataaaatc aggactccta acctgctcca gtcagcctgc ttccacgagg



 


61
cctgtcagtc agtgcccgac ttgtgactga gtgtgcagtg cccagcatgt accaggtcag


 


121
tgcagagggc tgcctgaggg ctgtgctgag agggagagga gcagagatgc tgctgagggt


 


181
ggagggaggc caagctgcca ggtttggggc tgggggccaa gtggagtgag aaactgggat


 


241
cccaggggga gggtgcagat gagggagcga cccagattag gtgaggacag ttctctcatt


 


301
agccttttcc tacaggtggt tgcattcttg gcaatggtca tgggaaccca cacctacagc


 


361
cactggccca gctgctgccc cagcaaaggg caggacacct ctgaggagct gctgaggtgg


 


421
agcactgtgc ctgtgcctcc cctagagcct gctaggccca accgccaccc agagtcctgt


 


481
agggccagtg aagatggacc cctcaacagc agggccatct ccccctggag atatgagttg


 


541
gacagagact tgaaccggct cccccaggac ctgtaccacg cccgttgcct gtgcccgcac


 


601
tgcgtcagcc tacagacagg ctcccacatg gacccccggg gcaactcgga gctgctctac


 


661
cacaaccaga ctgtcttcta caggcggcca tgccatggcg agaagggcac ccacaagggc


 


721
tactgcctgg agcgcaggct gtaccgtgtt tccttagctt gtgtgtgtgt gcggccccgt


 


781
gtgatgggct agccggacct gctggaggct ggtccctttt tgggaaacct ggagccaggt


 


841
gtacaaccac ttgccatgaa gggccaggat gcccagatgc ttggcccctg tgaagtgctg


 


901
tctggagcag caggatcccg ggacaggatg gggggctttg gggaaaacct gcacttctgc


 


961
acattttgaa aagagcagct gctgcttagg gccgccggaa gctggtgtcc tgtcattttc


 


1021
tctcaggaaa ggttttcaaa gttctgccca tttctggagg ccaccactcc tgtctcttcc


 


1081
tcttttccca tcccctgcta ccctggccca gcacaggcac tttctagata tttccccctt


 


1141
gctggagaag aaagagcccc tggttttatt tgtttgttta ctcatcactc agtgagcatc


 


1201
tactttgggt gcattctagt gtagttacta gtcttttgac atggatgatt ctgaggagga


 


1261
agctgttatt gaatgtatag agatttatcc aaataaatat ctttatttaa aaatgaaaaa


 


1321
aaaaaaaaaa aaaaa






Human IL-17E is encoded by the following amino acid sequence (NCBI Accession No. AF305200 and SEQ ID NO: 10):







MRERPRLGEDSSLISLFLQVVAFLAMVMGTHTYSHWPSCCPSKGQDTS


 


EELLRWSTVPVPPLEPARPNRHPESCRASEDGPLNSRAISPWRYELDR


 


DLNRLPQDLYHARCLCPHCVSLQTGSHMDPRGNSELLYHNQTVFYRRP


 


CHGEKGTHKGYCLERRLYRVSLACVCVRPRVMG






Human IL-17F is encoded by the following mRNA sequence (NCBI Accession No. NM_052872 and SEQ ID NO: 11):









1
gaacacaggc atacacagga agatacattc acagaaagag cttcctgcac aaagtaagcc



 


61
accagcgcaa cATGacagtg aagaccctgc atggcccagc catggtcaag tacttgctgc


 


121
tgtcgatatt ggggcttgcc tttctgagtg aggcggcagc tcggaaaatc cccaaagtag


 


181
gacatacttt tttccaaaag cctgagagtt gcccgcctgt gccaggaggt agtatgaagc


 


241
ttgacattgg catcatcaat gaaaaccagc gcgtttccat gtcacgtaac atcgagagcc


 


301
gctccacctc cccctggaat tacactgtca cttgggaccc caaccggtac ccctcggaag


 


361
ttgtacaggc ccagtgtagg aacttgggct gcatcaatgc tcaaggaaag gaagacatct


 


421
ccatgaattc cgttcccatc cagcaagaga ccctggtcgt ccggaggaag caccaaggct


 


481
gctctgtttc tttccagttg gagaaggtgc tggtgactgt tggctgcacc tgcgtcaccc


 


541
ctgtcatcca ccatgtgcag taagaggtgc atatccactc agctgaagaa gctgtagaaa


 


601
tgccactcct tacccagtgc tctgcaacaa gtcctgtctg acccccaatt ccctccactt


 


661
cacaggactc ttaataagac ctgcacggat ggaaacagaa aatattcaca atgtatgtgt


 


721
gtatgtacta cactttatat ttgatatcta aaatgttagg agaaaaatta atatattcag


 


781
tgctaatata ataaagtatt aataattt






Human IL-17F is encoded by the following amino acid sequence (NCBI Accession No. NM_052872 and SEQ ID NO: 12)







MTVKTLHGPAMVKYLLLSILGLAFLSEAAARKIPKVGHTFFQKPESCP


 


PVPGGSMKLDIGIINENQRVSMSRNIESRSTSPWNYTVTWDPNRYPSE


 


VVQAQCRNLGCINAQGKEDISMNSVPIQQETLVVRRKHQGCSVSFQLE


 


KVLVTVGCTCVTPVIHHVQ






Interleukin-17 Receptors:

The composition of the invention comprises a polynucleotide, a polypeptide, an antibody, a compound, or a small molecule, or fragment thereof, with means to inhibit or modify the transcription, transcript stability, translation, modification, localization, secretion, or function of a polynucleotide or polypeptide encoding an IL-17 receptor. One contemplated IL-17 heteromeric receptor complex comprises IL-17RA and IL-17RC. The present composition comprises a compound that is targeted to either element, IL-17RA or IL-17RC, of this receptor complex. IL-17RC exists in three different forms comprised by transcripts 1-3. However, additional IL-17 receptors are contemplated. In alternative embodiments, IL-17RB, IL-17RD, and IL-17RE are targeted in isolation or in combination by antagonists of IL-17 function. The invention comprises one or more antagonists of IL-17 receptors IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE.
IL-17RA is encoded by the following mRNA sequence (NCBI Accession No. NM_014339 and SEQ ID NO: 13):









1
ctgggcccgg gctggaagcc ggaagcgagc aaagtggagc cgactcgaac tccaccgcgg



 


61
aaaagaaagc ctcagaacgt tcgttcgctg cgtccccagc cggggccgag ccctccgcga


 


121
cgccagccgg gccATGgggg ccgcacgcag cccgccgtcc gctgtcccgg ggcccctgct


 


181
ggggctgctc ctgctgctcc tgggcgtgct ggccccgggt ggcgcctccc tgcgactcct


 


241
ggaccaccgg gcgctggtct gctcccagcc ggggctaaac tgcacggtca agaatagtac


 


301
ctgcctggat gacagctgga ttcaccctcg aaacctgacc ccctcctccc caaaggacct


 


361
gcagatccag ctgcactttg cccacaccca acaaggagac ctgttccccg tggctcacat


 


421
cgaatggaca ctgcagacag acgccagcat cctgtacctc gagggtgcag agttatctgt


 


481
cctgcagctg aacaccaatg aacgtttgtg cgtcaggttt gagtttctgt ccaaactgag


 


541
gcatcaccac aggcggtggc gttttacctt cagccacttt gtggttgacc ctgaccagga


 


601
atatgaggtg accgttcacc acctgcccaa gcccatccct gatggggacc caaaccacca


 


661
gtccaagaat ttccttgtgc ctgactgtga gcacgccagg atgaaggtaa ccacgccatg


 


721
catgagctca ggcagcctgt gggaccccaa catcaccgtg gagaccctgg aggcccacca


 


781
gctgcgtgtg agcttcaccc tgtggaacga atctacccat taccagatcc tgctgaccag


 


841
ttttccgcac atggagaacc acagttgctt tgagcacatg caccacatac ctgcgcccag


 


901
accagaagag ttccaccagc gatccaacgt cacactcact ctacgcaacc ttaaagggtg


 


961
ctgtcgccac caagtgcaga tccagccctt cttcagcagc tgcctcaatg actgcctcag


 


1021
acactccgcg actgtttcct gcccagaaat gccagacact ccagaaccaa ttccggacta


 


1081
catgcccctg tgggtgtact ggttcatcac gggcatctcc atcctgctgg tgggctccgt


 


1141
catcctgctc atcgtctgca tgacctggag gctagctggg cctggaagtg aaaaatacag


 


1201
tgatgacacc aaatacaccg atggcctgcc tgcggctgac ctgatccccc caccgctgaa


 


1261
gcccaggaag gtctggatca tctactcagc cgaccacccc ctctacgtgg acgtggtcct


 


1321
gaaattcgcc cagttcctgc tcaccgcctg cggcacggaa gtggccctgg acctgctgga


 


1381
agagcaggcc atctcggagg caggagtcat gacctgggtg ggccgtcaga agcaggagat


 


1441
ggtggagagc aactctaaga tcatcgtcct gtgctcccgc ggcacgcgcg ccaagtggca


 


1501
ggcgctcctg ggccgggggg cgcctgtgcg gctgcgctgc gaccacggaa agcccgtggg


 


1561
ggacctgttc actgcagcca tgaacatgat cctcccggac ttcaagaggc cagcctgctt


 


1621
cggcacctac gtagtctgct acttcagcga ggtcagctgt gacggcgacg tccccgacct


 


1681
gttcggcgcg gcgccgcggt acccgctcat ggacaggttc gaggaggtgt acttccgcat


 


1741
ccaggacctg gagatgttcc agccgggccg catgcaccgc gtaggggagc tgtcggggga


 


1801
caactacctg cggagcccgg gcggcaggca gctccgcgcc gccctggaca ggttccggga


 


1861
ctggcaggtc cgctgtcccg actggttcga atgtgagaac ctctactcag cagatgacca


 


1921
ggatgccccg tccctggacg aagaggtgtt tgaggagcca ctgctgcctc cgggaaccgg


 


1981
catcgtgaag cgggcgcccc tggtgcgcga gcctggctcc caggcctgcc tggccataga


 


2041
cccgctggtc ggggaggaag gaggagcagc agtggcaaag ctggaacctc acctgcagcc


 


2101
ccggggtcag ccagcgccgc agcccctcca caccctggtg ctcgccgcag aggagggggc


 


2161
cctggtggcc gcggtggagc ctgggcccct ggctgacggt gccgcagtcc ggctggcact


 


2221
ggcgggggag ggcgaggcct gcccgctgct gggcagcccg ggcgctgggc gaaatagcgt


 


2281
cctcttcctc cccgtggacc ccgaggactc gccccttggc agcagcaccc ccatggcgtc


 


2341
tcctgacctc cttccagagg acgtgaggga gcacctcgaa ggcttgatgc tctcgctctt


 


2401
cgagcagagt ctgagctgcc aggcccaggg gggctgcagt agacccgcca tggtcctcac


 


2461
agacccacac acgccctacg aggaggagca gcggcagtca gtgcagtctg accagggcta


 


2521
catctccagg agctccccgc agccccccga gggactcacg gaaatggagg aagaggagga


 


2581
agaggagcag gacccaggga agccggccct gccactctct cccgaggacc tggagagcct


 


2641
gaggagcctc cagcggcagc tgcttttccg ccagctgcag aagaactcgg gctgggacac


 


2701
gatggggtca gagtcagagg ggcccagtgc atgagggcgg ctccccaggg accgcccaga


 


2761
tcccagcttt gagagaggag tgtgtgtgca cgtattcatc tgtgtgtaca tgtctgcatg


 


2821
tgtatatgtt cgtgtgtgaa atgtaggctt taaaatgtaa atgtctggat tttaatccca


 


2881
ggcatccctc ctaacttttc tttgtgcagc ggtctggtta tcgtctatcc ccaggggaat


 


2941
ccacacagcc cgctcccagg agctaatggt agagcgtcct tgaggctcca ttattcgttc


 


3001
attcagcatt tattgtgcac ctactatgtg gcgggcattt gggataccaa gataaattgc


 


3061
atgcggcatg gccccagcca tgaaggaact taaccgctag tgccgaggac acgttaaacg


 


3121
aacaggatgg gccgggcacg gtggctcacg cctgtaatcc cagcacactg ggaggccgag


 


3181
gcaggtggat cactctgagg tcaggagttt gagccagcct ggccaacatg gtgaaacccc


 


3241
atctccacta aaaatagaaa aattagccgg gcatggtgac acatgcctgt agtcctagct


 


3301
acttgggagg ctgaggcagg agaattgctt gaatctggga ggcagaggtt gcagtgagcc


 


3361
gagattgtgc cattgcactg cagcctggat gacagagcga gactctatct caaaaaaaaa


 


3421
aaaaaaaaa






IL-17RA is encoded by the following amino acid sequence (NCBI Accession No. NM_14339 and SEQ ID NO: 14):







MGAARSPPSAVPGPLLGLLLLLLGVLAPGGASLRLLDHRALVCSQPGL


 


NCTVKNSTCLDDSWIHPRNLTPSSPKDLQIQLHFAHTQQGDLFPVAHI


 


EWTLQTDASILYLEGAELSVLQLNTNERLCVRFEFLSKLRHHHRRWRF


 


TFSHFVVDPDQEYEVTVHHLPKPIPDGDPNHQSKNFLVPDCEHARMKV


 


TTPCMSSGSLWDPNITVETLEAHQLRVSFTLWNESTHYQILLTSFPHM


 


ENHSCFEHMHHIPAPRPEEFHQRSNVTLTLRNLKGCCRHQVQIQPFFS


 


SCLNDCLRHSATVSCPEMPDTPEPIPDYMPLWVYWFITGISILLVGSV


 


ILLIVCMTWRLAGPGSEKYSDDTKYTDGLPAADLIPPPLKPRKVWIIY


 


SADHPLYVDVVLKFAQFLLTACGTEVALDLLEEQAISEAGVMTWVGRQ


 


KQEMVESNSKIIVLCSRGTRAKWQALLGRGAPVRLRCDHGKPVGDLFT


 


AAMNMILPDFKRPACFGTYVVCYFSEVSCDGDVPDLFGAAPRYPLMDR


 


FEEVYFRIQDLEMFQPGRMHRVGELSGDNYLRSPGGRQLRAALDRFRD


 


WQVRCPDWFECENLYSADDQDAPSLDEEVFEEPLLPPGTGIVKRAPLV


 


REPGSQACLAIDPLVGEEGGAAVAKLEPHLQPRGQPAPQPLHTLVLAA


 


EEGALVAAVEPGPLADGAAVRLALAGEGEACPLLGSPGAGRNSVLFLP


 


