INVARIANT CHAIN COMPOSITIONS USEFUL FOR TREATING AUTOIMMUNE DISEASES

Abstract: Pharmaceutical compositions comprising an invariant chain protein, or peptide fragment thereof, and a pharmaceutically acceptable carrier are disclosed. An invariant chain peptide fragment of the composition comprises an amino acid sequence of a binding motif for a major histocompatibility complex (MHC) molecule, such as an MHC class II molecule. Preferably the peptide fragment is about 10 to 35 amino acids in length, more preferably 10 to 20 amino acids in length, even more preferably 12 to 16 amino acids in length. The invention further provides a method for preparing an invariant chain peptide fragment for use in the disclosed compositions and methods. This method involves identifying an amino acid sequence of a binding motif for an MHC molecule, selecting a region of an invariant chain protein comprising the amino acid sequence of the MHC binding motif and preparing an invariant chain peptide fragment encompassing the selected region. Methods for treating autoimmune diseases are also disclosed. The methods of the invention involve administering to a subject in need of treatment a therapeutically effective amount of an invariant chain protein, or peptide fragment thereof, optionally with a pharmaceutically acceptable carrier.

Description: INVARIANT CHAIN COMPOSITIONS USEFUL FOR TREATING AUTOIMMUNE DISEASES Background of the Invention The activation of a T cell by an antigen generates a number of responses, including proliferation, cytokine production and induction of helper-effector functions, such as stimulation of cytotoxic T cells and antibody production by B cells. T cell activation requires an antigen-specific signal, which results from stimulation of a clonally-distributed T cell receptor (TCR) present on the surface of the T cell. In a natural immune response, the TCR is stimulated by recognition of an antigenic peptide bound to a major histocompatibility complex (MHC), either an MHC class I protein or an MHC class II protein, present on the surface of an antigen presenting cell (APC). Structurally, MHC molecules have a cleft-like binding site with which antigenic peptides associate. Typically, CD4 + T cells recognize peptides associated with MHC class II molecules. MHC class II molecules are found on a limited number of cell types (primarily B cells, monocytes/macrophages and dendritic cells) and, in most cases, present peptides derived from proteins taken up from the extracellular environment (i.e., exogenous antigens). In contrast, CD8 + T cells typically recognize peptides associated with MHC class I molecules. MHC class I molecules are found on almost all cell types and, in most cases, present peptides derived from endogenously synthesized proteins. Distinct intracellular processing and transport pathways exist for MHC class I and class II molecules. MHC class I molecules are thought to associate with antigenic peptides in the endoplasmic reticulum, whereas MHC class II molecules are thought to associate with antigenic peptides in the endosomal compartment. A distinguishing feature of the MHC class II processing pathway is the involvement of the invariant chain (Ii), a protein which interacts intracellularly with nascent MHC class II molecules but which is not typically complexed with mature MHC class II molecules on the cell surface. While induction of T cell responses specific for foreign antigens are critical for host defenses against pathogens, "inappropriate" T cell activation in response to a self protein ("autoantigen") can lead to autoimmunity. A significant initiating event in many autoimmune diseases is the recognition of self protein in association with MHC Class II molecules by auto-reactive T lymphocytes. This breakdown of immunologic tolerance to self protein occurs despite elaborate intrathymic and peripheral mechanisms designed to prevent or suppress the generation of auto-reactive T cells, such as clonal deletion of T cells and or induction of self antigen-specific anergy in T cells (see e.g., Sprent, J. (1988) Immunol. Rev. 1121:172-189; Blackman, M. et al. (1990) Science 24_.:1335-1341; Ramsdell, F. and Fowlkes, B.J. (1990) Science 24S.: 1342- 1348; and Schwartz, R. (1990) Science 24&: 1349-1356). For example, numerous studies of the characteristics of auto-reactive T cells involved in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, have defined immunodominant amino acid sequences of myelin basic protein (MBP) recognized by the auto-reactive T cells (Chou, C.-H. et al. (1977) J Neurochem. 28:115-119; Hashim, G. (1978) Immunol. Rev. 22:60-107; Zamvil, S. et al. (1986) Nature 3^4:258-260), and preferential T cell receptor gene usage (Heber-Katz, E. and Acha-Orbea, H. (1989) Immunol. Today 10:164-169; Heber-Katz, E. (1990) Clin. Immunol. & Immunopathol. 55:1-8). The precise mechanism(s) leading to the breakdown of tolerance to self proteins and resulting autoimmunity are not known, although both genetic and environmental factors have been implicated. A large number of diseases are believed to be autoimmune in nature or at least to involve an autoimmune component. These diseases are often chronic and debilitating, causing great suffering in patients afflicted with the diseases and creating heavy medical, social and economic burdens. For example, it is estimated that rheumatoid arthritis alone causes an annual economic loss in the United States of approximately $1 billion (McDuffie, F.C. (1985) Am. J. Med. 78:1). Current therapy for autoimmune diseases includes administration of corticosteroids (e.g., to suppress production of autoantibodies) and/or anti- inflammatory drugs (e.g., to relieve tissue damage from immune complexes). Plasma- pheresis, to remove autoantibodies and circulating immune complexes, may also be used. Each of these modalities are directed at reducing symptoms and generally do not halt the progression of the disease. Additonally, these treatments are often associated with unwanted side effects. Accordingly, there is a need for additional therapies for treatment of autoimmune diseases. Summary of the Invention This invention provides compositions and methods for inhibiting an interaction between an antigenic peptide and a major histocompatibility complex (MHC) molecule that are particularly useful for treating an autoimmune disease in a subject. In one embodiment, the invention provides a method for inhibiting an interaction between an antigenic peptide and an MHC molecule on an antigen presenting cell involving contacting the antigen presenting cell with an invariant chain protein, or peptide fragment thereof. In another embodiment, the invention provides a method for treating an autoimmune disease involving administering to a subject in need of treatment a therapeutically effective amount of a composition comprising an invariant chain protein, or peptide fragment thereof, optionally with a pharmaceutically acceptable carrier. According to the invention, an invariant chain protein or peptide is used to competitively inhibit binding of antigenic peptides, such as autoantigenic peptides, to MHC molecules. It has been discovered that the amino acid sequence of the invariant chain includes a pattern of amino acid residues that allow for association with the peptide binding site of MHC molecules, in particular MHC class II molecules. Additionally, it has been discovered that autoantigenic peptides share the amino acid sequence of this MHC binding motif. Accordingly, in an autoimmune reaction, the concentration of autoantigenic peptide that associates with MHC molecules can be decreased by administration of an invariant chain protein or peptide to competitively inhibit binding of autoantigenic peptides to MHC molecules, thereby inhibiting activation of autoreactive