VDPEDSPLGSSTPMASPDLLPEDVREHLEGLMLSLFEQSLSCQAQGGC


 


SRPAMVLTDPHTPYEEEQRQSVQSDQGYISRSSPQPPEGLTEMEEEEE


 


EEQDPGKPALPLSPEDLESLRSLQRQLLFRQLQKNSGWDTMGSESEGP


 


SA






IL-17RB is encoded by the following mRNA sequence (NCBI Accession No. NM_018725 and SEQ ID NO: 15):









1
agcgtgcggg tggcctggat cccgcgcagt ggcccggcgA TGtcgctcgt gctgctaagc



 


61
ctggccgcgc tgtgcaggag cgccgtaccc cgagagccga ccgttcaatg tggctctgaa


 


121
actgggccat ctccagagtg gatgctacaa catgatctaa tccccggaga cttgagggac


 


181
ctccgagtag aacctgttac aactagtgtt gcaacagggg actattcaat tttgatgaat


 


241
gtaagctggg tactccgggc agatgccagc atccgcttgt tgaaggccac caagatttgt


 


301
gtgacgggca aaagcaactt ccagtcctac agctgtgtga ggtgcaatta cacagaggcc


 


361
ttccagactc agaccagacc ctctggtggt aaatggacat tttcctacat cggcttccct


 


421
gtagagctga acacagtcta tttcattggg gcccataata ttcctaatgc aaatatgaat


 


481
gaagatggcc cttccatgtc tgtgaatttc acctcaccag gctgcctaga ccacataatg


 


541
aaatataaaa aaaagtgtgt caaggccgga agcctgtggg atccgaacat cactgcttgt


 


601
aagaagaatg aggagacagt agaagtgaac ttcacaacca ctcccctggg aaacagatac


 


661
atggctctta tccaacacag cactatcatc gggttttctc aggtgtttga gccacaccag


 


721
aagaaacaaa cgcgagcttc agtggtgatt ccagtgactg gggatagtga aggtgctacg


 


781
gtgcagctga ctccatattt tcctacttgt ggcagcgact gcatccgaca taaaggaaca


 


841
gttgtgctct gcccacaaac aggcgtccct ttccctctgg ataacaacaa aagcaagccg


 


901
ggaggctggc tgcctctcct cctgctgtct ctgctggtgg ccacatgggt gctggtggca


 


961
gggatctatc taatgtggag gcacgaaagg atcaagaaga cttccttttc taccaccaca


 


1021
ctactgcccc ccattaaggt tcttgtggtt tacccatctg aaatatgttt ccatcacaca


 


1081
atttgttact tcactgaatt tcttcaaaac cattgcagaa gtgaggtcat ccttgaaaag


 


1141
tggcagaaaa agaaaatagc agagatgggt ccagtgcagt ggcttgccac tcaaaagaag


 


1201
gcagcagaca aagtcgtctt ccttctttcc aatgacgtca acagtgtgtg cgatggtacc


 


1261
tgtggcaaga gcgagggcag tcccagtgag aactctcaag acctcttccc ccttgccttt


 


1321
aaccttttct gcagtgatct aagaagccag attcatctgc acaaatacgt ggtggtctac


 


1381
tttagagaga ttgatacaaa agacgattac aatgctctca gtgtctgccc caagtaccac


 


1441
ctcatgaagg atgccactgc tttctgtgca gaacttctcc atgtcaagca gcaggtgtca


 


1501
gcaggaaaaa gatcacaagc ctgccacgat ggctgctgct ccttgtagcc cacccatgag


 


1561
aagcaagaga ccttaaaggc ttcctatccc accaattaca gggaaaaaac gtgtgatgat


 


1621
cctgaagctt actatgcagc ctacaaacag ccttagtaat taaaacattt tataccaata


 


1681
aaattttcaa atattgctaa ctaatgtagc attaactaac gattggaaac tacatttaca


 


1741
acttcaaagc tgttttatac atagaaatca attacagttt taattgaaaa ctataaccat


 


1801
tttgataatg caacaataaa gcatcttcag ccaaacatct agtcttccat agaccatgca


 


1861
ttgcagtgta cccagaactg tttagctaat attctatgtt taattaatga atactaactc


 


1921
taagaacccc tcactgattc actcaatagc atcttaagtg aaaaaccttc tattacatgc


 


1981
aaaaaatcat tgtttttaag ataacaaaag tagggaataa acaagctgaa cccactttta


 


2041
aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa






IL-17RB is encoded by the following amino acid sequence (NCBI Accession No. NM_018725 and SEQ ID NO: 16):







MSLVLLSLAALCRSAVPREPTVQCGSETGPSPEWMLQHDLIPGDLRDL


 


RVEPVTTSVATGDYSILMNVSWVLRADASIRLLKATKICVTGKSNFQS


 


YSCVRCNYTEAFQTQTRPSGGKWTFSYIGFPVELNTVYFIGAHNIPNA


 


NMNEDGPSMSVNFTSPGCLDHIMKYKKKCVKAGSLWDPNITACKKNEE


 


TVEVNFTTTPLGNRYMALIQHSTIIGFSQVFEPHQKKQTRASVVIPVT


 


GDSEGATVQLTPYFPTCGSDCIRHKGTVVLCPQTGVPFPLDNNKSKPG


 


GWLPLLLLSLLVATWVLVAGIYLMWRHERIKKTSFSTTTLLPPIKVLV


 


VYPSEICFHHTICYFTEFLQNHCRSEVILEKWQKKKIAEMGPVQWLAT


 


QKKAADKVVFLLSNDVNSVCDGTCGKSEGSPSENSQDLFPLAFNLFCS


 


DLRSQIHLHKYVVVYFREIDTKDDYNALSVCPKYHLMKDATAFCAELL


 


HVKQQVSAGKRSQACHDGCCSL






IL-17RC, transcript variant 1, is encoded by the following mRNA sequence (NCBI Accession No. NM_153461 and SEQ ID NO: 17):









1
aaaacgaaag cactccgtgc tggaagtagg aggagagtca ggactcccag gacagagagt



 


61
gcacaaacta cccagcacag ccccctccgc cccctctgga ggctgaagag ggattccagc


 


121
ccctgccacc cacagacacg ggctgactgg ggtgtctgcc ccccttgggg gggggcagca


 


181
cagggcctca ggcctgggtg ccacctggca cctagaagAT Gcctgtgccc tggttcttgc


 


241
tgtccttggc actgggccga agcccagtgg tcctttctct ggagaggctt gtggggcctc


 


301
aggacgctac ccactgctct ccggtgagtc tggaaccctg gggagacgag gaaaggctca


 


361
gggttcagtt tttggctcag caaagcctta gcctggctcc tgtcactgct gccactgcca


 


421
gaactgccct gtctggtctg tctggtgctg atggtagaag agaagaacgg ggaaggggca


 


481
agagctgggt ctgtctttct ctgggagggt ctgggaatac ggagccccag aaaaagggcc


 


541
tctcctgccg cctctgggac agtgacatac tctgcctgcc tggggacatc gtgcctgctc


 


601
cgggccccgt gctggcgcct acgcacctgc agacagagct ggtgctgagg tgccagaagg


 


661
agaccgactg tgacctctgt ctgcgtgtgg ctgtccactt ggccgtgcat gggcactggg


 


721
aagagcctga agatgaggaa aagtttggag gagcagctga ctcaggggtg gaggagccta


 


781
ggaatgcctc tctccaggcc caagtcgtgc tctccttcca ggcctaccct actgcccgct


 


841
gcgtcctgct ggaggtgcaa gtgcctgctg cccttgtgca gtttggtcag tctgtgggct


 


901
ctgtggtata tgactgcttc gaggctgccc tagggagtga ggtacgaatc tggtcctata


 


961
ctcagcccag gtacgagaag gaactcaacc acacacagca gctgcctgac tgcagggggc


 


1021
tcgaagtctg gaacagcatc ccgagctgct gggccctgcc ctggctcaac gtgtcagcag


 


1081
atggtgacaa cgtgcatctg gttctgaatg tctctgagga gcagcacttc ggcctctccc


 


1141
tgtactggaa tcaggtccag ggccccccaa aaccccggtg gcacaaaaac ctgactggac


 


1201
cgcagatcat taccttgaac cacacagacc tggttccctg cctctgtatt caggtgtggc


 


1261
ctctggaacc tgactccgtt aggacgaaca tctgcccctt cagggaggac ccccgcgcac


 


1321
accagaacct ctggcaagcc gcccgactgc gactgctgac cctgcagagc tggctgctgg


 


1381
acgcaccgtg ctcgctgccc gcagaagcgg cactgtgctg gcgggctccg ggtggggacc


 


1441
cctgccagcc actggtccca ccgctttcct gggagaacgt cactgtggac aaggttctcg


 


1501
agttcccatt gctgaaaggc caccctaacc tctgtgttca ggtgaacagc tcggagaagc


 


1561
tgcagctgca ggagtgcttg tgggctgact ccctggggcc tctcaaagac gatgtgctac


 


1621
tgttggagac acgaggcccc caggacaaca gatccctctg tgccttggaa cccagtggct


 


1681
gtacttcact acccagcaaa gcctccacga gggcagctcg ccttggagag tacttactac


 


1741
aagacctgca gtcaggccag tgtctgcagc tatgggacga tgacttggga gcgctatggg


 


1801
cctgccccat ggacaaatac atccacaagc gctgggccct cgtgtggctg gcctgcctac


 


1861
tctttgccgc tgcgctttcc ctcatcctcc ttctcaaaaa ggatcacgcg aaagggtggc


 


1921
tgaggctctt gaaacaggac gtccgctcgg gggcggccgc caggggccgc gcggctctgc


 


1981
tcctctactc agccgatgac tcgggtttcg agcgcctggt gggcgccctg gcgtcggccc


 


2041
tgtgccagct gccgctgcgc gtggccgtag acctgtggag ccgtcgtgaa ctgagcgcgc


 


2101
aggggcccgt ggcttggttt cacgcgcagc ggcgccagac cctgcaggag ggcggcgtgg


 


2161
tggtcttgct cttctctccc ggtgcggtgg cgctgtgcag cgagtggcta caggatgggg


 


2221
tgtccgggcc cggggcgcac ggcccgcacg acgccttccg cgcctcgctc agctgcgtgc


 


2281
tgcccgactt cttgcagggc cgggcgcccg gcagctacgt gggggcctgc ttcgacaggc


 


2341
tgctccaccc ggacgccgta cccgcccttt tccgcaccgt gcccgtcttc acactgccct


 


2401
cccaactgcc agacttcctg ggggccctgc agcagcctcg cgccccgcgt tccgggcggc


 


2461
tccaagagag agcggagcaa gtgtcccggg cccttcagcc agccctggat agctacttcc


 


2521
atcccccggg gactcccgcg ccgggacgcg gggtgggacc aggggcggga cctggggcgg


 


2581
gggacgggac ttaaataaag gcagacgctg tttttctacc catgtggccc aaaaaaaaaa


 


2641
aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa a






IL-17RC, transcript variant 1, is encoded by the following amino acid sequence (NCBI Accession No. NM_153461 and SEQ ID NO: 18):







MPVPWFLLSLALGRSPVVLSLERLVGPQDATHCSPVSLEPWGDEERLR


 


VQFLAQQSLSLAPVTAATARTALSGLSGADGRREERGRGKSWVCLSLG


 


GSGNTEPQKKGLSCRLWDSDILCLPGDIVPAPGPVLAPTHLQTELVLR


 


CQKETDCDLCLRVAVHLAVHGHWEEPEDEEKFGGAADSGVEEPRNASL


 


QAQVVLSFQAYPTARCVLLEVQVPAALVQFGQSVGSVVYDCFEAALGS


 


EVRIWSYTQPRYEKELNHTQQLPDCRGLEVWNSIPSCWALPWLNVSAD


 


GDNVHLVLNVSEEQHFGLSLYWNQVQGPPKPRWHKNLTGPQIITLNHT


 


DLVPCLCIQVWPLEPDSVRTNICPFREDPRAHQNLWQAARLRLLTLQS


 


WLLDAPCSLPAEAALCWRAPGGDPCQPLVPPLSWENVTVDKVLEFPLL


 


KGHPNLCVQVNSSEKLQLQECLWADSLGPLKLDDVLLLETRGPQDNRS


 


LCALEPSGCTSLPSKASTRAARLGEYLLQDLQSGQCLQLWDDDLGALW


 


ACPMDKYIHKRWALVWLACLLFAAALSLILLLKKDHAKGWLRLLKQDV


 


RSGAAARGRAALLLYSADDSGFERLVGALASALCQLPLRVAVDLWSRR


 


ELSAQGPVAWFHAQRRQTLQEGGVVVLLFSPGAVALCSEWLQDGVSGP


 


GAHGPHDAFRASLSCVLPDFLQGRAPGSYVGACFDRLLHPDAVPALFR


 


TVPVFTLPSQLPDFLGALQQPRAPRSGRLQERAEQVSRALQPALDSYF


 


HPPGTPAPGRGVGPGAGPGAGDGT






IL-17RC, transcript variant 2, is encoded by the following mRNA sequence (NCBI Accession No. NM_153460 and SEQ ID NO: 19):









   1
aaaacgaaag cactccgtgc tggaagtagg aggagagtca ggactcccag gacagagagt



 


  61
gcacaaacta cccagcacag ccccctccgc cccctctgga ggctgaagag ggattccagc


 


 121
ccctgccacc cacagacacg ggctgactgg ggtgtctgcc ccccttgggg gggggcagca


 


 181
cagggcctca ggcctgggtg ccacctggca cctagaagAT Gcctgtgccc tggttcttgc


 


 241
tgtccttggc actgggccga agcccagtgg tcctttctct ggagaggctt gtggggcctc


 


 301
aggacgctac ccactgctct ccgggcctct cctgccgcct ctgggacagt gacatactct


 


 361
gcctgcctgg ggacatcgtg cctgctccgg gccccgtgct ggcgcctacg cacctgcaga


 


 421
cagagctggt gctgaggtgc cagaaggaga ccgactgtga cctctgtctg cgtgtggctg


 


 481
tccacttggc cgtgcatggg cactgggaag agcctgaaga tgaggaaaag tttggaggag


 


 541
cagctgactc aggggtggag gagcctagga atgcctctct ccaggcccaa gtcgtgctct


 


 601
ccttccaggc ctaccctact gcccgctgcg tcctgctgga ggtgcaagtg cctgctgccc


 


 661
ttgtgcagtt tggtcagtct gtgggctctg tggtatatga ctgcttcgag gctgccctag


 


 721
ggagtgaggt acgaatctgg tcctatactc agcccaggta cgagaaggaa ctcaaccaca


 


 781
cacagcagct gcctgactgc agggggctcg aagtctggaa cagcatcccg agctgctggg


 


 841
ccctgccctg gctcaacgtg tcagcagatg gtgacaacgt gcatctggtt ctgaatgtct


 


 901
ctgaggagca gcacttcggc ctctccctgt actggaatca ggtccagggc cccccaaaac


 


 961
cccggtggca caaaaacctg actggaccgc agatcattac cttgaaccac acagacctgg


 


1021
ttccctgcct ctgtattcag gtgtggcctc tggaacctga ctccgttagg acgaacatct


 


1081
gccccttcag ggaggacccc cgcgcacacc agaacctctg gcaagccgcc cgactgcgac


 


1141
tgctgaccct gcagagctgg ctgctggacg caccgtgctc gctgcccgca gaagcggcac


 


1201
tgtgctggcg ggctccgggt ggggacccct gccagccact ggtcccaccg ctttcctggg


 


1261
agaacgtcac tgtggacaag gttctcgagt tcccattgct gaaaggccac cctaacctct


 


1321
gtgttcaggt gaacagctcg gagaagctgc agctgcagga gtgcttgtgg gctgactccc


 


1381
tggggcctct caaagacgat gtgctactgt tggagacacg aggcccccag gacaacagat


 


1441
ccctctgtgc cttggaaccc agtggctgta cttcactacc cagcaaagcc tccacgaggg


 


1501
cagctcgcct tggagagtac ttactacaag acctgcagtc aggccagtgt ctgcagctat


 


1561
gggacgatga cttgggagcg ctatgggcct gccccatgga caaatacatc cacaagcgct


 


1621
gggccctcgt gtggctggcc tgcctactct ttgccgctgc gctttccctc atcctccttc


 


1681
tcaaaaagga tcacgcgaaa gggtggctga ggctcttgaa acaggacgtc cgctcggggg


 


1741
cggccgccag gggccgcgcg gctctgctcc tctactcagc cgatgactcg ggtttcgagc


 


1801
gcctggtggg cgccctggcg tcggccctgt gccagctgcc gctgcgcgtg gccgtagacc


 


1861
tgtggagccg tcgtgaactg agcgcgcagg ggcccgtggc ttggtttcac gcgcagcggc


 


1921
gccagaccct gcaggagggc ggcgtggtgg tcttgctctt ctctcccggt gcggtggcgc


 


1981
tgtgcagcga gtggctacag gatggggtgt ccgggcccgg ggcgcacggc ccgcacgacg


 


2041
ccttccgcgc ctcgctcagc tgcgtgctgc ccgacttctt gcagggccgg gcgcccggca


 


2101
gctacgtggg ggcctgcttc gacaggctgc tccacccgga cgccgtaccc gcccttttcc


 


2161
gcaccgtgcc cgtcttcaca ctgccctccc aactgccaga cttcctgggg gccctgcagc


 


2221
agcctcgcgc cccgcgttcc gggcggctcc aagagagagc ggagcaagtg tcccgggccc


 


2281
ttcagccagc cctggatagc tacttccatc ccccggggac tcccgcgccg ggacgcgggg


 


2341
tgggaccagg ggcgggacct ggggcggggg acgggactta aataaaggca gacgctgttt


 


2401
ttctacccat gtggcccaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa


 


2461
aaaaaaaaaa aaaaaaaa






IL-17RC, transcript variant 2, is encoded by the following amino acid sequence (NCBI Accession No. NM_153460 and SEQ ID NO: 20):







MPVPWFLLSLALGRSPVVLSLERLVGPQDATHCSPGLSCRLWDSDILCLP


 


GDIVPAPGPVLAPTHLQTELVLRCQKETDCDLCLRVAVHLAVHGHWEEPE


 


DEEKFGGAADSGVEEPRNASLQAQVVLSFQAYPTARCVLLEVQVPAALVQ


 


FGQSVGSVVYDCFEAALGSEVRIWSYTQPRYEKELNHTQQLPDCRGLEVW


 


NSIPSCWALPWLNVSADGDNVHLVLNVSEEQHFGLSLYWNQVQGPPKPRW


 


HKNLTGPQIITLNHTDLVPCLCIQVWPLEPDSVRTNICPFREDPRAHQNL


 


WQAARLRLLTLQSWLLDAPCSLPAEAALCWRAPGGDPCQPLVPPLSWENV


 


TVDKVLEFPLLKGHPNLCVQVNSSEKLQLQECLWADSLGPLKDDVLLLET


 


RGPQDNRSLCALEPSGCTSLPSKASTRAARLGEYLLQDLQSGQCLQLWDD


 


DLGALWACPMDKYIHKRWALVWLACLLFAAALSLILLLKKDHAKGWLRLL


 


KQDVRSGAAARGRAALLLYSADDSGFERLVGALASALCQLPLRVAVDLWS


 


RRELSAQGPVAWFHAQRRQTLQEGGVVVLLFSPGAVALCSEWLQDGVSGP


 


GAHGPHDAFRASLSCVLPDFLQGRAPGSYVGACFDRLLHPDAVPALFRTV


 


PVFTLPSQLPDFLGALQQPRAPRSGRLQERAEQVSRALQPALDSYFHPPG


 


TPAPGRGVGPGAGPGAGDGT






IL-17RC, transcript variant 3, is encoded by the following mRNA sequence (NCBI Accession No. NM_032732 and SEQ ID NO: 21):









   1
aaaacgaaag cactccgtgc tggaagtagg aggagagtca ggactcccag gacagagagt



 


  61
gcacaaacta cccagcacag ccccctccgc cccctctgga ggctgaagag ggattccagc


 


 121
ccctgccacc cacagacacg ggctgactgg ggtgtctgcc ccccttgggg gggggcagca


 


 181
cagggcctca ggcctgggtg ccacctggca cctagaagAT Gcctgtgccc tggttcttgc


 


 241
tgtccttggc actgggccga agcccagtgg tcctttctct ggagaggctt gtggggcctc


 


 301
aggacgctac ccactgctct ccgggcctct cctgccgcct ctgggacagt gacatactct


 


 361
gcctgcctgg ggacatcgtg cctgctccgg gccccgtgct ggcgcctacg cacctgcaga


 


 421
cagagctggt gctgaggtgc cagaaggaga ccgactgtga cctctgtctg cgtgtggctg


 


 481
tccacttggc cgtgcatggg cactgggaag agcctgaaga tgaggaaaag tttggaggag


 


 541
cagctgactc aggggtggag gagcctagga atgcctctct ccaggcccaa gtcgtgctct


 


 601
ccttccaggc ctaccctact gcccgctgcg tcctgctgga ggtgcaagtg cctgctgccc


 


 661
ttgtgcagtt tggtcagtct gtgggctctg tggtatatga ctgcttcgag gctgccctag


 


 721
ggagtgaggt acgaatctgg tcctatactc agcccaggta cgagaaggaa ctcaaccaca


 


 781
cacagcagct gcctgccctg ccctggctca acgtgtcagc agatggtgac aacgtgcatc


 


 841
tggttctgaa tgtctctgag gagcagcact tcggcctctc cctgtactgg aatcaggtcc


 


 901
agggcccccc aaaaccccgg tggcacaaaa acctgactgg accgcagatc attaccttga


 


 961
accacacaga cctggttccc tgcctctgta ttcaggtgtg gcctctggaa cctgactccg


 


1021
ttaggacgaa catctgcccc ttcagggagg acccccgcgc acaccagaac ctctggcaag


 


1081
ccgcccgact gcgactgctg accctgcaga gctggctgct ggacgcaccg tgctcgctgc


 


1141
ccgcagaagc ggcactgtgc tggcgggctc cgggtgggga cccctgccag ccactggtcc


 


1201
caccgctttc ctgggagaac gtcactgtgg acaaggttct cgagttccca ttgctgaaag


 


1261
gccaccctaa cctctgtgtt caggtgaaca gctcggagaa gctgcagctg caggagtgct


 


1321
tgtgggctga ctccctgggg cctctcaaag acgatgtgct actgttggag acacgaggcc


 


1381
cccaggacaa cagatccctc tgtgccttgg aacccagtgg ctgtacttca ctacccagca


 


1441
aagcctccac gagggcagct cgccttggag agtacttact acaagacctg cagtcaggcc


 


1501
agtgtctgca gctatgggac gatgacttgg gagcgctatg ggcctgcccc atggacaaat


 


1561
acatccacaa gcgctgggcc ctcgtgtggc tggcctgcct actctttgcc gctgcgcttt


 


1621
ccctcatcct ccttctcaaa aaggatcacg cgaaagggtg gctgaggctc ttgaaacagg


 


1681
acgtccgctc gggggcggcc gccaggggcc gcgcggctct gctcctctac tcagccgatg


 


1741
actcgggttt cgagcgcctg gtgggcgccc tggcgtcggc cctgtgccag ctgccgctgc


 


1801
gcgtggccgt agacctgtgg agccgtcgtg aactgagcgc gcaggggccc gtggcttggt


 


1861
ttcacgcgca gcggcgccag accctgcagg agggcggcgt ggtggtcttg ctcttctctc


 


1921
ccggtgcggt ggcgctgtgc agcgagtggc tacaggatgg ggtgtccggg cccggggcgc


 


1981
acggcccgca cgacgccttc cgcgcctcgc tcagctgcgt gctgcccgac ttcttgcagg


 


2041
gccgggcgcc cggcagctac gtgggggcct gcttcgacag gctgctccac ccggacgccg


 


2101
tacccgccct tttccgcacc gtgcccgtct tcacactgcc ctcccaactg ccagacttcc


 


2161
tgggggccct gcagcagcct cgcgccccgc gttccgggcg gctccaagag agagcggagc


 


2221
aagtgtcccg ggcccttcag ccagccctgg atagctactt ccatcccccg gggactcccg


 


2281
cgccgggacg cggggtggga ccaggggcgg gacctggggc gggggacggg acttaaataa


 


2341
aggcagacgc tgtttttcta cccatgtggc ccaaaaaaaa aaaaaaaaaa aaaaaaaaaa


 


2401
aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaa






IL-17RC, transcript variant 3, is encoded by the following amino acid sequence (NCBI Accession No. NM_032732 and SEQ ID NO: 22):







MPVPWFLLSLALGRSPVVLSLERLVGPQDATHCSPGLSCRLWDSDILCLP


 


GDIVPAPGPVLAPTHLQTELVLRCQKETDCDLCLRVAVHLAVHGHWEEPE


 


DEEKFGGAADSGVEEPRNASLQAQVVLSFQAYPTARCVLLEVQVPAALVQ


 


FGQSVGSVVYDCFEAALGSEVRIWSYTQPRYEKELNHTQQLPALPWLNVS


 


ADGDNVHLVLNVSEEQHFGLSLYWNQVQGPPKPRWHKNLTGPQIITLNHT


 


DLVPCLCIQVWPLEPDSVRTNICPFREDPRAHQNLWQAARLRLLTLQSWL


 


LDAPCSLPAEAALCWRAPGGDPCQPLVPPLSWENVTVDKVLEFPLLKGHP


 


NLCVQVNSSEKLQLQECLWADSLGPLKDDVLLLETRGPQDNRSLCALEPS


 


GCTSLPSKASTRAARLGEYLLQDLQSGQCLQLWDDDLGALWACPMDKYIH


 


KRWALVWLACLLFAAALSLILLLKKDHAKGWLRLLKQDVRSGAAARGRAA


 


LLLYSADDSGFERLVGALASALCQLPLRVAVDLWSRRELSAQGPVAWFHA


 


QRRQTLQEGGVVVLLFSPGAVALCSEWLQDGVSGPGAHGPHDAFRASLSC


 


VLPDFLQGRAPGSYVGACFDRLLHPDAVPALFRTVPVFTLPSQLPDFLGA


 


LQQPRAPRSGRLQERAEQVSRALQPALDSYFHPPGTPAPGRGVGPGAGPG


 


AGDGT






IL-17RD, transcript 1, is encoded by the following mRNA sequence (NCBI Accession No. NM_001080973 and SEQ ID NO: 23):









   1
gcggccgccg cggccaccgc ccactcgggg ctggccagcg gcgggcggcc ggggcgcaga



 


  61
gaacggcctg gctgggcgag cgcacggccA TGgccccgtg gctgcagctc tgctccgtct


 


 121
tctttacggt caacgcctgc ctcaacggct cgcagctggc tgtggccgct ggcgggtccg


 


 181
gccgcgcgcg gggcgccgac acctgtggct ggaggggagt ggggccagcc agcagaaaca


 


 241
gtgggctgta caacatcacc ttcaaatatg acaattgtac cacctacttg aatccagtgg


 


 301
ggaagcatgt gattgctgac gcccagaata tcaccatcag ccagtatgct tgccatgacc


 


 361
aagtggcagt caccattctt tggtccccag gggccctcgg catcgaattc ctgaaaggat


 


 421
ttcgggtaat actggaggag ctgaagtcgg agggaagaca gtgccaacaa ctgattctaa


 


 481
aggatccgaa gcagctcaac agtagcttca aaagaactgg aatggaatct caacctttcc


 


 541
tgaatatgaa atttgaaacg gattatttcg taaaggttgt cccttttcct tccattaaaa


 


 601
acgaaagcaa ttaccaccct ttcttcttta gaacccgagc ctgtgacctg ttgttacagc


 


 661
cggacaatct agcttgtaaa cccttctgga agcctcggaa cctgaacatc agccagcatg


 


 721
gctcggacat gcaggtgtcc ttcgaccatg caccgcacaa cttcggcttc cgtttcttct


 


 781
atcttcacta caagctcaag cacgaaggac ctttcaagcg aaagacctgt aagcaggagc


 


 841
aaactacaga gacgaccagc tgcctccttc aaaatgtttc tccaggggat tatataattg


 


 901
agctggtgga tgacactaac acaacaagaa aagtgatgca ttatgcctta aagccagtgc


 


 961
actccccgtg ggccgggccc atcagagccg tggccatcac agtgccactg gtagtcatat


 


1021
cggcattcgc gacgctcttc actgtgatgt gccgcaagaa gcaacaagaa aatatatatt


 


1081
cacatttaga tgaagagagc tctgagtctt ccacatacac tgcagcactc ccaagagaga


 


1141
ggctccggcc gcggccgaag gtctttctct gctattccag taaagatggc cagaatcaca


 


1201
tgaatgtcgt ccagtgtttc gcctacttcc tccaggactt ctgtggctgt gaggtggctc


 


1261
tggacctgtg ggaagacttc agcctctgta gagaagggca gagagaatgg gtcatccaga


 