T cells. In one embodiment of the invention, a subject suffering from an autoimmune disease is treated by administering to the subject a composition containing intact invariant chain protein. Preferably, the invariant chain protein is from the same species as the subject. In another embodiment, a peptide fragment of invariant chain is administered to the subject. The peptide fragment of invariant chain chosen for use in the method is one which encompasses an amino acid sequence of a binding motif for an MHC protein expressed by the subject. Preferably, the peptide fragment encompasses an amino acid sequence of a binding motif for an MHC class II protein, such as a human MHC class II protein (e.g., HLA- DR, HLA-DQ or HLA-DP). The peptide fragment administered to the subject can be about 10-35 amino acids in length, more preferably, 10-20 amino acids in length, or even more preferably, 12-16 amino acids in length. The invariant chain protein, or peptide fragment thereof, is administered to the subject at a dosage and by a route sufficient to achieve the desired result (e.g., inhibition of at least one symptom of the autoimmune disease). For example, the protein or peptide may be administered intravenously or subcutaneously. Alternatively, the protein or peptide may be administered intramuscularly, intraperitoneally or orally. Another aspect of the invention pertains to a process for preparing an invariant chain peptide fragment useful for inhibiting an interaction between an antigenic peptide and an MHC molecule on an antigen presenting cell. This process involves identifying an amino acid sequence of a binding motif for an MHC protein expressed by the subject, selecting a region of an invariant chain protein which encompasses the amino acid sequence of the binding motif for the MHC protein, and preparing an invariant chain peptide fragment corresponding to the selected region of the invariant chain protein that contains the MHC binding motif. Preferably, an MHC class II binding motif is used in the process and the invariant chain peptide fragment so prepared thus contains an amino acid sequence of an MHC class II binding motif. The invariant chain peptide fragment can be prepared by standard techniques, such as by chemical synthesis or by proteolytically digesting the invariant chain protein and isolating a proteolytic fragment encompassing the selected region of the invariant chain protein. The invariant chain peptide fragment so prepared is preferably 10-35 amino acids in length, more preferably, 10-20 amino acids in length, or even more preferably, 12-16 amino acids in length. Pharmaceutical compositions for treatment of an autoimmune disease in a subject are also encompassed by the invention. In one embodiment, the pharmaceutical composition includes an invariant chain protein in an amount sufficient to inhibit at least one symptom of an autoimmune disease in a subject and a pharmaceutically acceptable carrier. Preferably, the invariant chain protein is human. In another embodiment, the pharmaceutical composition includes a peptide fragment of an invariant chain protein in an amount sufficient to inhibit at least one symptom of an autoimmune disease in a subject and a pharmaceutically acceptable carrier. The peptide fragment chosen for inclusion in the composition encompasses an amino acid sequence of a binding motif for an MHC protein (e.g., an MHC class II protein). Brief Description of the Drawings Figure 7 is a graphic representation of the proliferative response of T cells derived from rats immunized with acetylated peptide PLP 224 upon stimulation with acetylated and nonacetylated peptide PLP 224 at various concentrations. Figure 2 is a graphic representation of the proliferation of HT-2 cells in response to IL-2 produced by T cells derived from rats immunized with acetylated peptide PLP 224 upon stimulation of the T cells with acetylated and nonacetylated peptide PLP 224. Figure 3 is a schematic diagram of the location of synthetic peptide encompassing the MHC class II (RT1.B/D) binding motif relative to the structure of proinsulin prior to enzymatic cleavage into insulin (A + B chains linked by disulfide bonds) and C-peptide. The binding motif spans amino acids of the B and C chains in proinsulin containing one pair of basic (Arg-Arg) residues cleaved by a site-specific endoprotease during processing. Figure 4A-C are graphic representations of the proliferation of T cell lines specific for GAD412 (panel A), GAD520 (panel B) and PI (panel C) peptides in the presence or absence of anti-MHC class II antibody (for reference, mean cpm for GAD412 T cells incubated with APCs and medium = 850 ± 297; GAD 520 = 74 ± 30; and PI = 1763 ± 181). Figure 5 is a flow cytometric profile of PI peptide-specific T cell line expression of cell surface antigens following 72 hour stimulation with concanavalin A. Histograms and percent positive expression for each primary antibody (in parentheses) were generated by FACScan analysis of 10,000 cells. Figure 6 is a graphic representation of the proliferative response of an anti-POMCac T cell line upon stimulation with acetylated and nonacetylated POMC peptide at various concentrations (in μg/ml). (Average background mean cpm ± SD = 145 ± 43). Figure 7A-B are graphic representations of the proliferative responses of an anti- hormone specific T cell lines upon stimulation with hormone antigen (concentration in μg/ml), showing inhibition of proliferation by the addition of anti-MHC class II antibodies. Panel A shows the proliferative response of anti-POMC specific T cells (background mean cpm ± SD = 852 ± 444). Panel B shows the proliferative response of anti-CRH specific T cells (background mean cpm ± SD = 81 ± 24). Figure 8A-B are graphic representations of the processing and presentation of intact CRH (40 μg/ml) vs. CRH peptide (20 μg/ml) by T cell lines specific for either acetylated CRH peptide (panel A) or non-acetylated CRH peptide (panel B) (average medium only cpm ± SD = 77 ± 28). Figure 9 A-C is a graphic representation of the ability of CRH-stimulated T cells from different sources to present POMC peptide to POMC-specific T cells. Panel A shows the antigen presentation ability of anti-POMC T cells. Panel B shows the antigen presentation ability of anti-GAD T cells. Panel C shows the antigen presentation ability of thymocytes. (average background mean cpm ± SD = 159 ± 29). Figure 10 is a graphic representation of the proliferative response of IL-2 dependent HT-2 cells to 40 hour culture supernates obtained from mixtures of anti-POMC T cells plus irradiated APC (thymocytes or anti-POMC T cells) in the presence or absence of 20 μg/ml POMC peptide. Detailed Description of the Invention This invention pertains to the use of invariant chain protein, or a peptide fragment thereof, to inhibit an interaction between an antigenic peptide and a major histocompatibility complex (MHC) protein expressed by an antigen presenting cell (APC). By inhibiting the interaction of an antigenic peptide with an MHC protein on an APC, recognition of this antigenic peptide by a T cell is inhibited, thereby also inhibiting a T cell response against the antigenic peptide. An interaction between an antigenic peptide and an MHC molecule expressed by an APC is inhibited by contacting the APC with an invariant chain protein, or peptide fragment thereof, in an amount sufficient to inhibit the interaction between the antigenic peptide and the MHC molecule expressed by the APC. As used herein, the term "antigen presenting cell" is intended to include B lymphocytes, "professional" antigen presenting cells (e.g., monocytes, dendritic cells, Langerhan cells) and other cells (e.g., keratinocytes, endothelial cells, astrocytes, fibroblasts, oligodendrocytes) which can present antigen to immune cells. A preferred antigenic peptide to be inhibited from binding to an MHC molecule is a peptide of an autoantigen. As used herein, the term "autoantigen" refers to a self protein that is capable of eliciting an immune response, such as a T cell response, in a subject. Accordingly, the invention is particularly useful for treating autoimmune diseases. The invention provides invariant chain compositions useful for treating autoimmune diseases. The invention still further provides methods for treating autoimmune diseases involving administering to a subject in need of treatment an invariant chain composition of the invention. The invention is based, at least in part, on the discovery that the amino acid sequence of an invariant chain protein of a particular species contains one or more regions corresponding to a binding motif for an MHC molecule(s) (e.g., MHC class II molecule) of that species. Thus, regions of the invariant chain protein are capable of occupying the antigenic binding site of MHC molecules. The same MHC binding motif is present in immunogenic peptide fragments of autoantigens, enabling these peptides to associate with MHC molecules. Accordingly, an invariant chain protein, or a peptide fragment thereof, can be used to inhibit binding of auoantigenic peptide fragments to an MHC molecule by competing for the peptide binding site of the MHC molecule, thereby decreasing the concentration of autoantigenic peptide that associates with the MHC molecule and inhibiting stimulation of autoreactive T cells. Various aspects of the invention are described in further detail in the following subsections: I. Invariant Chain Protein In one embodiment, the compositions and methods of the invention utilize an invariant chain protein. The invariant chain (Ii) is a type II transmembrane protein existing in humans in two major forms of about 33 kD (p33) and 35 kD (p35), and two minor forms of about 41kD (p41) and 43 kD (p43). p33 and p35 arise by alternative usage of two in-frame AUG codons, at positions 8 and 56 from the cap site (see Strubin, M. et al. (1986) Cell 42:619-625, whereas the larger forms (p41 and p43) arise by inclusion of an additional exon by alternative splicing (see Strubin, M. et al. (1986) EMBO J. 5_:3483-3488). In the invariant chain, a hydrophobic N-terminal sequence serves as both a signal sequence and membrane anchor (see Lipp, J. and Dobberstein, B. (1986) Cell 46_: 1103-1112). Invariant chain protein for use in the invention can be obtained by standard techniques known in the art. For example, the native protein can be purified from cells. Alternatively, a recombinant form of invariant chain can be expressed in cells using nucleic acid encoding the invariant chain and the recombinant protein then isolated. The nucleotide sequences of invariant chain cDNAs, and predicted amino acid sequences of invariant chain proteins, have been described for several species. The nucleotide sequences of alternative forms of human invariant chain cDNAs are disclosed in Claesson, L. et al. (1983) Proc. Natl. Acad. Sci. USA SΩ.7395-7399; Strubin, M. et al. (1984) EMBO J. 2:869-872; Strubin, M. et al. (1986) EMBO J. 5:3483-3488; and Strubin, M. et al. (1986) Cell 42:619-625. Mouse invariant chain cDNA sequences are disclosed in Koch, N. et al. (1987) EMBOJ. 6_: 1677- 1683; and Zhu, L. and Jones, P.P. (1989) Nucleic Acids Res. 12:447-448. Rat invariant chain cDNA sequences are disclosed in Henkes, W. et al. (1988) Nucleic Acids Res. 1^:11822; and McKnight, A.J. et al. (1989) Nucleic Acids Res. 12:3983-3984. A cDNA encoding an invariant chain protein can be cloned into an expression vector and the expression vector introduced into an appropriate host cell to thereby express invariant chain protein. Invariant chain can be expressed in a prokaryotic or, more preferably, a eukaryotic host cell. A soluble form of human invariant chain protein can be expressed recombinantly as described in Teyton, L. et al. (1990) Nature 248:39-44. Briefly, a full-length Ii cDNA is modified by removing the region encoding the N-terminal 29 residues. This deletion unmasks the signal sequence cleavage site and leads to the production of a secreted soluble form of invariant chain. As used herein, the term "invariant chain protein" is intended to include membrane-bound or soluble forms (e.g., N- terminally truncated forms) of all naturally-occurring variants of the invariant chain. TT. Selection of Invariant Chain Peptide Fragments In another embodiment of the invention, a peptide fragment of an invariant chain protein is utilized in the methods and compositions of the invention. An invariant chain peptide for use in the invention is selected based upon the presence of a binding motif for a major histocompatibility comples (MHC) molecule. Accordingly, the invention provides a method for preparing an invariant chain peptide fragment suitable for inhibiting an interaction between an antigenic peptide and an MHC protein involving: 1) identifying an amino acid sequence of a binding motif for an MHC protein; 2) selecting a region of an invariant chain protein comprising the amino acid sequence of the MHC binding motif; and 3) preparing an invariant chain peptide fragment encompassing the selected region of the invariant chain protein. An invariant chain peptide so selected is particularly useful for treating autoimmune diseases by inhibiting an interaction between an autoantigenic peptide and an MHC protein. The term "binding motif for an MHC molecule" refers to a pattern of amino acid residues present within a peptide (or region of a whole protein) that allow the peptide to bind to the antigenic binding site of an MHC molecule. That is, the binding motif for a particular MHC molecule defines the critical amino acid residues of a peptide fragment that are necessary for binding of the fragment to that MHC molecule. For example, as described herein, the binding motif for the rat MHC class II molecule RTLB^ consists of a serine residue separated from a glutamic acid residue by five amino acid residues (i.e., S-x-x-x-x-x- E; SEQ ID NO: 1). As demonstrated in the Examples, this binding motif can be used to predict immunogenic peptide fragments of autoantigens in a number of animal models of autoimmunity (i.e., autoantigenic peptides comprise an amino acid sequence having the motif). The S-E binding motif is also present at three locations within rat invariant chain: at positions 69-75 (S-Q-N-L-Q-L-E; SEQ ID NO: 2), 177-183 (S-K-N-S-L-E-E; SEQ ID NO: 3) and 256-262 (S-E-P-L-D-M-E; SEQ ID NO: 4). Accordingly, a peptide fragments of rat invariant chain encompassing one of these regions can be selected to inhibit binding of autoantigenic peptide fragments to the RT1.B* MHC molecule. Other binding motifs for either MHC class I or MHC class II molecules have been described in the art (see e.g., Margalit, H. et al. (1987) J. Immunol. 12&2213-2229; Sette, A. et al. (\9 ) J.Immunol. 141:45-48; Rothbard, J.B. et al. (1988) Cell 52:515-523; Rothbard, J.B. and Taylor, W.R. (1988) EMBOJ. 2:93-100; Sette, A. et al. (1989) Proc. Natl. Acad. Sci. USA £6:3296-3300; Jardetzky, T.S. et al. (1990) EMBOJ. 2:1797-1803; Hill, CM. et al. (1991) J. Immunol.142:189-197; Falk, K. et al. (1991) Nature 251:290-296; Kropshofer, H. et al. (1992) J. Exp. Med. 125:1799-1803; Sidney, J. et al. (1992) J. Immunol. 142:2634- 2640; Hunt, D.F. et al. (1992) Science 256.: 1817-1820; Rudensky, A.Y. et al. (1992) Nature 252:431; Corr, M. et al. (1993) J. Exp. Med. 17_8_: 1877-1892; Chicz, R.M. et al. (1993) J Exp. Med. 12&:27-47; Sette, A. et al. (1993) J Immunol. 