1321
agatccacga gtcccagttc atcattgtgg tttgttccaa aggtatgaag tactttgtgg


 


1381
acaagaagaa ctacaaacac aaaggaggtg gccgaggctc ggggaaagga gagctcttcc


 


1441
tggtggcggt gtcagccatt gccgaaaagc tccgccaggc caagcagagt tcgtccgcgg


 


1501
cgctcagcaa gtttatcgcc gtctactttg attattcctg cgagggagac gtccccggta


 


1561
tcctagacct gagtaccaag tacagactca tggacaatct tcctcagctc tgttcccact


 


1621
tgcactcccg agaccacggc ctccaggagc cggggcagca cacgcgacag ggcagcagaa


 


1681
ggaactactt ccggagcaag tcaggccggt ccctatacgt cgccatttgc aacatgcacc


 


1741
agtttattga cgaggagccc gactggttcg aaaagcagtt cgttcccttc catcctcctc


 


1801
cactgcgcta ccgggagcca gtcttggaga aatttgattc gggcttggtt ttaaatgatg


 


1861
tcatgtgcaa accagggcct gagagtgact tctgcctaaa ggtagaggcg gctgttcttg


 


1921
gggcaaccgg accagccgac tcccagcacg agagtcagca tgggggcctg gaccaagacg


 


1981
gggaggcccg gcctgccctt gacggtagcg ccgccctgca acccctgctg cacacggtga


 


2041
aagccggcag cccctcggac atgccgcggg actcaggcat ctatgactcg tctgtgccct


 


2101
catccgagct gtctctgcca ctgatggaag gactctcgac ggaccagaca gaaacgtctt


 


2161
ccctgacgga gagcgtgtcc tcctcttcag gcctgggtga ggaggaacct cctgcccttc


 


2221
cttccaagct cctctcttct gggtcatgca aagcagatct tggttgccgc agctacactg


 


2281
atgaactcca cgcggtcgcc cctttgtaac aaaacgaaag agtctaagca ttgccacttt


 


2341
agctgctgcc tccctctgat tccccagctc atctccctgg ttgcatggcc cacttggagc


 


2401
tgaggtctca tacaaggata tttggagtga aatgctggcc agtacttgtt ctcccttgcc


 


2461
ccaacccttt accggatatc ttgacaaact ctccaatttt ctaaaatgat atggagctct


 


2521
gaaaggcatg tccataaggt ctgacaacag cttgccaaat ttggttagtc cttggatcag


 


2581
agcctgttgt gggaggtagg gaggaaatat gtaaagaaaa acaggaagat acctgcacta


 


2641
atcattcaga cttcattgag ctctgcaaac tttgcctgtt tgctattggc taccttgatt


 


2701
tgaaatgctt tgtgaaaaaa ggcactttta acatcatagc cacagaaatc aagtgccagt


 


2761
ctatctggaa tccatgttgt attgcagata atgttctcat ttatttttga tgtagaattt


 


2821
acattgccat gggtgttaaa taagctttga gtcaaaagtc aagaaagtga ctgaatatac


 


2881
agtcaccttt tatgaaatga gtctctgtgt tactgggtgg catgactgat tgaggtgaag


 


2941
ctcacggggc caggctgacc gtcttgaccg ttccacttga gataggttgg tcatcgtgca


 


3001
gaaggcccca ggacctcagc acacacagcc tcctcttggt ctgagtaggc atcatgtggg


 


3061
ggccagatct gcctgctgtt tccatgggtt acatttactg tgctgtatct cagatgttgg


 


3121
tgtctggaag tttattctta agagactgct acccagctgg tctgtattat tggaagttgc


 


3181
agttcgtgct ttggttggcc ttctggtcta aagctgtgtc ctgaatatta gggatcacaa


 


3241
ttcactgaaa tacagcagtg tgtggaggtg atggccagtt aatctgctga actggttttg


 


3301
actaatgaca aacctctttt taagatggta gaatggaggt gatagtcaca aaagtaaatg


 


3361
ttccattttt atgaatgact ttctacagag tttctatttc taaagaaaaa acaattgttc


 


3421
acatcccatc tgatgattag catgtgtgta atgaatgctg tcttggtctc ccctgtggaa


 


3481
acccttctcc ctgtgcctta gagcaggtgt gtacatctct cactaccttt ctcatgggtg


 


3541
ctgttagatt ttggcacccg ttttctcagc attcagccca gggaatgtgg ttttcacttc


 


3601
ttcgtcagat aagaccaaca tgaaggggta tgttgagaaa catcctgagg caaggtggga


 


3661
ggtgggatgg gacaggactt tcccttccaa gcacatgcat ggcaggtggg gaaagggggg


 


3721
cttgcacccc tgctggaaag aaaaggtttg tgtatatttc tgatgcaaat gtcatactca


 


3781
ctgctctgta aaggcagctg gcagcttttt gggaaaagaa cgtgctcgtc tgttctctgg


 


3841
catcaagttt cttgcagctg ctctgaggga gagacagtga gctgcaagac tgcctcccca


 


3901
taacaacagg caactcagag aagagtcatt ttatgttgtt cctatggaat ctggaatgag


 


3961
tgcagagctc ctacccacac atgactgccc cgccatttca tcctaggcat tctgtgaagg


 


4021
agattggtta gtccaaactt gctaacatac gaaaattcac ttggaacatg atgagagatt


 


4081
tcttattgag gccaagagat gtttcctgtc ccagaggaac cattaggagt cgcttttagg


 


4141
gtattcagct ttgttcatga aataaggcat ctctgagaaa gtggccccag ggagagaatg


 


4201
gaggactggg aggagaagca ttaactgagc tccaagggtg tgtgggcaga gagcttgcta


 


4261
tgtgaactca ctccttaaga aaatggaaga gaaaaagaga gtgctagtta aaaaatcggg


 


4321
atgttttagt ttggatttag ggttttgata cttatgttga aatactaatg tttctgatca


 


4381
ataaaatcaa actcttaata taccgagtaa tgaaaccata gtgtgattgc ctcagaataa


 


4441
attgagaagt ccaacttcct agttttgttt aattagtttc actttttcta ctctccccag


 


4501
tatgctagaa atgggaatcg ttgccctgca gattacggca aaacatctgt tttaagcaaa


 


4561
gctgcatttt ttgactcaga aattgtccca gacggtggat ataagatgaa attcagaaaa


 


4621
acgttctgcc aagtcacagg cttttagata ttatggaaac aagaaatgga aaacaggatg


 


4681
atctccatga gaggccttga tcctgagagt aaaaggcttg tgtagatagg ttagacaacg


 


4741
tcctctagaa aagagaccag ggataagtcc aggtttccag gaaaaccaag aagcctgcgg


 


4801
gtagctgaag gtagagtgct agttgttcat cttaacttac caatgagcta cagaaaggac


 


4861
ttagcatctg atgtcatcag ctttgccagg agagtgatca aggaggttaa agctcaggta


 


4921
aaggtgtgcc ttctcagaga ttggctacaa gcaacagaga ccacctcaac agagaccacc


 


4981
tcaacagact cagcccagcc atacaaggtg ccaaagctcc tccagagggc tgtcttgggc


 


5041
ctttgaggca attgatctcc agaaagagtc agaagtcatt ccagtccagg cccaggtatt


 


5101
cagatggtga cccagccaga taatagtatc ttgagcaaat aatagtatct tgagtgcaaa


 


5161
taagcaggaa gactgtcctt caaaaaatgt ggggttacat gattttcaga gccttttttt


 


5221
cagagttgag catcttttct tttaaaagaa ataaggggca agaggaccaa ttttattcct


 


5281
tgaggaaaaa tgacacaccc ttctcccaaa agaaagaaaa ctctctggcc ccccaacttc


 


5341
aacactaatt tggctccctg aagaagagag aaaatattat ttctgtcttt attgaagaga


 


5401
aatgggcaat gccaatgtga aggttactag tcttttttat tttctattgg tgaagactac


 


5461
tactgctctt atttagcaga tcttatacct tcagtggtca ccagtatagc aggtgaggta


 


5521
taaggaaaac agcagtgtga tgataaatgg taattaatat actttgtctg tgtcagcaat


 


5581
agggaatggt ggggactgtg gcaaactgaa gcgcccctgt tccacccaca gtgggtaatt


 


5641
ttccagtcga ctgtggccat gaagtacttc ctgatcttcc catttttcaa gaaaagctga


 


5701
caatctggat ttttatatga aaaattctga ttttaaaaaa tattggcaac taagttaaaa


 


5761
ttcaagtgaa tttagaccca gcagaagaca tggatggacc tgatttggtc cactgactac


 


5821
cagtttgtta acctgtgctt tataagattt gaaggaaagg cattcatggt aattacagac


 


5881
ggtgccacca gaaaatgctc ttgctaaatg cagccagtag ttagattgct tctttctcca


 


5941
gtctcccccg caaagaaatt tgacgtgatt ctgaatgcac tggacatgtc ttgattgcgt


 


6001
ctttacattt cacagtgtct taaaagaaag gcaagccagt tgttaatttc agaatcagat


 


6061
ttatgctctc tcaatttaaa aaatgctggg aacaatttca tttttttttt tttgagatgg


 


6121
agtcttgctc tgttgcccag gctggagtgc agtggcgtga tctcggctca ctgcaagctc


 


6181
cacctcccgg gttcacgcca ttctcctgcc tcagcctcct gagtagctgg gactacaggc


 


6241
gcccaccacc acgcctggct aatttttttg tatttttagt agagacgggg tttcactgtg


 


6301
ttagccagga tgatctcgat ctcctgacct ggtgatccgc ttgcctcggc ctcccaaagt


 


6361
gctgggatta caggcgtgag ccactgcgcc cggcctaaca atttcattta aactccacaa


 


6421
cctaaagggc tttgtttata gttttagctc ttggcataat ttttttcagg tggtgtgcaa


 


6481
ttctgagcat aggccaagac atgattagga aagcaggcag ttgtagagag taaggcaagg


 


6541
aacctcctag cgtccattag agccaggtat ttgcattatc ttccgtttta agtggtctgt


 


6601
gaattgactg tgttttggag gtgtgaaaca gtatacagag aaaagctttt cctgatactg


 


6661
agatatcagt taggagtcca aatggggtgt tgggtcatcc ttgccatatc acctcctttc


 


6721
caggctcaga gtgaaaatag acaaaaggaa atctgactgc aagccagtgg ctttgattcc


 


6781
agtttcagag tttagggact aggagagagt ttagattatc tagcatattc tccccctggt


 


6841
gtcagacagg gctgtgcctg aattattcca gacatatggc tgtagatggt attctttatt


 


6901
ttataagaag gagattctgt aacctaccct gctgatcaga tagttctttg tatgtcttag


 


6961
agaaattcaa gccagcttcc ttttgttcgg cttgtagtgg agaaagaaca gctggtcacc


 


7021
ttccatgtat tcaaaaacca cagtgaagtc atccccctgg tgtttttatt tcagtgataa


 


7081
ataattccac ccacttaaac cattcttcat ggctcttgtt ttccaggggc ctaataattt


 


7141
tcactgctgt aatgtttctc agcttcacac ttagtttagt tgcccaaaca atgttggtgc


 


7201
cttactcaca ttggtgcctt gtgaagacga ggctcaggat ggggattatg gggaaattct


 


7261
tgcacaccca gctcctctta ccacttaaaa atataatggc actttcacaa aatgatatgt


 


7321
cacctatatt cattgagaat tatttgactg ccacattttt cccctgatga tagtcatcta


 


7381
tcataacttg tgtttgtttt cctcctgaga tcaaacactt ggtgcttatt cctgatgtat


 


7441
actctgagac cagctcttac cttctgagtg gcagctaccc ctccctccca attttagatc


 


7501
ctatttttac acatctctat agatatcacc tttatttcat gactcacaat attaaatggt


 


7561
acagacttca gtttaaccac tggtgtggta acagcagtag ttgctaagta ccaccttccc


 


7621
attgctgttt gagggctaat ttgcaaagac atttgaatct cccagtgaag atgtctgggg


 


7681
aattttggcc agttgtcttc cctcttgccc ttttgttctt taaaattcag cttggaccat


 


7741
agacacctcc aggatcttgt ttatgttctg ctctcaattg accaagcact gcgttttgca


 


7801
caatcagaag tctcacaaaa gcaaacagtt atgactgcat atctgatgtt tatatcctat


 


7861
aaaatttcag gaagattcag agtcaatctt ctatttgtac atgatgtaga caaaattagc


 


7921
tgctccaatt gttagacaaa aaattgccat tggattacac taatgtgctc atctgttgtt


 


7981
ttaaaagttt ggtatcaggc ggggcacggt ggctcacgcc tgtaatccca gcattttggg


 


8041
aggccaaggt gggcggatca cctgaggtcc agagttcaag accagcctga ccaacatggt


 


8101
gaaaccctgt ctctactaaa aatacaaaat taatcaggcg tggttgtgtg tgcctgtaat


 


8161
cccagctact cgagaggctg aggcaggaga atcgcttgaa tccgggaggc agaggttgca


 


8221
gtgagctgag atcacgccat tgcactctag cctgggcaac aagagcgaaa ctccgtctca


 


8281
acaacaacaa caaaaagttt ggtatgtttc tctcaagaaa aaagcatggt gagtccagac


 


8341
agcagcaaaa gcttttgtga aaaccaattg tgttcatcta gatagtaagt aactcctatt


 


8401
tttactgtta attttttaaa agagaatttt tccctgtgga aactccctgt tagtacgtcc


 


8461
taggggagaa agcctgtgga atatggtggt tattgatggc gttgcctttg tttcatcttt


 


8521
gagtttgccc tttgtgggat ctagtgggat aatgagcact gacagaactc ttaacagcgt


 


8581
gctgtatttt tgacattgaa aatgttaatg acttgatttg tacataactc tgtaactagg


 


8641
tgaaagtaga tcacagctga catttacaaa atgtttttgt accttagaat ttctgcatta


 


8701
aataaaatgt tttgttttaa






IL-17RD, transcript 1, is encoded by the following amino acid sequence (NCBI Accession No. NM_001080973 and SEQ ID NO: 24):







MAPWLQLCSVFFTVNACLNGSQLAVAAGGSGRARGADTCGWRGVGPASRN


 


SGLYNITFKYDNCTTYLNPVGKHVIADAQNITISQYACHDQVAVTILWSP


 


GALGIEFLKGFRVILEELKSEGRQCQQLILKDPKQLNSSFKRTGMESQPF


 


LNMKFETDYFVKVVPFPSIKNESNYHPFFFRTRACDLLLQPDNLACKPFW


 


KPRNLNISQHGSDMQVSFDHAPHNFGFRFFYLHYKLKHEGPFKRKTCKQE


 


QTTETTSCLLQNVSPGDYIIELVDDTNTTRKVMHYALKPVHSPWAGPIRA


 


VAITVPLVVISAFATLFTVMCRKKQQENIYSHLDEESSESSTYTAALPRE


 


RLRPRPKVFLCYSSKDGQNHMNVVQCFAYFLQDFCGCEVALDLWEDFSLC


 


REGQREWVIQKIHESQFIIVVCSKGMKYFVDKKNYKHKGGGRGSGKGELF


 


LVAVSAIAEKLRQAKQSSSAALSKFIAVYFDYSCEGDVPGILDLSTKYRL


 


MDNLPQLCSHLHSRDHGLQEPGQHTRQGSRRNYFRSKSGRSLYVAICNMH


 


QFIDEEPDWFEKQFVPFHPPPLRYREPVLEKFDSGLVLNDVMCKPGPESD


 


FCLKVEAAVLGATGPADSQHESQHGGLDQDGEARPALDGSAALQPLLHTV


 


KAGSPSDMPRDSGIYDSSVPSSELSLPLMEGLSTDQTETSSLTESVSSSS


 


GLGEEEPPALPSKLLSSGSCKADLGCRSYTDELHAVAPL






IL-17RD, transcript 2, is encoded by the following mRNA sequence (NCBI Accession No. NM_017563 and SEQ ID NO: 25, note that this sequence contains an alternative start codon from nucleotide position 208-210):









   1
atccgctctt cttttcctcc gggaaaagaa acgggaagtg gccgtgggcc ggtgaattcc



 


  61
gtgtagtggc caagctttgt tccaaagagg gggaggtggt gacagtctct tgcccactga


 


 121
agcgtgccag acagagtgct aggcatgggg gcagaggtga atcagatgac agccacctct


 


 181
caccacgagg agtggctgaa agtgtgaCTG gactacaggc aatcctggcc ttggcaggga


 


 241
gtggggccag ccagcagaaa cagtgggctg tacaacatca ccttcaaata tgacaattgt


 


 301
accacctact tgaatccagt ggggaagcat gtgattgctg acgcccagaa tatcaccatc


 


 361
agccagtatg cttgccatga ccaagtggca gtcaccattc tttggtcccc aggggccctc


 


 421
ggcatcgaat tcctgaaagg atttcgggta atactggagg agctgaagtc ggagggaaga


 


 481
cagtgccaac aactgattct aaaggatccg aagcagctca acagtagctt caaaagaact


 


 541
ggaatggaat ctcaaccttt cctgaatatg aaatttgaaa cggattattt cgtaaaggtt


 


 601
gtcccttttc cttccattaa aaacgaaagc aattaccacc ctttcttctt tagaacccga


 


 661
gcctgtgacc tgttgttaca gccggacaat ctagcttgta aacccttctg gaagcctcgg


 


 721
aacctgaaca tcagccagca tggctcggac atgcaggtgt ccttcgacca tgcaccgcac


 


 781
aacttcggct tccgtttctt ctatcttcac tacaagctca agcacgaagg acctttcaag


 


 841
cgaaagacct gtaagcagga gcaaactaca gagacgacca gctgcctcct tcaaaatgtt


 


 901
tctccagggg attatataat tgagctggtg gatgacacta acacaacaag aaaagtgatg


 


 961
cattatgcct taaagccagt gcactccccg tgggccgggc ccatcagagc cgtggccatc


 


1021
acagtgccac tggtagtcat atcggcattc gcgacgctct tcactgtgat gtgccgcaag


 


1081
aagcaacaag aaaatatata ttcacattta gatgaagaga gctctgagtc ttccacatac


 


1141
actgcagcac tcccaagaga gaggctccgg ccgcggccga aggtctttct ctgctattcc


 


1201
agtaaagatg gccagaatca catgaatgtc gtccagtgtt tcgcctactt cctccaggac


 


1261
ttctgtggct gtgaggtggc tctggacctg tgggaagact tcagcctctg tagagaaggg


 


1321
cagagagaat gggtcatcca gaagatccac gagtcccagt tcatcattgt ggtttgttcc


 


1381
aaaggtatga agtactttgt ggacaagaag aactacaaac acaaaggagg tggccgaggc


 


1441
tcggggaaag gagagctctt cctggtggcg gtgtcagcca ttgccgaaaa gctccgccag


 


1501
gccaagcaga gttcgtccgc ggcgctcagc aagtttatcg ccgtctactt tgattattcc


 


1561
tgcgagggag acgtccccgg tatcctagac ctgagtacca agtacagact catggacaat


 


1621
cttcctcagc tctgttccca cttgcactcc cgagaccacg gcctccagga gccggggcag


 


1681
cacacgcgac agggcagcag aaggaactac ttccggagca agtcaggccg gtccctatac


 


1741
gtcgccattt gcaacatgca ccagtttatt gacgaggagc ccgactggtt cgaaaagcag


 


1801
ttcgttccct tccatcctcc tccactgcgc taccgggagc cagtcttgga gaaatttgat


 


1861
tcgggcttgg ttttaaatga tgtcatgtgc aaaccagggc ctgagagtga cttctgccta


 


1921
aaggtagagg cggctgttct tggggcaacc ggaccagccg actcccagca cgagagtcag


 


1981
catgggggcc tggaccaaga cggggaggcc cggcctgccc ttgacggtag cgccgccctg


 


2041
caacccctgc tgcacacggt gaaagccggc agcccctcgg acatgccgcg ggactcaggc


 


2101
atctatgact cgtctgtgcc ctcatccgag ctgtctctgc cactgatgga aggactctcg


 


2161
acggaccaga cagaaacgtc ttccctgacg gagagcgtgt cctcctcttc aggcctgggt


 


2221
gaggaggaac ctcctgccct tccttccaag ctcctctctt ctgggtcatg caaagcagat


 


2281
cttggttgcc gcagctacac tgatgaactc cacgcggtcg cccctttgta acaaaacgaa


 


2341
agagtctaag cattgccact ttagctgctg cctccctctg attccccagc tcatctccct


 


2401
ggttgcatgg cccacttgga gctgaggtct catacaagga tatttggagt gaaatgctgg


 


2461
ccagtacttg ttctcccttg ccccaaccct ttaccggata tcttgacaaa ctctccaatt


 


2521
ttctaaaatg atatggagct ctgaaaggca tgtccataag gtctgacaac agcttgccaa


 


2581
atttggttag tccttggatc agagcctgtt gtgggaggta gggaggaaat atgtaaagaa


 


2641
aaacaggaag atacctgcac taatcattca gacttcattg agctctgcaa actttgcctg


 


2701
tttgctattg gctaccttga tttgaaatgc tttgtgaaaa aaggcacttt taacatcata


 


2761
gccacagaaa tcaagtgcca gtctatctgg aatccatgtt gtattgcaga taatgttctc


 


2821
atttattttt gatgtagaat ttacattgcc atgggtgtta aataagcttt gagtcaaaag


 


2881
tcaagaaagt gactgaatat acagtcacct tttatgaaat gagtctctgt gttactgggt


 


2941
ggcatgactg attgaggtga agctcacggg gccaggctga ccgtcttgac cgttccactt


 


3001
gagataggtt ggtcatcgtg cagaaggccc caggacctca gcacacacag cctcctcttg


 


3061
gtctgagtag gcatcatgtg ggggccagat ctgcctgctg tttccatggg ttacatttac


 


3121
tgtgctgtat ctcagatgtt ggtgtctgga agtttattct taagagactg ctacccagct


 


3181
ggtctgtatt attggaagtt gcagttcgtg ctttggttgg ccttctggtc taaagctgtg


 


3241
tcctgaatat tagggatcac aattcactga aatacagcag tgtgtggagg tgatggccag


 


3301
ttaatctgct gaactggttt tgactaatga caaacctctt tttaagatgg tagaatggag


 


3361
gtgatagtca caaaagtaaa tgttccattt ttatgaatga ctttctacag agtttctatt


 


3421
tctaaagaaa aaacaattgt tcacatccca tctgatgatt agcatgtgtg taatgaatgc


 


3481
tgtcttggtc tcccctgtgg aaacccttct ccctgtgcct tagagcaggt gtgtacatct


 


3541
ctcactacct ttctcatggg tgctgttaga ttttggcacc cgttttctca gcattcagcc


 


3601
cagggaatgt ggttttcact tcttcgtcag ataagaccaa catgaagggg tatgttgaga


 


3661
aacatcctga ggcaaggtgg gaggtgggat ggggcaggac tttcccttcc aagcacatgc


 


3721
atggcaggtg gggaaagggg ggcttgcacc cctgctggaa agaaaaggtt tgtgtatatt


 


3781
tctgatgcaa atgtcatact cactgctctg taaaggcagc tggcagcttt ttgggaaaag


 


3841
aacgtgctcg tctgttctct ggcatcaagt ttcttgcagc tgctctgagg gagagacagt


 


3901
gagctgcaag actgcctccc cataacaaca ggcaactcag agaagagtca ttttatgttg


 


3961
ttcctatgga atctggaatg agtgcagagc tcctacccac acatgactgc cccgccattt


 


4021
catcctaggc attctgtgaa ggagattggt tagtccaaac ttgctaacat acgaaaattc


 


4081
acttggaaca tgatgagaga tttcttattg aggccaagag atgtttcctg tcccagagga


 


4141
accattagga gtcgctttta gggtattcag ctttgttcat gaaataaggc atctctgaga


 


4201
aagtggcccc agggagagaa tggaggactg ggaggagaag cattaactga gctccaaggg


 


4261
tgtgtgggca gagagcttgc tatgtgaact cactccttaa gaaaatggaa gagaaaaaga


 


4321
gagtgctagt taaaaaatcg ggatgtttta gtttggattt agggttttga tacttatgtt


 


4381
gaaatactaa tgtttctgat caataaaatc aaactcttaa tataccgagt aatgaaacca


 


4441
tagtgtgatt gcctcagaat aaattgagaa gtccaacttc ctagttttgt ttaattagtt


 


4501
tcactttttc tactctcccc agtatgctag aaatgggaat cgttgccctg cagattacgg


 


4561
caaaacatct gttttaagca aagctgcatt ttttgactca gaaattgtcc cagacggtgg


 


4621
atataagatg aaattcagaa aaacgttctg ccaagtcaca ggcttttaga tattatggaa


 


4681
acaagaaatg gaaaacagga tgatctccat gagaggcctt gatcctgaga gtaaaaggct


 


4741
tgtgtagata ggttagacaa cgtcctctag aaaagagacc agggataagt ccaggtttcc


 


4801
aggaaaacca agaagcctgc gggtagctga aggtagagtg ctagttgttc atcttaactt


 


4861
accaatgagc tacagaaagg acttagcatc tgatgtcatc agctttgcca ggagagtgat


 


4921
caaggaggtt aaagctcagg taaaggtgtg ccttctcaga gattggctac aagcaacaga


 


4981
gaccacctca acagagacca cctcaacaga ctcagcccag ccatacaagg tgccaaagct


 


5041
cctccagagg gctgtcttgg gcctttgagg caattgatct ccagaaagag tcagaagtca


 


5101
ttccagtcca ggcccaggta ttcagatggt gacccagcca gataatagta tcttgagcaa


 


5161
ataatagtat cttgagtgca aataagcagg aagactgtcc ttcaaaaaat gtggggttac


 


5221
atgattttca gagccttttt ttcagagttg agcatctttt cttttaaaag aaataagggg


 


5281
caagaggacc aattttattc cttgaggaaa aatgacacac ccttctccca aaagaaagaa


 


5341
aactctctgg ccccccaact tcaacactaa tttggctccc tgaagaagag agaaaatatt


 


5401
atttctgtct ttattgaaga gaaatgggca atgccaatgt gaaggttact agtctttttt


 


5461
attttctatt ggtgaagact actactgctc ttatttagca gatcttatac cttcagtggt


 


5521
caccagtata gcaggtgagg tataaggaaa acagcagtgt gatgataaat ggtaattaat


 


5581
atactttgtc tgtgtcagca atagggaatg gtggggactg tggcaaactg aagcgcccct


 


5641
gttccaccca cagtgggtaa ttttccagtc gactgtggcc atgaagtact tcctgatctt


 


5701
cccatttttc aagaaaagct gacaatctgg atttttatat gaaaaattct gattttaaaa


 


5761
aatattggca actaagttaa aattcaagtg aatttagacc cagcagaaga catggatgga


 


5821
cctgatttgg tccactgact accagtttgt taacctgtgc tttataagat ttgaaggaaa


 


5881
ggcattcatg gtaattacag acggtgccac cagaaaatgc tcttgctaaa tgcagccagt


 


5941
agttagattg cttctttctc cagtctcccc cgcaaagaaa tttgacgtga ttctgaatgc


 


6001
actggacatg tcttgattgc gtctttacat ttcacagtgt cttaaaagaa aggcaagcca


 


6061
gttgttaatt tcagaatcag atttatgctc tctcaattta aaaaatgctg ggaacaattt


 


6121
catttttttt tttttgagat ggagtcttgc tctgttgccc aggctggagt gcagtggcgt


 


6181
gatctcggct cactgcaagc tccacctccc gggttcacgc cattctcctg cctcagcctc


 


6241
ctgagtagct gggactacag gcgcccacca ccacgcctgg ctaatttttt tgtattttta


 


6301
gtagagacgg ggtttcactg tgttagccag gatgatctcg atctcctgac ctggtgatcc


 


6361
gcttgcctcg gcctcccaaa gtgctgggat tacaggcgtg agccactgcg cccggcctaa


 


6421
caatttcatt taaactccac aacctaaagg gctttgttta tagttttagc tcttggcata


 


6481
atttttttca ggtggtgtgc aattctgagc ataggccaag acatgattag gaaagcaggc


 


6541
agttgtagag agtaaggcaa ggaacctcct agcgtccatt agagccaggt atttgcatta


 


6601
tcttccgttt taagtggtct gtgaattgac tgtgttttgg aggtgtgaaa cagtatacag


 


6661
agaaaagctt ttcctgatac tgagatatca gttaggagtc caaatggggt gttgggtcat


 


6721
ccttgccata tcacctcctt tccaggctca gagtgaaaat agacaaaagg aaatctgact


 


6781
gcaagccagt ggctttgatt ccagtttcag agtttaggga ctaggagaga gtttagatta


 


6841
tctagcatat tctccccctg gtgtcagaca gggctgtgcc tgaattattc cagacatatg


 


6901
gctgtagatg gtattcttta ttttataaga aggagattct gtaacctacc ctgctgatca


 