151:3163-3170). In one embodiment, an invariant chain peptide is selected that encompasses a binding motif for a human MHC class II molecule, such as an HLA-DR, HLA-DQ or HLA-DP molecule. Examples of binding motifs for human MHC class II molecules include: an HLA-DR 1 binding motif comprising a tyrosine residue separated by six amino acid residues from a lysine residue (Y-x-x-x-x-x-x-K; SEQ ID NO: 5) (Jardetsky, T.S. et al. (1990) EMBOJ. 2:1797-1803); an HLA-DRlwDl binding motif comprising a bulky hydrophobic residue (e.g., tyrosine, leucine, valine, isoleucine, phenylalanine or methionine) separated by four amino acid residues from a small amino acid residue (e.g., threonine, alanine, serine or glycine) (Y/L/V/I/F/M-x-x-x-x-T/A/S/G; SEQ ID NO: 6) (Hill, CM. et al. (1991) J. Immunol. 142:189-197); an HLA-DR3 binding motif comprising hydrophobic residues (e.g., isoleucine, tyrosine, leucine, valine, alanine) at positions 1 and 3, preferably followed by a hydrophilic hydrogen bonding donor residue (e.g., asparagine, glutamine, arginine, lysine. glutamic acid, aspartic acid, serine or threonine) at position 4 and a positively charged residue (e.g., lysine, arginine or histidine) at position 6 (I/Y/L/V/A -x-I/Y/L/V/A-N/G/R/K/E/D/S/T-x-K/R H; SEQ ID NO: 7) (Sidney, J. et al. (1992) J. Immunol. 142:2634-2640); an HLA-DR4w4 binding motif comprising a hydrophobic or aromatic residue (leucine, isoleucine, valine, methionine, phenylalanine, tyrosine or typtophan) separated by four amino acid residues from a hydroxyl (serine or threonine) or aliphatic (leucine, isoleucine, valine or methionine) residue (L/I/V/M/F/Y/W-x-x-x-x-S/T/L/I/V/M; SEQ ID NO: 8) (Sette, A. et al. (1993) J. Immunol. 151:3163-3170); an HLA-DR2a/DR2b binding motif comprising a isoleucine, leucine or valine residue separated by nine amino acid residues from a histidine, lysine or arginine residue (I/L/V-x-x- x-x-x-x-x-x-x-H/K/R; SEQ ID NO: 9) (Chicz, R.M. et al. (1993) J. Exp. Med. H8_:27-47); an HLADR3/DRw52 binding motif comprising a phenylalanine, isoleucine, leucine, valine or tyrosine residue separated by two amino acids from an aspartic acid, asparagine, glutamine or threonine residue (F/I/L/V/Y-x-x-D/N/Q/T; SEQ ID NO: 10) (Chicz, R.M. et al. (1993) J. Exp. Med. 12&:27-47); an HLA-DR4 binding motif comprising a phenylalanine, leucine or valine residue separated by seven amino acid residues from an asparagine, glutamine, serine or threonine residue (F/L/V-x-x-x-x-x-x-x-N/Q/S/T; SEQ ID NO: 11) (Chicz, R.M. et al. (1993) J. Exp. Med. 12£:27-47); an HLA-DR7 binding motif comprising a phenylalanine, isoleucine, leucine or valine residue separated by four amino acid residues from an asparagine, serine or threonine residue (F/I/L/V-x-x-x-x-N/S/T; SEQ ID NO: 12) (Chicz, R.M. et al. (1993) J. Exp. Med. 12_i:27-47); an HLA-DR8 binding motif comprising a phenylalanine, isoleucine, leucine, valine or tyrosine residue separated by three amino acid residues from a histidine, lysine or arginine residue (F/I/L/V/Y-x-x-x-H/K/R; SEQ ID NO: 13) (Chicz, R.M. et al. (1993) J. Exp. Med. 128_:27-47). An MHC binding motif described herein or known in the art can be used to select invariant chain peptides, or alternatively, an MHC binding motif can be identified by known techniques. For example, to identify an MHC binding motif, the amino acid sequences of a series of peptides capable of binding to a particular MHC molecule can be compared to thereby identify amino acid residues conserved at particular positions within the peptides. Additionally or alternatively, a peptide capable of binding to a particular MHC molecule can be systematically mutated and the mutated peptides assayed for their ability to bind the MHC molecule to identify amino acid residues critical for MHC binding (for further descriptions of identification of MHC binding motifs, see the references cited supra). Once a region of an invariant chain protein has been identified that contains a binding motif for an MHC molecule, a peptide fragment encompassing this region can be prepared by conventional techniques. A peptide fragment having the amino acid sequence of this region can be chemically synthesized, for example using commercially available resins (e.g.,/ methylbenzhydrylamine; RapidAmide from NEN/Dupont, Wilmington, DE) and F-moc as the protecting group for the terminal amino acid on the lengthening peptide. Peptides can also be chemically synthesized using an an automated peptide synthesizer (e.g., Peptide Synthesizer 432A from Applied Biosystems, Foster City, CA). Alternatively, a peptide fragment can be obtained by proteolytic digestion of an invariant chain protein, followed by isolation of the peptide fragment of interest. Proteases with defined proteolytic specificity are available in the art (e.g., typsin). Proteolytic peptide fragments can be isolated, for example, by high pressure liquid chromatography (HLPC). In one embodiment, the invariant chain peptide fragment (e.g., synthesized or obtained by proteolytic digestion) is about 10-35 amino acids in length. Alternatively, the peptide fragment can be about 10-20 amino acids in length, or about 12-16 amino acids in length. Additionally, the invariant chain peptide fragment may be modified to increase its solubility, stability, ability to interact with MHC molecules or other desired functional property. For example, one or more charged amino acid residues (e.g., lysine, arginine, glutamic acid, aspartic acid) not encoded within the invariant chain protein may be added to the C-terminal and/or N-terminal end of an invariant chain peptide to increase its solubility. A preferred modification of a peptide is N-terminal acetylation, which may promote α-helix formation and MHC interactions (see e.g., Main R. et al. (1983) Trends Neurosci. 6:229-235). HI, Pharmaceutical Compositions The invariant chain proteins and peptides of the invention can be formulated into a composition suitable for pharmaceutical administration. The pharmaceutical composition typically includes an invariant chain protein, or peptide fragment thereof, and a pharmaceutically acceptable carrier. As used herein the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. In one embodiment, the invariant chain protein, or peptide fragment thereof, is included in the composition in an amount sufficient to inhibit an interaction between an antigenic peptide and an MHC molecule expressed by an antigen presenting cell. In another embodiment, the invariant chain protein, or peptide fragment thereof, is included in the composition in an amount sufficient to inhibit at least one symptom of an autoimmune disease in a subject. An invariant chain pharmaceutical composition is formulated that is compatible with its intended route of administration. For example, solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous ad^ninistration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL^ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, asorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound (i.e., invariant chain protein or peptide) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze- drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811. For example, Iiposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of invariant chain protein or peptide is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension. It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of individuals. IV. Methods for Treating Autoimmune Diseases According to the invention, an autoimmune disease in a subject is treated by administering to the subject a therapeutically effective amount of a composition containing an invariant chain protein, or peptide fragment thereof, and a pharmaceutically acceptable carrier. The invariant chain proteins or peptides of the invention are administered to subjects in a biologically compatible form suitable for pharmaceutical administration in vivo, by which is meant that the form of the protein or peptide administered is one in which any toxic effects are outweighed by the therapeutic effects of the protein or peptide. The term "subject" is intended to include living organisms in which an immune response can be elicited, e.g., mammals. Examples of subjects include humans, monkeys, horses, cows, dogs, cats, mice, rats, and transgenic species thereof. Administration of a ligand of the invention as described herein can be in any pharmacological form including a therapeutically active amount of an invariant chain protein or peptide alone or in combination with another therapeutic molecule (e.g., an anti-inflammatory agent or a steroid) and a pharmaceutically acceptable carrier. Administration of a therapeutically effective amount of the compositions of the invention is defined as an amount, at dosages and for periods of time, sufficient to achieve the desired result. For example, the desired result can include inhibition of at least one symptom of the autoimmune disease, slowing or halting the progression of the disease or other clinically desirable result. A therapeutically effective amount of an invariant chain protein or peptide may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of protein or peptide to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, the composition may be administered at once, or several divided doses may be administered daily for a period of time. The dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. The concentration of active compound in the composition will depend on absorption, inactivation, and excretion rates of the compound as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time - 13 - according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The invariant chain composition may be administered in a convenient manner suitable to achieve the desired result. In a preferred embodiment, the composition is administered intravenously. In another preferred embodiment, the composition is administered subcutaneously. Alternatively, the composition can be administered by an orally or a parenteral route, such as intradermally, intramuscularly or intraperitoneally. Depending on the route of administration, the active compound may be coated in a material to protect the compound from the action of enzymes, acids and other natural conditions which may inactivate the compound. Typical systemic dosages for the conditions described herein are those ranging from 0.01 to 5 mg/kg body weight, more preferably 0.05 to 1 mg/kg body weight, even more preferably 0.1 to 0.5 mg/kg of body weight. The method of the invention is useful for treating autoimmune diseases. The term "autoimmune disease" as used herein is intended to include diseases known to be autoimmune in nature as well as disorders associated with an autoimmune component. Examples of such diseases and disorders include multiple sclerosis, insulin dependent diabetes mellitus, arthritis (e.g., rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis), myesthenia gravis, myocarditis, Guillan-Barre Syndrome, systemic lupus erythematosis, autoimmune thyroiditis, dermatitis, psoriasis, Sjδgren's Syndrome, alopecia areata, Crohn's disease, aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, allergy, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, drug eruptions, leprosy reversal reactions, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral progressive sensorineural hearing loss, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, polychondritis, Wegener's granulomatosis, chronic active hepatitis, Stevens- Johnson syndrome, idiopathic sprue, lichen planus, Graves ophthalmopathy, sarcoidosis, primary biliary cirrhosis, uveitis posterior, and interstitial lung fibrosis. This invention is further illustrated by the following examples which should not be construed as limiting. The contents of all references, patents and published patent applications cited throughout this application are hereby incorporated by reference. EXAMPLE 1; Experimental allerigc encephalomyelitis (EAE) is a CD4+ T lymphocyte-mediated inflammatory disease of the central nervous system that is employed as an animal model of the human disease multiple sclerosis (MS). EAE can be induced in naive recipient rodents either by active immunization of animals with mylein basic protein (MBP) and adjuvant emulsion, or by injection of activated MBP-specific T cells (see e.g., Zamvil, S. et al. (1985) Nature 212:355; Richert, J. et al. (1979) J. Immunol. 122:494; Ben-Nun, A. et al. (1981) Eur. J. Immunol. 11:195; Hickey, W.F. et al. (1987) Cell. Immunol. 1_!2:272). However, there is evidence suggesting that T cell responses specific for proteolipid apoprotein (PLP) may be the immunologically dominant phenomenon in the spontaneously occurring human demyelinating disease MS (see e.g., Kennedy, M.K. et al. (1990)J Immunol. 144:909: Whitham, R.H. et al. (1991) J. Immunol. 14_>:101). Several encephalitogenic determinants of PLP in synthetic peptides have been identified for different strains of mice and rabbits (Whitham, R.H. et al. (1991) J. Immunol. 142:3803; Tuohy, V.K. et al. (1989) J. Immunol. 142:1523; Tuohy, V.K. et al. (1988) J. Immunol. 141:1126; Sobel, R.A. (1990) J. Neuropathol. Exp. Neurol.42:468; Tuohy, V.K. et al. (1992) J Neuroimmunol. 22:67; Greer, J.M. et al. (1992) J. Immunol. 142:783; Linington, C et al. (1990) J. Neuroimmunol. 3_Q:135). The standard method for identifying such encephalitogenic areas has been to synthesize overlapping peptides and test each peptide individually for its ability to induce inflammation in the targeted tissue. In this example, an MHC class II binding motif was used to identify an encephalitogenic T cell epitope in PLP for the Lewis rat. This motif entails a serine residue separated from a glutamic acid residue by five amino acid residues (S-x-x-x-x-x-E) (SEQ ID NO: 1). This example demonstrates that an encephalitogenic T cell epitope can be predicted solely on the basis of the presence of an amino acid sequence encompassing an MHC class II binding motif. Moreover, the results described herein demonstrate that N-terminal acetylation of the PLP peptide plays an important role in the induction of EAE in Lewis rats as well as in T cell proliferative responses and IL-2 production in vitro. The following methodologies were used in this example: MATERIALS AND METHODS Experimental Animals. Female Lewis rats, 2 to 3 months of age, were purchased from Charles River Laboratory, Wilmington, MA. They were housed in the animal research facility of Dartmouth Medical School and were cared for according to NIH guidelines on laboratory animal welfare. Peptide synthesis. All peptides were initially synthesized with a primary structure based on the amino acid sequence of rat PLP (disclosed in Laursen, R.A. et al. (1984) Proc. Natl. Acad. Sci. USA £1:2912; and Milner, R.J. et al. (1985) Cell 42:931) using the RaMPS Multiple Peptide Synthesis System (NEN-DuPont, Wilmington, DE) according to the manufacturer's instructions. Peptides were synthesized on a RapidAmide resin (p-methylbenzhydrylamine resin) with F-moc as the protecting group for the terminal amino acid on the lengthening peptide. To produce identical peptides varying only by N-terrninal acetylation, the peptide resin was divided into two portions following the addition of the N-terminal amino acid to the peptide. One half of the peptide-resin compound was N-terminally acetylated while the other half was not. Acetylation was done by an acetic anhydride and diisopropylethylamine method using the manufacturer's instructions (NEN- Dupont). Completed peptides were cleaved from the resin by treatment with trifluoroacetic acid and phenol. After diethyl ether extractions and peptide solubilization in water, the peptides were lyophilized and stored at -80°C until use. Unless otherwise indicated, the C- terminal