6961
gatagttctt tgtatgtctt agagaaattc aagccagctt ccttttgttc ggcttgtagt


 


7021
ggagaaagaa cagctggtca ccttccatgt attcaaaaac cacagtgaag tcatccccct


 


7081
ggtgttttta tttcagtgat aaataattcc acccacttaa accattcttc atggctcttg


 


7141
ttttccaggg gcctaataat tttcactgct gtaatgtttc tcagcttcac acttagttta


 


7201
gttgcccaaa caatgttggt gccttactca cattggtgcc ttgtgaagac gaggctcagg


 


7261
atggggatta tggggaaatt cttgcacacc cagctcctct taccacttaa aaatataatg


 


7321
gcactttcac aaaatgatat gtcacctata ttcattgaga attatttgac tgccacattt


 


7381
ttcccctgat gatagtcatc tatcataact tgtgtttgtt ttcctcctga gatcaaacac


 


7441
ttggtgctta ttcctgatgt atactctgag accagctctt accttctgag tggcagctac


 


7501
ccctccctcc caattttaga tcctattttt acacatctct atagatatca cctttatttc


 


7561
atgactcaca atattaaatg gtacagactt cagtttaacc actggtgtgg taacagcagt


 


7621
agttgctaag taccaccttc ccattgctgt ttgagggcta atttgcaaag acatttgaat


 


7681
ctcccagtga agatgtctgg ggaattttgg ccagttgtct tccctcttgc ccttttgttc


 


7741
tttaaaattc agcttggacc atagacacct ccaggatctt gtttatgttc tgctctcaat


 


7801
tgaccaagca ctgcgttttg cacaatcaga agtctcacaa aagcaaacag ttatgactgc


 


7861
atatctgatg tttatatcct ataaaatttc aggaagattc agagtcaatc ttctatttgt


 


7921
acatgatgta gacaaaatta gctgctccaa ttgttagaca aaaaattgcc attggattac


 


7981
actaatgtgc tcatctgttg ttttaaaagt ttggtatcag gcggggcacg gtggctcacg


 


8041
cctgtaatcc cagcattttg ggaggccaag gtgggcggat cacctgaggt ccagagttca


 


8101
agaccagcct gaccaacatg gtgaaaccct gtctctacta aaaatacaaa attaatcagg


 


8161
cgtggttgtg tgtgcctgta atcccagcta ctcgagaggc tgaggcagga gaatcgcttg


 


8221
aatccgggag gcagaggttg cagtgagctg agatcacgcc attgcactct agcctgggca


 


8281
acaagagcga aactccgtct caacaacaac aacaaaaagt ttggtatgtt tctctcaaga


 


8341
aaaaagcatg gtgagtccag acagcagcaa aagcttttgt gaaaaccaat tgtgttcatc


 


8401
tagatagtaa gtaactccta tttttactgt taatttttta aaagagaatt tttccctgtg


 


8461
gaaactccct gttagtacgt cctaggggag aaagcctgtg gaatatggtg gttattgatg


 


8521
gcgttgcctt tgtttcatct ttgagtttgc cctttgtggg atctagtggg ataatgagca


 


8581
ctgacagaac tcttaacagc gtgctgtatt tttgacattg aaaatgttaa tgacttgatt


 


8641
tgtacataac tctgtaacta ggtgaaagta gatcacagct gacatttaca aaatgttttt


 


8701
gtaccttaga atttctgcat taaataaaat gttttgtttt aa






IL-17RD, transcript 2, is encoded by the following amino acid sequence (NCBI Accession No. NM_017563 and SEQ ID NO: 26):







MDYRQSWPWQGVGPASRNSGLYNITFKYDNCTTYLNPVGKHVIADAQNIT


 


ISQYACHDQVAVTILWSPGALGIEFLKGFRVILEELKSEGRQCQQLILKD


 


PKQLNSSFKRTGMESQPFLNMKFETDYFVKVVPFPSIKNESNYHPFFFRT


 


RACDLLLQPDNLACKPFWKPRNLNISQHGSDMQVSFDHAPHNFGFRFFYL


 


HYKLKHEGPFKRKTCKQEQTTETTSCLLQNVSPGDYIIELVDDTNTTRKV


 


MHYALKPVHSPWAGPIRAVAITVPLVVISAFATLFTVMCRKKQQENIYSH


 


LDEESSESSTYTAALPRERLRPRPKVFLCYSSKDGQNHMNVVQCFAYFLQ


 


DFCGCEVALDLWEDFSLCREGQREWVIQKIHESQFIIVVCSKGMKYFVDK


 


KNYKHKGGGRGSGKGELFLVAVSAIAEKLRQAKQSSSAALSKFIAVYFDY


 


SCEGDVPGILDLSTKYRLMDNLPQLCSHLHSRDHGLQEPGQHTRQGSRRN


 


YFRSKSGRSLYVAICNMHQFIDEEPDWFEKQFVPFHPPPLRYREPVLEKF


 


DSGLVLNDVMCKPGPESDFCLKVEAAVLGATGPADSQHESQHGGLDQDGE


 


ARPALDGSAALQPLLHTVKAGSPSDMPRDSGIYDSSVPSSELSLPLMEGL


 


STDQTETSSLTESVSSSSGLGEEEPPALPSKLLSSGSCKADLGCRSYTDE


 


LHAVAPL






IL-17RE, transcript variant 1, is encoded by the following mRNA sequence (NCBI Accession No. NM_153480 and SEQ ID NO: 27):









   1
cgagggctcc tgctggtact gtgttcgctg ctgcacagca aggccctgcc acccaccttc



 


  61
aggccatgca gccatgttcc gggagcccta attgcacaga agcccATGgg gagctccaga


 


 121
ctggcagccc tgctcctgcc tctcctcctc atagtcatcg acctctctga ctctgctggg


 


 181
attggctttc gccacctgcc ccactggaac acccgctgtc ctctggcctc ccacacggat


 


 241
gacagtttca ctggaagttc tgcctatatc ccttgccgca cctggtgggc cctcttctcc


 


 301
acaaagcctt ggtgtgtgcg agtctggcac tgttcccgct gtttgtgcca gcatctgctg


 


 361
tcaggtggct caggtcttca acggggcctc ttccacctcc tggtgcagaa atccaaaaag


 


 421
tcttccacat tcaagttcta taggagacac aagatgccag cacctgctca gaggaagctg


 


 481
ctgcctcgtc gtcacctgtc tgagaagagc catcacattt ccatcccctc cccagacatc


 


 541
tcccacaagg gacttcgctc taaaaggacc caaccttcgg atccagagac atgggaaagt


 


 601
cttcccagat tggactcaca aaggcatgga ggacccgagt tctcctttga tttgctgcct


 


 661
gaggcccggg ctattcgggt gaccatatct tcaggccctg aggtcagcgt gcgtctttgt


 


 721
caccagtggg cactggagtg tgaagagctg agcagtccct atgatgtcca gaaaattgtg


 


 781
tctgggggcc acactgtaga gctgccttat gaattccttc tgccctgtct gtgcatagag


 


 841
gcatcctacc tgcaagagga cactgtgagg cgcaaaaaat gtcccttcca gagctggcca


 


 901
gaagcctatg gctcggactt ctggaagtca gtgcacttca ctgactacag ccagcacact


 


 961
cagatggtca tggccctgac actccgctgc ccactgaagc tggaagctgc cctctgccag


 


1021
aggcacgact ggcataccct ttgcaaagac ctcccgaatg ccacagctcg agagtcagat


 


1081
gggtggtatg ttttggagaa ggtggacctg cacccccagc tctgcttcaa gttctctttt


 


1141
ggaaacagca gccatgttga atgcccccac cagactgggt ctctcacatc ctggaatgta


 


1201
agcatggata cccaagccca gcagctgatt cttcacttct cctcaagaat gcatgccacc


 


1261
ttcagtgctg cctggagcct cccaggcttg gggcaggaca ctttggtgcc ccccgtgtac


 


1321
actgtcagcc aggcccgggg ctcaagccca gtgtcactag acctcatcat tcccttcctg


 


1381
aggccagggt gctgtgtcct ggtgtggcgg tcagatgtcc agtttgcctg gaagcacctc


 


1441
ttgtgtccgg atgtctctta cagacacctg gggctcttga tcctggcact gctggccctc


 


1501
ctcaccctac tgggtgttgt tctggccctc acctgccggc gcccacagtc aggcccgggc


 


1561
ccagcgcggc cagtgctcct cctgcacgcg gcggactcgg aggcgcagcg gcgcctggtg


 


1621
ggagcgctgg ctgaactgct acgggcagcg ctgggcggcg ggcgcgacgt gatcgtggac


 


1681
ctgtgggagg ggaggcacgt ggcgcgcgtg ggcccgctgc cgtggctctg ggcggcgcgg


 


1741
acgcgcgtag cgcgggagca gggcactgtg ctgctgctgt ggagcggcgc cgaccttcgc


 


1801
ccggtcagcg gccccgaccc ccgcgccgcg cccctgctcg ccctgctcca cgctgccccg


 


1861
cgcccgctgc tgctgctcgc ttacttcagt cgcctctgcg ccaagggcga catccccccg


 


1921
ccgctgcgcg ccctgccgcg ctaccgcctg ctgcgcgacc tgccgcgtct gctgcgggcg


 


1981
ctggacgcgc ggcctttcgc agaggccacc agctggggcc gccttggggc gcggcagcgc


 


2041
aggcagagcc gcctagagct gtgcagccgg ctcgaacgag aggccgcccg acttgcagac


 


2101
ctaggttgag cagagctcca ccgcagtccc gggtgtctgc ggccgcaacg caacggacac


 


2161
tggctggaac cccggaatga gccttcgacc ctgaaatcct tggggtgcct cgaggacgac


 


2221
tggccgaaaa gccgcattcc ctgcctcaca ggccggaagt cccagcccag tccccgcgcg


 


2281
cgtccctctt cctcctcata ctttcccttg actgagagct cctctaaccc ctgttctgat


 


2341
gggggagggc ggtcttccca cttcctctcc agaactccag aaagagcagt gtgcttatgc


 


2401
ttcagtccag gctggagagg ttggggccgg ggtagggagg caggagccat gtcagttctg


 


2461
aaggagggtg aggcggtggg ggattgcagg gggcggctga gagaaaacct ccttgggggc


 


2521
cagggattcc ctttcccact ctgaggctct ggccagaggg agagaggact ctggacctag


 


2581
gaaaagaggc ttttggctcc aggtggtcag gacagtgggg gttgggggtg gggtgggtgg


 


2641
gtgctggcgg tggggaccaa gatccggaaa gatgaataaa gacaaacatg acaaactaag


 


2701
aaaaaaaaaa aaaaaaa 






IL-17RE, transcript variant 1, is encoded by the following amino acid sequence (NCBI Accession No. NM_153480 and SEQ ID NO: 28):







MGSSRLAALLLPLLLIVIDLSDSAGIGFRHLPHWNTRCPLASHTDDSFTG


 


SSAYIPCRTWWALFSTKPWCVRVWHCSRCLCQHLLSGGSGLQRGLFHLLV


 


QKSKKSSTFKFYRRHKMPAPAQRKLLPRRHLSEKSHHISIPSPDISHKGL


 


RSKRTQPSDPETWESLPRLDSQRHGGPEFSFDLLPEARAIRVTISSGPEV


 


SVRLCHQWALECEELSSPYDVQKIVSGGHTVELPYEFLLPCLCIEASYLQ


 


EDTVRRKKCPFQSWPEAYGSDFWKSVHFTDYSQHTQMVMALTLRCPLKLE


 


AALCQRHDWHTLCKDLPNATARESDGWYVLEKVDLHPQLCFKFSFGNSSH


 


VECPHQTGSLTSWNVSMDTQAQQLILHFSSRMHATFSAAWSLPGLGQDTL


 


VPPVYTVSQARGSSPVSLDLIIPFLRPGCCVLVWRSDVQFAWKHLLCPDV


 


SYRHLGLLILALLALLTLLGVVLALTCRRPQSGPGPARPVLLLHAADSEA


 


QRRLVGALAELLRAALGGGRDVIVDLWEGRHVARVGPLPWLWAARTRVAR


 


EQGTVLLLWSGADLRPSGPDPRAAPLLALLHAAPRPLLLLAYFSRLCAKG


 


DIPPPLRALPRYRLLRDLPRLLRALDARPFAEATSWGRLGARQRRQSRLE


 


LCSRLEREAARLADLG






IL-17RE, transcript variant 2, is encoded by the following mRNA sequence (NCBI Accession No. NM_153481 and SEQ ID NO: 29):









   1
cgagggctcc tgctggtact gtgttcgctg ctgcacagca aggccctgcc acccaccttc



 


  61
aggccatgca gccatgttcc gggagcccta attgcacaga agcccatggg gagctccaga


 


 121
ctggcagccc tgctcctgcc tctcctcctc atagtcatcg acctctctga ctctgctggg


 


 181
attggctttc gccacctgcc ccactggaac acccgctgtc ctctggcctc ccacacggtc


 


 241
ttcaacgggg cctcttccac ctcctggtgc agaaatccaa aaagtcttcc acattcaagt


 


 301
tctataggag acacaagATG ccagcacctg ctcagaggaa gctgctgcct cgtcgtcacc


 


 361
tgtctgagaa gagccatcac atttccatcc cctccccaga catctcccac aagggacttc


 


 421
gctctaaaag gacccaacct tcggatccag agacatggga aagtcttccc agattggact


 


 481
cacaaaggca tggaggaccc gagttctcct ttgatttgct gcctgaggcc cgggctattc


 


 541
gggtgaccat atcttcaggc cctgaggtca gcgtgcgtct ttgtcaccag tgggcactgg


 


 601
agtgtgaaga gctgagcagt ccctatgatg tccagaaaat tgtgtctggg ggccacactg


 


 661
tagagctgcc ttatgaattc cttctgccct gtctgtgcat agaggcatcc tacctgcaag


 


 721
aggacactgt gaggcgcaaa aaatgtccct tccagagctg gccagaagcc tatggctcgg


 


 781
acttctggaa gtcagtgcac ttcactgact acagccagca cactcagatg gtcatggccc


 


 841
tgacactccg ctgcccactg aagctggaag ctgccctctg ccagaggcac gactggcata


 


 901
ccctttgcaa agacctcccg aatgccacag ctcgagagtc agatgggtgg tatgttttgg


 


 961
agaaggtgga cctgcacccc cagctctgct tcaagttctc ttttggaaac agcagccatg


 


1021
ttgaatgccc ccaccagact gggtctctca catcctggaa tgtaagcatg gatacccaag


 


1081
cccagcagct gattcttcac ttctcctcaa gaatgcatgc caccttcagt gctgcctgga


 


1141
gcctcccagg cttggggcag gacactttgg tgccccccgt gtacactgtc agccaggccc


 


1201
ggggctcaag cccagtgtca ctagacctca tcattccctt cctgaggcca gggtgctgtg


 


1261
tcctggtgtg gcggtcagat gtccagtttg cctggaagca cctcttgtgt ccggatgtct


 


1321
cttacagaca cctggggctc ttgatcctgg cactgctggc cctcctcacc ctactgggtg


 


1381
ttgttctggc cctcacctgc cggcgcccac agtcaggccc gggcccagcg cggccagtgc


 


1441
tcctcctgca cgcggcggac tcggaggcgc agcggcgcct ggtgggagcg ctggctgaac


 


1501
tgctacgggc agcgctgggc ggcgggcgcg acgtgatcgt ggacctgtgg gaggggaggc


 


1561
acgtggcgcg cgtgggcccg ctgccgtggc tctgggcggc gcggacgcgc gtagcgcggg


 


1621
agcagggcac tgtgctgctg ctgtggagcg gcgccgacct tcgcccggtc agcggccccg


 


1681
acccccgcgc cgcgcccctg ctcgccctgc tccacgctgc cccgcgcccg ctgctgctgc


 


1741
tcgcttactt cagtcgcctc tgcgccaagg gcgacatccc cccgccgctg cgcgccctgc


 


1801
cgcgctaccg cctgctgcgc gacctgccgc gtctgctgcg ggcgctggac gcgcggcctt


 


1861
tcgcagaggc caccagctgg ggccgccttg gggcgcggca gcgcaggcag agccgcctag


 


1921
agctgtgcag ccggctcgaa cgagaggccg cccgacttgc agacctaggt tgagcagagc


 


1981
tccaccgcag tcccgggtgt ctgcggccgc aacgcaacgg acactggctg gaaccccgga


 


2041
atgagccttc gaccctgaaa tccttggggt gcctcgagga cgactggccg aaaagccgca


 


2101
ttccctgcct cacaggccgg aagtcccagc ccagtccccg cgcgcgtccc tcttcctcct


 


2161
catactttcc cttgactgag agctcctcta acccctgttc tgatggggga gggcggtctt


 


2221
cccacttcct ctccagaact ccagaaagag cagtgtgctt atgcttcagt ccaggctgga


 


2281
gaggttgggg ccggggtagg gaggcaggag ccatgtcagt tctgaaggag ggtgaggcgg


 


2341
tgggggattg cagggggcgg ctgagagaaa acctccttgg gggccaggga ttccctttcc


 


2401
cactctgagg ctctggccag agggagagag gactctggac ctaggaaaag aggcttttgg


 


2461
ctccaggtgg tcaggacagt gggggttggg ggtggggtgg gtgggtgctg gcggtgggga


 


2521
ccaagatccg gaaagatgaa taaagacaaa catgacaaac taagaaaaaa aaaaaaaaaa


 


2581
a






IL-17RE, transcript variant 2, is encoded by the following amino acid sequence (NCBI Accession No. NM_153481 and SEQ ID NO: 30):







MPAPAQRKLLPRRHLSEKSHHISIPSPDISHKGLRSKRTQPSDPETWESL


 


PRLDSQRHGGPEFSFDLLPEARAIRVTISSGPEVSVRLCHQWALECEELS


 


SPYDVQKIVSGGHTVELPYEFLLPCLCIEASYLQEDTVRRKKCPFQSWPE


 


AYGSDFWKSVHFTDYSQHTQMVMALTLRCPLKLEAALCQRHDWHTLCKDL


 


PNATARESDGWYVLEKVDLHPQLCFKFSFGNSSHVECPHQTGSLTSWNVS


 


MDTQAQQLILHFSSRMHATFSAAWSLPGLGQDTLVPPVYTVSQARGSSPV


 


SLDLIIPFLRPGCCVLVWRSDVQFAWKHLLCPDVSYRHLGLLILALLALL


 


TLLGVVLALTCRRPQSGPGPARPVLLLHAADSEAQRRLVGALAELLRAAL


 


GGGRDVIVDLWEGRHVARVGPLPWLWAARTRVAREQGTVLLLWSGADLRP


 


VSGPDPRAAPLLALLHAAPRPLLLLAYFSRLCAKGDIPPPLRALPRYRLL


 


RDLPRLLRALDARPFAEATSWGRLGARQRRQSRLELCSRLEREAARLADL


 


G






IL-17RE, transcript variant 5, is encoded by the following mRNA sequence (NCBI Accession No. NM_153483 and SEQ ID NO: 31):









   1
ggtgcgtccc ccaacctgat gctagcccct ttcctgttac ttctcaccca cagcaggagc



 


  61
cccttgtctt tcaggccatg cagccatgtt ccgggagccc taattgcaca gaagcccATG


 


 121
gggagctcca gactggcagc cctgctcctg cctctcctcc tcatagtcat cgacctctct


 


 181
gactctgctg ggattggctt tcgccacctg ccccactgga acacccgctg tcctctggcc


 


 241
tcccacacgg atgacagttt cactggaagt tctgcctata tcccttgccg cacctggtgg


 


 301
gccctcttct ccacaaagcc ttggtgtgtg cgagtctggc actgttcccg ctgtttgtgc


 


 361
cagcatctgc tgtcaggtgg ctcaggtctt caacggggcc tcttccacct cctggtgcag


 


 421
aaatccaaaa agtcttccac attcaagttc tataggagac acaagatgcc agcacctgct


 


 481
cagaggaagc tgctgcctcg tcgtcacctg tctgagaaga gccatcacat ttccatcccc


 


 541
tccccagaca tctcccacaa gggacttcgc tctaaaagga cccaaccttc ggatccagag


 


 601
acatgggaaa gtcttcccag attggactca caaaggcatg gaggacccga gttctccttt


 


 661
gatttgctgc ctgaggcccg ggctattcgg gtgaccatat cttcaggccc tgaggtcagc


 


 721
gtgcgtcttt gtcaccagtg ggcactggag tgtgaagagc tgagcagtcc ctatgatgtc


 


 781
cagaaaattg tgtctggggg ccacactgta gagctgcctt atgaattcct tctgccctgt


 


 841
ctgtgcatag aggcatccta cctgcaagag gacactgtga ggcgcaaaaa atgtcccttc


 


 901
cagagctggc cagaagccta tggctcggac ttctggaagt cagtgcactt cactgactac


 


 961
agccagcaca ctcagatggt catggccctg acactccgct gcccactgaa gctggaagct


 


1021
gccctctgcc agaggcacga ctggcatacc ctttgcaaag acctcccgaa tgccacagct


 


1081
cgagagtcag atgggtggta tgttttggag aaggtggacc tgcaccccca gctctgcttc


 


1141
aagttctctt ttggaaacag cagccatgtt gaatgccccc accagactgg gtctctcaca


 


1201
tcctggaatg taagcatgga tacccaagcc cagcagctga ttcttcactt ctcctcaaga


 


1261
atgcatgcca ccttcagtgc tgcctggagc ctcccaggct tggggcagga cactttggtg


 


1321
ccccccgtgt acactgtcag ccaggcccgg ggctcaagcc cagtgtcact agacctcatc


 


1381
attcccttcc tgaggccagg gtgctgtgtc ctggtgtggc ggtcagatgt ccagtttgcc


 


1441
tggaagcacc tcttgtgtcc ggatgtctct tacagacacc tggggctctt gatcctggca


 


1501
ctgctggccc tcctcaccct actgggtgtt gttctggccc tcacctgccg gcgcccacag


 


1561
tcaggcccgg gcccagcgcg gccagtgctc ctcctgcacg cggcggactc ggaggcgcag


 


1621
cggcgcctgg tgggagcgct ggctgaactg ctacgggcag cgctgggcgg cgggcgcgac


 


1681
gtgatcgtgg acctgtggga ggggaggcac gtggcgcgcg tgggcccgct gccgtggctc


 


1741
tgggcggcgc ggacgcgcgt agcgcgggag cagggcactg tgctgctgct gtggagcggc


 


1801
gccgaccttc gcccggtcag cggccccgac ccccgcgccg cgcccctgct cgccctgctc


 


1861
cacgctgccc cgcgcccgct gctgctgctc gcttacttca gtcgcctctg cgccaagggc


 


1921
gacatccccc cgccgctgcg cgccctgccg cgctaccgcc tgctgcgcga cctgccgcgt


 


1981
ctgctgcggg cgctggacgc gcggcctttc gcagaggcca ccagctgggg ccgccttggg


 


2041
gcgcggcagc gcaggcagag ccgcctagag ctgtgcagcc ggctcgaacg agaggccgcc


 


2101
cgacttgcag acctaggttg agcagagctc caccgcagtc ccgggtgtct gcggccgcaa


 


2161
cgcaacggac actggctgga accccggaat gagccttcga ccctgaaatc cttggggtgc


 


2221
ctcgaggacg actggccgaa aagccgcatt ccctgcctca caggccggaa gtcccagccc


 


2281
agtccccgcg cgcgtccctc ttcctcctca tactttccct tgactgagag ctcctctaac


 


2341
ccctgttctg atgggggagg gcggtcttcc cacttcctct ccagaactcc agaaagagca


 


2401
gtgtgcttat gcttcagtcc aggctggaga ggttggggcc ggggtaggga ggcaggagcc


 


2461
atgtcagttc tgaaggaggg tgaggcggtg ggggattgca gggggcggct gagagaaaac


 


2521
ctccttgggg gccagggatt ccctttccca ctctgaggct ctggccagag ggagagagga


 


2581
ctctggacct aggaaaagag gcttttggct ccaggtggtc aggacagtgg gggttggggg


 


2641
tggggtgggt gggtgctggc ggtggggacc aagatccgga aagatgaata aagacaaaca


 


2701
tgacaaacta agaaaaaaaa aaaaaaaaa






IL-17RE, transcript variant 5, is encoded by the following amino acid sequence (NCBI Accession No. NM_153483 and SEQ ID NO: 32):







MGSSRLAALLLPLLLIVIDLSDSAGIGFRHLPHWNTRCPLASHTDDSFTG


 


SSAYIPCRTWWALFSTKPWCVRVWHCSRCLCQHLLSGGSGLQRGLFHLLV


 


QKSKKSSTFKFYRRHKMPAPAQRKLLPRRHLSEKSHHISIPSPDISHKGL


 


RSKRTQPSDPETWESLPRLDSQRHGGPEFSFDLLPEARAIRVTISSGPEV


 


SVRLCHQWALECEELSSPYDVQKIVSGGHTVELPYEFLLPCLCIEASYLQ


 


EDTVRRKKCPFQSWPEAYGSDFWKSVHFTDYSQHTQMVMALTLRCPLKLE


 


AALCQRHDWHTLCKDLPNATARESDGWYVLEKVDLHPQLCFKFSFGNSSH


 


VECPHQTGSLTSWNVSMDTQAQQLILHFSSRMHATFSAAWSLPGLGQDTL


 


VPPVYTVSQARGSSPVSLDLIIPFLRPGCCVLVWRSDVQFAWKHLLCPDV


 


SYRHLGLLILALLALLTLLGVVLALTCRRPQSGPGPARPVLLLHAADSEA


 


QRRLVGALAELLRAALGGGRDVIVDLWEGRHVARVGPLPWLWAARTRVAR


 


EQGTVLLLWSGADLRPVSGPDPRAAPLLALLHAAPRPLLLLAYFSRLCAK


 


GDIPPPLRALPRYRLLRDLPRLLRALDARPFAEATSWGRLGARQRRQSRL


 


ELCSRLEREAARLADLG






Silencing Expression with MicroRNAs

The invention comprises compositions with means to inhibit the activity of IL-17 or an IL-17R, by delivering microRNA (miRNA) molecules to an ocular or adnexal tissue with an appropriate pharmaceutical carrier. Compositions that comprise a miRNA targeted to either IL-17 or an IL-17R antagonize the function of an IL-17R. The composition comprises one or more miRNA(s) that bind to one or more regions of IL-17 or an IL-17R. The following table contains exemplary miRNAs that have been shown to partially or completely silence the expression of human IL-17 or an IL-17R.







TABLE 1







Summary of miRNAs, their human target genes,


nucleotide sequences, and their sequence


identifier numbers.












Polynucleotide
SEQ




sequence
ID


Target Gene
miRNA
(5′ to 3′)
NO:





IL-17R
miR-24
UGGCUCAGUUCGGAACAG
33


 


IL-17R
miR-378
CUCCUGACUCCAGGUCCUGUGU
34


 