amino acids of all of the peptides were amidated. To determine whether amidation of the C-terminal amino acid, a byproduct of standard peptide synthesis on RapidAmide resin, affects immunogenicity, the peptide PLP 224 was also synthesized on a Wang resin (Dupont NEN) which results in a carboxyl rather than a carboxylamide moiety at the C- terminus of the peptide. The N-acetylated peptide PLP 224 was also synthesized using the Peptide Synthesizer 432A (Applied Biosystems, Foster City, CA) to corroborate the results via an alternative peptide synthesizing mechanism. The acetylation state and specificity of synthesis of the purified peptides was confirmed by mass spectroscopic analysis; most specifically, it was determined that the N-terminal amino acid had become acetylated. Immunization and lymph node cell preparation. PLP peptides were dissolved in PBS at a concentration of 0.5 mg ml and emulsified with equal volume of complete Freund's adjuvant (CFA) supplemented with 10 mg/ml of Mycobacterium tuberculosis H37RA (DIFCO, Detroit, MI). To produce actively induced EAE, rats were immunized subcutaneously at four sites in the flanks with a total of 0.4 ml of emulsion for each rat, thus yielding an immunizing dose of 100 μg of CM peptide per rat. To produce T-lymphocyte lines for in vitro study and adoptive transfer of EAE, 0.1 ml of the same PLP-CFA emulsion were injected intradermally in the skin of the lateral lower legs of Lewis rats (50 μg of antigenic peptide per animal). Nine days later, draining popleteal lymph nodes were isolated, the lymphocytes dissociated and cultured in the presence of the immunizing peptide at 20 μg/ml. The medium employed to initiate the T cell lines and for proliferation assays (termed "initiation medium") was composed of RPMI-1640 supplemented with 1 % rat serum, 5 % NCTC-109, 5 x 10"5 M 2-mercaptoethanol, 2 mM glutamine, 100 μg/ml penicillin, 100 μg/ml streptomycin and 100 μg/ml fungizone. After 3 days in culture, the T l mphoblasts were separated by specific density using Histopaque 1.077 (Sigma, St. Louis, MO) diluted to a specific gravity o_ 1.066. The T-lymphoblasts suspended at the density phase interface were collected, washed with PBS, and cultured in a medium identical to initiation medium, except that rat serum was replaced by 10 % fetal bovine serum (HyClone Labs., Logan Utah) and the medium was supplemented with 5 % IL- 2-enriched supernatant of rat splenocytes cultured for 48 hours in the presence of 5.0 μg/ml Con A. Ten days later, the cells were used for antigen specificity assays or they were restimulated with their specific antigen for further in vitro passage and subsequent adoptive transfer studies. All of the T-lymphocyte lines were propagated for extensive periods by cyclical restimulation with antigen in the presence of irradiated syngeneic antigen presenting cells, and expanded in a medium supplemented with 5 % cytokine enriched supernatant from Con A stimulated splenocytes. Antigen Specificity Assays. The T-lymphocyte line cells were cultured in triplicate in 0.2 ml of "initiation medium" at 5 x 10^ cells per well in 96-well U bottom microtiter plates. 2.5 x 10^ irradiated (2000 rads) mixed lymph node and thymus cells from Lewis rat were added to each well as antigen presenting cells (APCs). Appropriate peptide antigens were added to the culture wells at varying concentrations. At 48 hours, each well received 0.5 μCi [-1H] thymidine in a volume of 50 μl. The cells were harvested after additional 16 hr of culture using 1295-001 Cell Harvester (LKB-Wallac Inc., Gaithersburg, MD). Counts per minute were determined by liquid scintillation counting as an indicator of cell proliferation. In addition, during selected proliferation assays, 100 μl of supernatant from each well of the 96- well plates was harvested at 24 hours and 48 hours and used for IL-2 bioassays. In such assays, an equal volume of fresh initiation medium was added to each well after the supernatant was harvested to maintain volume consistency. Abs OX-6, anti-MHC class II I-A, and OX-17, anti-MHC class II I-E, were used in proliferation inhibition assays. EAE induction and Grading. Actively induced EAE was produced by immunizing rats with an antigen-adjuvant emulsion, as noted above. Adoptive EAE was induced by the intravenous injection of PLP peptide specific T-lymphoblasts that had been stimulated in vitro for 3 days with Con A at 3.0 μg/ml or PLP peptide at 20 μg/ml in the presence of accessory cells. For adoptive transfer experiments, rats received between 5 and 30 x 10^ T cells based on the specific experiment's protocol. Clinical EAE was scored daily for all of the rats as follows: 0, no disease; 1, tail weakness or flaccid tail; 2, hind limb paralysis; 3, in addition to paralysis, animal exhibited a moribund state by not responding to stimuli (Hickey, W.F. et al. (1987) Cell. Immunol. 102:272; Hickey, W.F. et al. (1983) J. Immunol. 111:2805). Histological studies. For all rats employed in the study of peptide encephalitogenicity, the spinal chords were removed postmortem 15 days afer immunization and fixed in 10 % formalin. Paraffin embedded tissues were cut and stained with hematoxylin-eosin for histological examination. Severity of inflammation in the spinal chord sections was graded as follows: 0, no inflammation; 1, rare scattered small foci of inflammation; 2, multiple isolated foci of cell infiltration; 3, multiple confluent foci of inflammation; and, 4, foci of necrosis and/or neutrophilic infiltration. Immunohistochemistry. The lower part of the spinal cord including the lumbar enlargement was removed and snap frozen in O.C.T. Compound (Miles Inc., Elkhart, IN) without previous fixation. Cryostat sections 6 μm thick were cut and mounted on glass slides for immunohistochemical staining according to the protocol described in Hickey, W.F. et al. (1983) J. Immunol. 131:2805. In brief, following a 30 sec. exposure to absolute methanol at -20 °C and extensive rinsing in 0.5 M Tris buffer (pH 7.6), the sections were incubated with appropriate primary antibodies at 4 °C over night. After further buffer washes, the slides were incubated with biotinylated secondary anti-murine IgG antibodies for 40 min., washed in buffer, and then incubated with avidin-biotinylated horse radish peroxidase complex (Vector laboratories, Burlingame, CA) for 2 hrs. The chromatic reaction was developed by incubating slides with 3,3'-diaminobenzidine in the presence of 0.03 % H2O2. Following dehydration and mounting of coverslips, the slides were assessed histologically. The antibodies used in this experiment were all murine monoclonal antibodies specific for immunologically important rat molecules. These reagents were purchased from Harlan-Bioproducts for Science, Indianapolis, IN. The antibodies and their specificities were: OX-6, anti-RTl.B (rat MHC class II, I-A) (McMaster, W.R. and Williams, A.F. (1979) Eur. J. Immunol. 