IL-17R
Let-7g
UGAGGUAGUAGUUUGUACAGU
35









Pharmaceutically-Appropriate Carriers

Exemplary compounds incorporated to facilitate and expedite transdermal delivery of topical compositions into ocular or adnexal tissues include, but are not limited to, alcohol (ethanol, propanol, and nonanol), fatty alcohol (lauryl alcohol), fatty acid (valeric acid, caproic acid and capric acid), fatty acid ester (isopropyl myristate and isopropyl n-hexanoate), alkyl ester (ethyl acetate and butyl acetate), polyol (propylene glycol, propanedione and hexanetriol), sulfoxide (dimethylsulfoxide and decylmethylsulfoxide), amide (urea, dimethylacetamide and pyrrolidone derivatives), surfactant (sodium lauryl sulfate, cetyltrimethylammonium bromide, polaxamers, spans, tweens, bile salts and lecithin), terpene (d-limonene, alpha-terpeneol, 1,8-cineole and menthone), and alkanone (N-heptane and N-nonane). Moreover, topically-administered compositions comprise surface adhesion molecule modulating agents including, but not limited to, a cadherin antagonist, a selectin antagonist, and an integrin antagonist.
Optionally, the composition further contains a compound selected from the group consisting of a physiological acceptable salt, poloxamer analogs with carbopol, carbopol/hydroxypropyl methyl cellulose (HPMC), carbopol-methyl cellulose, carboxymethylcellulose (CMC), hyaluronic acid, cyclodextrin, and petroleum.
Drug Delivery by Contact Lens
The invention comprises a contact lens and a composition that inhibits an activity of an inflammatory interleukin-1 cytokine. For example, the composition is incorporated into or coated onto said lens. The composition is chemically bound or physically entrapped by the contact lens polymer. Alternatively, a color additive is chemically bound or physically entrapped by the polymer composition that is released at the same rate as the therapeutic drug composition, such that changes in the intensity of the color additive indicate changes in the amount or dose of therapeutic drug composition remaining bound or entrapped within the polymer. Alternatively, or in addition, an ultraviolet (UV) absorber is chemically bound or physically entrapped within the contact lens polymer. The contact lens is either hydrophobic or hydrophilic.
Exemplary materials used to fabricate a hydrophobic lens with means to deliver the compositions of the invention include, but are not limited to, amefocon A, amsilfocon A, aquilafocon A, arfocon A, cabufocon A, cabufocon B, carbosilfocon A, crilfocon A, crilfocon B, dimefocon A, enflufocon A, enflofocon B, erifocon A, fluorofocon A, flusilfocon A, flusilfocon B, flusilfocon C, flusilfocon D, flusilfocon E, hexafocon A, hofocon A, hybufocon A, itabisfluorofocon A, itafluorofocon A, itafocon A, itafocon B, kolfocon A, kolfocon B, kolfocon C, kolfocon D, lotifocon A, lotifocon B, lotifocon C, melafocon A, migafocon A, nefocon A, nefocon B, nefocon C, onsifocon A, oprifocon A, oxyfluflocon A, paflufocon B, paflufocon C, paflufocon D, paflufocon E, paflufocon F, pasifocon A, pasifocon B, pasifocon C, pasifocon D, pasifocon E, pemufocon A, porofocon A, porofocon B, roflufocon A, roflufocon B, roflufocon C, roflufocon D, roflufocon E, rosilfocon A, satafocon A, siflufocon A, silafocon A, sterafocon A, sulfocon A, sulfocon B, telafocon A, tisilfocon A, tolofocon A, trifocon A, unifocon A, vinafocon A, and wilofocon A.
Exemplary materials used to fabricate a hydrophilic lens with means to deliver the compositions of the invention include, but are not limited to, abafilcon A, acofilcon A, acofilcon B, acquafilcon A, alofilcon A, alphafilcon A, amfilcon A, astifilcon A, atlafilcon A, balafilcon A, bisfilcon A, bufilcon A, comfilcon A, crofilcon A, cyclofilcon A, darfilcon A, deltafilcon A, deltafilcon B, dimefilcon A, droxfilcon A, elastofilcon A, epsilfilcon A, esterifilcon A, etafilcon A, focofilcon A, galyfilcon A, genfilcon A, govafilcon A, hefilcon A, hefilcon B, hefilcon C, hilafilcon A, hilafilcon B, hioxifilcon A, hioxifilcon B, hioxifilcon C, hydrofilcon A, lenefilcon A, licryfilcon A, licryfilcon B, lidofilcon A, lidofilcon B, lotrafilcon A, lotrafilcon B, mafilcon A, mesafilcon A, methafilcon B, mipafilcon A, nelfilcon A, netrafilcon A, ocufilcon A, ocufilcon B, C, ocufilcon D, ocufilcon E, ofilcon A, omafilcon A, oxyfilcon A, pentafilcon A, perfilcon A, pevafilcon A, phemfilcon A, polymacon, senofilcon A, silafilcon A, siloxyfilcon A, surfilcon A, tefilcon A, tetrafilcon A, trilfilcon A, vifilcon A, vifilcon B, and xylofilcon A.
Antibody Compositions:
Compositions of the claimed invention comprise at least one antibody. This antibody is either monoclonal or polyclonal. The claimed antibody targets an intracellular or extracellular IL-17 cytokine or IL-17 receptor, preferably, the IL-17A or F cytokine or the IL-17RA or IL-17RC receptor. This antibody binds to at least one intracellular or extracellular sequence, or epitope, of an IL-17 cytokine or IL-17 receptor. In certain embodiments, the claimed antibody is a single-chain antibody. Alternatively, the antibody is a humanized, recombinant, or chimeric antibody. This antibody is optionally derived from commercially-available antibodies designed for in vitro or in vivo use. The claimed antibody is conjugated directly or indirectly to one or more compound(s) that inhibit or modify the activity of an IL-17 cytokine or an IL-17 receptor. Alternatively, the claimed antibody is an intracellular antibody, or intrabody.
The claimed antibody binds to one or more regions of an IL-17 cytokine. Exemplary regions to which the claimed antibody binds include, but are not limited to, an intracellular domain, an extracellular domain, a catalytic domain, a protein-binding domain, a ligand-binding domain, a scaffolding domain, a signal peptide, a domain of an immature cytokine, a precursor domain, a fibronectin domain, a linker region, a regulatory domain, an oligomerization domain, or a signaling domain.
EXAMPLES
Example 1
CD4+IL-17+ T Cell Abundance in a Mouse Model of DES
Dry Eye Syndrome (DES) was induced in mice by subcutaneous injection of scopolamine and placement in controlled-environment chambers. Following induction of DES and an incubation period, the abundance of CD4+IL-17+ T cells in draining lymph nodes was measured using flow cytometry. For Examples 1-4, the monoclonal anti-mouse IL-17 antibody used was obtained from R&D Systems, Inc. (Clone: 50104, Cat. #MAB421). FIG. 1 shows that the abundance of IL-17-producing CD4+ T cells in the draining lymph nodes of mice with DES increases compared to those of healthy controls.
Example 2
IL-17 mRNA Expression in Conjunctiva of DES Mice
IL-17 mRNA transcripts expressed within the conjunctiva of DES versus normal mice was quantified using real time polymerase chain reaction (PCR). The conjunctiva is the thin, transparent tissue that covers the outer surface of the eye. This structure begins at the outer edge of the cornea, covering the visible part of the sclera, and lining the inside of the eyelids. DES mice demonstrated a three fold increase in the abundance of IL-17 mRNA transcripts in this structure compared to healthy controls, as shown in FIG. 2.
Example 3
IL-17RA Expression on Ocular Surfaces
IL-17 receptor expression on ocular surfaces was analyzed using immunofluorescence microscopy. In contrast to the dramatic upregulation of IL-17 mRNA in the conjunctiva of DES mice, FIG. 3 shows that IL-17RA protein was constitutively expressed on corneal as well as conjunctival epithelium of both DES and control groups.
Example 4
In Vivo Blockade of IL-17 in DES Mice
Healthy and DES mice were intraperitoneally injected with neutralizing anti-IL-17 antibodies to determine the effect of blocking IL-17 activity on both the induction and progression of DES. The results showed a significant decrease in the intensity of clinical signs of DES (measured by corneal fluorescein staining (CFS) scoring) during the induction as well as the progression phases of the disease in the anti-IL-17 antibody-treated group as compared to the control antibody-treated group (shown in FIG. 4, panels a and b). Furthermore, lymph nodes and conjunctiva of the anti-IL-17 antibody-treated group showed reductions in the abundance of Th17 cells and the expression of IL-17 mRNA, respectively, compared to the control-antibody treated group (shown in FIG. 4, panels c and d).
FIG. 5 shows the oxford schema for grading corneal and conjunctival staining used for scoring clinical severity in this example.
Example 5
Recovery of Regulatory T-Cell (Treg) Suppressor Function by Anti-IL-17 Therapy
The in vitro Treg suppression assay using CD3 stimulated primed-T cells (isolated from the LN of dry eye mice) and Tregs (isolated from the LN of mice treated with anti-IL-17 or isotype antibodies) shows a significant recovery in the suppressor potential of Tregs only in mice treated with anti-IL-17 antibody (i.p.) compared to those isolated from the isotype antibody treated groups (p=0.029). The suppressor potential of Tregs isolated from different groups is calculated in relation to the suppression potential of Tregs of normal mice, considered as 100% (FIG. 7).
In dry eye disease there is a significant functional loss of Treg suppression of about 50%. Anti-IL-17 antibody treatment promotes Treg function and restores and/or augments Treg-mediated immune suppression.
Example 6
Topical Application of Anti-IL-17 Antibody Ameliorates Dry Eye Disease
FIG. 8A shows a schematic diagram of the experimental design to study the effects of in vivo IL-17 blockade using topical application of anti-IL17-antibody or isotype-antibody on clinical signs. CFS are significantly lower in anti-IL-17 antibody-treated mice compared to isotype antibody-treated and untreated groups (FIGS. 8B and 8C).
Example 7
Topical Application of Anti-IL-17 Antibody Reduces Frequencies of Pathogenic Th17 Cells Both in Conjunctiva and the Draining Lymph Nodes
Conjunctiva and the draining lymph nodes were harvested at Day 10 (as shown in FIG. 8) from Anti-IL17 antibody and Isotype antibody treated mice. Real-time PCR was performed to analyze mRNA expression levels of IL-17 (Th17 cells) and Foxp3 (Treg cells). FIGS. 9A and 9B show that treatment with an anti-IL-17 antibody specifically decreases expression of IL-17 in Th17 cells of the conjunctiva and lymph nodes.
Example 8
Topical Application of Anti-IL-17 Antibody Inhibits Dry Eye Induced Corneal Lymphatic Vessels via Decreased Secretion of Lymphangiogenesis-Specific Growth Factors, Particularly VEGF-C and D in Dry Eye Corneas
Induction of new lymphatic vessels in dry eye corneas facilitate the migration of resident corneal antigen presenting cells to the draining lymph nodes, which, in turn, induce generation of adaptive immunity to ocular surface. Untreated and control Ab treated Dry Eye groups show an invasion of lymphatic vessels into the cornea (FIG. 10A), compared to Normal cornea. Treatment with anti-IL-17 antibody decreases invasion of lymphatic vessels into the cornea (FIG. 10A). Anti-IL17 antibody treatment decreases mRNA expression of known angiogenic molecules, such as VEGF-C, VEGF-D, and VEGFR-3 (FIG. 10B).
Example 9
Topical Application of Anti-IL-17 Antibody Maintains the Normal Phenotype of CD11b+ Cells in Cornea
Corneas of Anti-IL-17 antibody-treated group show that similar to normal cornea, majority of CD11b+ cells have phenotype of resident dendritic cells. However, corneas of isotype-antibody treated group show that the phenotype of majority of CD11b+ cells are similar to the infiltrating pathogenic macrophages/monocytes (FIG. 11).
Example 10
Topical Application of Anti-IL-17 Antibody Prevents Corneal Nerve Degeneration
FIG. 12 shows representative micrographs of corneal whole mount depicting epithelial and sub-epithelial nerves (Tubulin-III, Red) in different groups. Patterns of nerves in the corneas of Anti-IL17-antibody treated group show similarity to those in the normal corneas, whereas corneas of isotype-antibody treated group show loss of epithelial nerves.
Example 11
Human Corneal Epithelial Cells Respond to IL-17 Cytokine by Increased Secretion of Lymphangiogenesis-Specific Growth Factors
To delineate the mechanism(s) of IL-17 mediated lymphangiogenesis in the corneas of dry eye mice (as shown in FIG. 4) and to ensure that IL-17 has similar effects on human cornea, primary human corneal epithelial cells were cultured for 24 h in the presence of IL-17 and the gene expression levels of different VEGF-species were compared to normal untreated cells (FIG. 14A). Real time PCR analyses show that IL-17 treated human corneal epithelial cells express higher levels of lymphangiogenesis-specific growth factors, particularly VEGF-D (4-fold) and VEGF-C (1.8-fold) compared to untreated cells (FIG. 14B).
Example 12
Topical Application of Anti-IL-17 Antibody Enhances Corneal Nerve Regeneration
Anti-IL-17 antibody treatment is applied to the isotype-antibody treated group of Example 10 or non-treated group of mice. Corneas are treated as described above for Example 10. Anti-IL-17 antibody treatment enhances nerve regeneration such that the amount of nerve fibers associated with damaged corneas is increased compared to untreated or isotype-treated corneas.
Other Embodiments
While the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.
The patent and scientific literature referred to herein establishes the knowledge that is available to those with skill in the art. All United States patents and published or unpublished United States patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. Genbank and NCBI submissions indicated by accession number cited herein are hereby incorporated by reference. All other published references, documents, manuscripts and scientific literature cited herein are hereby incorporated by reference.
While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

## Claims

1. A method for reducing the severity of dry eye syndrome comprising
identifying a subject characterized as suffering from dry eye syndrome;
topically administering directly to an eye of a subject a composition that inhibits binding of an inflammatory interleukin-17 (IL-17) cytokine to an IL-17 receptor; and
inhibiting or reducing eye dryness associated with said dry eye syndrome, thereby reducing the severity of said dry eye syndrome, wherein said dry eye syndrome is a non-Sjogren's syndrome associated dry eye syndrome associated with meibomian gland dysfunction, and is not uveitis, intraocular conditions, or inflammation of interior tissues of the eye.

2. The method of claim 1, wherein said identifying step comprises detection of a sign or symptom selected from the group consisting of eye dryness, scratching, stinging, itching, burning, irritation, pain, redness, inflammation, discharge, and excessive watering, and wherein said method inhibits or reduces the severity of at least one of said signs or symptoms.

3. The method of claim 1, wherein said method comprises sequential or simultaneous administration of a composition that inhibits binding of an inflammatory IL-17 cytokine to an IL-17 receptor and a secondary composition.

4. The method of claim 1, wherein the form of said composition is a solid, an ointment, a gel, a liquid, an aerosol, a mist, a polymer, a contact lens, a film, an emulsion, or a suspension.

5. The method of claim 1, wherein said method does not comprise systemic administration or substantial dissemination to non-ocular tissue.

6. The method of claim 1, wherein said composition further comprises a compound selected from the group consisting of a physiologically acceptable salt, poloxamer analogs with carbopol, carbopol/HPMC, carbopol-methyl cellulose, a mucolytic agent, carboxymethylcellulose (CMC), hyaluronic acid, cyclodextrin, and petroleum.

7. The method of claim 1, wherein said method comprises administration of both a composition that inhibits binding of an inflammatory IL-17 cytokine to an IL-17 receptor and a second composition comprising one or more inflammatory antagonist(s).

8. The method of claim 1, wherein said composition comprises:
(a) a monoclonal or polyclonal antibody;
(b) an antibody that targets an intracellular or extracellular IL-17 cytokine or IL-17 receptor;
(c) an antibody that binds to at least one intracellular or extracellular sequence of an IL-17 cytokine or IL-17 receptor;
(d) a single-chain antibody;
(e) a humanized, recombinant, or chimeric antibody;
(f) an antibody conjugated directly or indirectly to a compound that inhibits or modifies the activity of an IL-17 cytokine or an IL-17 receptor or
(g) a composition that inhibits or modifies the transcription, transcript stability, translation, modification, localization, secretion, or function of a polynucleotide or polypeptide encoding an inflammatory interleukin-17 cytokine or an IL-17 receptor.

9. The method of claim 1, wherein said composition inhibits an activity of an inflammatory cytokine selected from the group consisting of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F.

10. The method of claim 1, wherein said composition inhibits an activity of an inflammatory cytokine receptor selected from the group consisting of IL-17RA, IL-17RB, IL-17RC, IL-17RD, IL-17RE, and IL-17RF.