2:426); OX-8, anti-rat CD8 (Mason, D.W. et al. (1983) Immunol. Rev. 24:57); W3/25, anti-rat CD4 (Mason, D.W. et al. (1983) Immunol. Rev. 24:57; and Jefferies, W.A. et al. (1985) J. Exp. Med. 162:117); and OX-42, anti-rat CD1 lb/c (Robinson, A.P.et al. (1990) Immunology 52:239). IL-2 Bioassay. HT-2 cells, a murine lymphoma line that has a requirement for IL-2 for growth (Watson, J. (1979) J. Exp. Med. 15Q:1510), were plated into 96 well plates at 5 x 10 3 cells/well in 0.2 ml of medium. Fifty microliters of the supernatants harvested from proliferation assay plates was added to the wells of the IL-2 assay plate. An IL-2 standard was also added as a positive control. After 24 hours of incubation, the plate was pulsed with 0.5 μCI [3H]thymidine per well. Sixteen hours later, the cells were harvested and radioactive thymidine incorporation was determined as a relative indicator of IL-2 production. Ultrastructure. For ultrastructural examination, rats with paralytic EAE induced by adoptive transfer of anti-PLP peptide T cells were deeply anesthetized and perfused via the aorta with calcium- and magnesium-free modified PBS. This was followed by 200 ml of 4 %p- formaldehyde in 0.1 M phosphate buffer, pH. 7.4. The CNS tissues were removed and further fixed in 1 % glutaraldehyde and 3 % j. -formaldehyde in cacodylate buffer. Tissues were then postfixed in osmium tetroxide, dehydrated, and embedded in epon. One-micron sections were cut from each block of tissue and stained with toluedine blue for histologic inspection. From these sections, appropriate areas for ultrastructural study were selected. RESULTS Table I: Peptides used in this studva Peptides Sequences PLP 217 217 KVCGSNLLSICKTAEFQ 233 (SEQ ID NO: 14) PLP 220 220GSNLLSICKTAEFQM234 (SEQ ID NO: 15) PLP 224 224 LSICKTAEFQMTFHLFI2 40 (SEQ ID NO: 16) PLP 224-233 24 LSICKTAEFQ 2 33 (SEQ ID NO: 17) a Each peptide was either N-terminally acetylated and nonacetylated. Peptide PLP 224 was also synthesized without C-terminal amide. The selection of these peptides for study is based on the presence of an MHC class II molecule binding motif, which entails a serine residue separated from a glutamine acid residue by five amino acid residues (S-x-x-x-x-x-E) (SEQ ID NO: 1). Scanning the rat PLP sequence revealed only one area, between residue 225 and 231 , containing such a putative motif. This area lies in a small extracellular loop of hydrophobic residues, termed the C3 domain, according to Laursen's model (Laursen, R.A. et al. (1984) Proc. Natl. Acad. Sci USA £1:2912). Prompted by Rothbard's observation that acetylation of T cell epitopes could enhance T cell proliferative responses in vitro (Rothbard, J.B. et al. (1989) Philos. Trans. R Soc. Lond-Biol. Sci. 222:553), the N-terminal acetyl group in the PLP peptides was included. In addition, peptide PLP 224 was also synthesized on a Wang resin, yielding acetylated or nonacetylated peptides with a free C-terminal carboxyl group. The solubility of all of these synthetic peptides is suitable for both in vivo and in vitro work, and is much better than native whole PLP protein. There is no difference in solubility between the acetylated and nonacetylated PLP peptides. The ease of solubility of the peptides decreases as more amino acids are added at the C-terminal end, as would be predicted by previous hydrophobicity domain predictions based on PLP sequence (Laursen, R.A. (1984) Proc. Natl. Acad. Sci USA £1:2912; Milner, R.J. et al. (1985) Cell 42:931, Hudson, L.D. et al. (1989) J. Cell Biol. 1_0_2-' 17). Nevertheless, all four peptides produced a vigorous T cell response. It is notable that acetylated peptide PLP 224 was the most encephalitogenic of the three, although it was not as readily dissolved in aqueous media as were the others. The predicted m.w. of synthetic peptides was confirmed by using mass spectroscopy. In addition, all peptides were shown to be greater than 90% pure by using HPLC analysis. Active induction of EAE. Three peptides, either N-acetylated or with a free N-terminal, were tested for their ability to induce EAE. Three to six Lewis rats were immunized with each peptide and the animals were followed up for development of clinical disease for up to 30 days postimmunization. As shown in Table II, only one rat, which had been immunized with acetylated peptide PLP 217, developed clinical signs of EAE after active immunization. However, histologic examination of the spinal cords from these actively immunized with acetylated peptides PLP 217 and PLP 224 developed the typical inflammation in the lower spinal cord with average histologic severity scores histologic severity scores of 2.2 and 2.0, respectively. Mild histologic inflammation was also found in two of the four animal immunized with the acetylated peptide PLP 220. In contrast to the three longer peptides, no histologic inflammation was observed in animals immunized with acetylated peptide PLP 224-233. Most significantly, none of the animals immunized with the nonacetylated peptides presented with either clinical signs of CNS inflammation. Table II: Active and adoptive induction of EAE a Active EAE Adoptive EAE Peptides 0 Clinical Histologic Clinical Histologic Nonacetylated PLP 217 0/5 (0) 0/5 (0) 0/1 (0) 0/1 (0) PLP 220 0/3 (0) 0/3 (0) 0/2(0) 2/2 (1.5) PLP 224 0/4 (0) 0/4 (0) 0/2 (0) 0/2 (0) Acetylated PLP 217 1/6 (1) 6/6 (2.2) 2/7 (1.5) c 6/7 (2.3) PLP 220 0/4 (0) 2/4 (0.7) 0/1 (0) 0/1 (0) PLP 224 0/6(0) 6/6 (2.0) 3/7 (2.3)c 7/7 (2.2) PLP 224-233 0/4(0) 0/4 (0) 0/4 (0) 0/4 (0) a The fraction represents the numbers of rats with clinical disease or histologic inflammation over the total rats tested for that peptide. The numbers in parentheses represent the mean severity score of clinical disease or histologic inflammation. b All of the peptides had a C-terminal amide group. c One rat received T cells stimulated with acetylated peptide PLP 217 or PLP 224. All of the other rats received the Con A-stimulated T cells. Adoptive induction of EAE. T lymphocyte lines against acetylated and nonacetylated PLP peptides were generated and their specificity for the inducing PLP peptide Ag was confirmed in vitro (see below and Table III). The results of the adoptive transfer experiments are summarized in Table II. Two of the seven recipients of T cells specific for acetylated peptide PLP 217 developed clinical signs of EAE, with the average score of 1.5. Six of these animals exhibited histologic inflammation, with the average severity score of 2.3. Three of the seven recipients of T cells specific for acetylated PLP 224 developed paralytic clinical EAE between days 4 and 6, with the average clinical score of 2.3, and all of these animals showed histologic inflammation with the average score of 2.2. Of the rats injected with T cells specific for nonacetylated peptide PLP 217 or nonacetylated peptide PLP 224, and the one recipient of T cells specific to acetylated peptide PLP 220, none exhibited clinical signs or histologic abnormalities characteristic of EAE. Rats injected with T cells against non- acetylated peptide PLP 220 developed histologic inflammation in the spinal cord although they exhibited no clinical illness. The four animals that received activated T cells specific for acetylated peptide PLP 224-233 developed neither clinical EAE nor histologic inflammation. In the early phases of this study, it was noted that development of clinical signs of EAE depended to some extent on the number of T cells injected. Although 6 x 10^ T cells were able to induce histologic inflammation, at least 15 x 10^ cells were required for the development of clinical disease. However, this phenomenon could not explain the failure of the nonacetylated peptides to induce disease, because in all cases, the rats received a minimum of 15 x 10^ cells before the T cell line was determined to be nonencephalitogenic. Moφhologic features. Microscopic examination of the spinal cords from the rats with either active EAE or adoptive EAE showed extensive submeningeal and perivascular inflammatory infiltration consisting of mononuclear cells. These infiltrates could be frequently observed to extend beyond the perivascular area and into the CNS parenchyma. In some rats without clinical EAE, as noted in Table II, severe inflammation could be found in the spinal cords. Thus, it seems that there is possibly a divergence between the development of clinical signs and intensity of histologic inflammation in PLP-induced EAE which is distinct from the findings in MBP-induced EAE in the Lewis rat (Hickey, W.F. et al. (1983) J. Immunol. 131:2805). Ultrastructural examination of axons at the edge of an area of inflammation clearly demonstrated demyelination of a few axons; but extensive demyelination was never observed with these peptide Ags, as previously reported for whole PLP (Yamamura, T. et al. (1986) J Neurol. Sci. 26:269). Immunohistochemical findings. Immunohistochemical analysis showed that the most prevalent cell types in the inflammatory infiltrates were CD4 + T cells and macrophages; scattered CD8 + T cells were also found in the lesions. MHC class II expression was increased on microglial cells and perivascular cells in the vicinity of the lesions. These findings are identical with EAE induced by MBP immunization or by transfer of MBP- specific T cells (Hickey, W.F. et al. (1987) Cell Immunol. 1QS..212; Hickey, W.F. et al. (1983) J. Immunol. 111:2805). Ag-specificity and 11-2 biossays. The specificity of T cell lines used in adoptive EAE experiments and the importance of N-acetylation of PLP peptides on T cell response were further confirmed in vitro. As shown in Table III, the acetylated peptide PLP 224-specific T cells exhibit strong response, not only to the Ag with which they were induced, but also to the two other overlapping peptides PLP 217 and PLP 220 of both the acetylated and nonacetylated forms. However, these anti-PLP peptide T cell lines did not respond to either purified guinea pig MBP or to the synthetic encephalitogenic peptide for the Lewis rat derived from the sequence of guinea pig-MBP (Mannie, M.D. et al. (1985) Proc. Natl. Acad Sci. USA £2:5519). Furthermore, it was determined that the anti-MHC class II, I-A (RT-IB) Ab OX-6 inhibited Ag-induced T cell proliferation, whereas anti-MHC class II, I-E (RT-1D) Ab OX- 17 did not, indicating that T cell recognition of these PLP peptides is restricted by Lewis rat RT-IB 1 (Table III). Phenotyping by flow cytometric analysis showed that 95% of these T cells are CD4 positive. In all instances, it was noted that the T cell lines responded more strongly to acetylated peptides than to non-acetylated peptides (see Fig. 1). Over the peptide concentration range of 1 to 20 μg/ml, there were three-to sevenfold greater T cell responses to the N-acetylated than to the nonacetylated peptides. Moreover, IL-2 production assays were consistent with the enhanced ability of acetylated peptides to induce a stronger T cell response than nonacetylated peptides (see Fig. 2). The effect of C-terminal amidation of both acetylated and nonacetylated peptide PLP 224 on the T cell response to Ag was also examined (Table III). The data show that the T cell line responded comparably to acetylated peptide PLP 224s with a C-terminal amide group or carboxyl group, demonstrating that in this system the amide moiety is not as important as N-terminal acetylation in enhancing T cell responses. Table III: Proliferative response of T cell lines induced by acetylated PLP 224 upon stimulation by different peptides a Antigens Concentration CPM (mean ± SD) SI Experiment l c No antigen 0.0 μg/ml 0 ± 20 1.0 Ac-PLP 224 5.0 μg/ml 24,348 ± 4,782 e 486.9 0.1 μg/ml 4,375 ± 863 87.5 PLP 224 5.0 μg/ml 17,284 ± l,260 e 345.9 0.1 μg/ml 302 ± 54 6.6 Ac-PLP 217 5.0 μg/ml 21,654 ± 1,263 433.8 Ac-PLP 220 5.0 μg/ml 24,328 ± 1,462 486.6 GP-MBP 20.0 μg/ml 72 ± 18 1.4 MBP peptide (a.a. 68-88) 20.0 μg/ml 42 ± IS 0.8 PLP 263-276 d 20.0 μg/ml 55 ± 16 1.1 Experiment 2 C No antigen 0.0 μg/ml 403 ± 43 1.0 Ac-PLP 224 20.0 μg/ml 55,337 ± 4,276 137 Ac-PLP 224+ OX-6 20.0 μg/ml 12,695 ± 4,922 31 Ac-PLP 224 + OX-17 20.0 μg/ml 42,309 ± 6,077 104 Experiment 3 C No antigen 0.0 μg/ml 63 ± 2.8 1.0 Ac-PLP 224 5.0 μg/ml 1,945 ± 367 30.8 Ac-PLP 224-COOH 5.0 μg/ml 1,714 ± 170 27.2 a The results are derive dfrom three representative experiments, a.a., amino acid; Ac- means N-terminal acetylation; -COOH indicates carboxyl group on C-terminal amino acid of the peptide; all of the other peptides were amidated on their C-terminal amino acids. ". SI means stimulation index as defined by the magnitude of the proliferative response [ 3 H]thymidine incorporation generated counts per minute) for specific Ag compared with a base line incorporation of [ 3 H]thymidine without Ag. c These T cell lines were distinct, being established at separate times. " The nonacetylated C-terminal portion of the PLP molecule, used here as a control Ag. e Statistical comparisons were made between the T cell responses to the acetylated and nonacetylated peptides at equal concentration using a t-test method. Significant differences were found at concentrations of 5.0 μg/ml (p<0.05) and 0.1 μg/ml(p<0.01). The importance of N-terminal acetylation is highlighted by the results obtained when T cell lines induced with a nonacetylated peptide PLP were stimulated with the acetylated version of that peptide to which they had not been previously exposed (Table IV). Table IV: Response of T cell lines induced by nonacetylated PLP 220 to acetylated PLP 220 Δg Concentration CPM (mean + S.D.. S No antigen 0.0 μg/ml 192 ± 23 1.0 Ac-PLP 220 2.5 μg/ml 56,045 ± 4,921 291 0.5 μg/ml 43,688 ± 3,318 a 227 0.1 μg/ml 30,007 ± 2,417 156 PLP 220 2.5 μg/ml 56,673 ± 5,555 279 0.5 μg/ml 23,510 ± l,638 a 122 0.1 μg/ml 8,417 ± 2,329 43 e Statistical comparisons were made between the T cell responses to the acetylated and nonacetylated peptides at equal concentration using a t-test method. Significant differences were found at concentrations of 5.0 μg/ml (p<0.05) and 0.1 μg/ml(p<0.01). In every instance, the Ag-induced proliferation of the T cells and their IL-2 production was greater for the acetylated peptide than for an equal quantity of nonacetylated peptide, even when the T cells were induced by-and previously only stimulated with-the nonacetylated from of PLP peptide. Moreover, this enhanced ability of the acetylated peptide to induce greater proliferation at a given Ag concentration than the nonacetylated form applied not only to the peptide species used to induce the T cell line, but also to the other peptides which partially overlapped with the specific peptide. Thus, the above information, when combined with the clinical and histologic findings, provides strong evidence that the N- terminal acetylation of the PLP peptides used here may play a significant role in the pathogenesis of PLP-induced EAE, the T cell proliferative response to these peptides, and IL- 2 production. EXAMPLE ?; Type I diabetes (also referred to as insulin-dependent diabetes mellitus), an autoimmune disease which occurs in humans and animals, is characterized by the destruction of insulin-secreting islet β-cells of the pancreas. Epidemiological studies in man have documented a strong genetic predisposition linked to HLA-DR3, -DR4 and -DQ3.2 class II alleles of the human MHC (see e.g., Wolf, E. et al. (1983) Diabetologia 24:224-230; Platz, P. et al. (1981) Diabetologia 21:108-115; Warram, J. et al. (1994) in Joslin's Diabetes Mellitus, R. Kahn and G. Weir (eds.), Philadelphia, PA, Lea & Febiger, pp. 201-215; and Tait, B.D. et al. (1991) Bailliere's Clin. Endocrinol. & Metab. 5:211-228). This suggests a significant association between pathogenic pancreatic autoantigen(s) and antigen presentation to T lymphocytes in the context of these specific MHC class II molecules. In this example, a rat MHC class II (RTl.B*) binding motif was used to predict potentially autoreactive CD4 + T cell epitopes in two islet β-cell constituents: the enzyme glutamic acid decarboxylase (GAD) and the insulin precurser hormone, proinsulin (PI). Seventeen-amino acid long peptide fragments of GAD and PI containing the binding motif were synthesized and used to generate peptide-specific, MHC Class Il-restricted, CD4 + T cell lines. Once established, the T cell lines specific for rat islet GAD and PI were adoptively transferred to naive rats. At 10 days post-transfer, insulitis had developed in rats receiving proinsulin-specific T cells, while no insulitis was observed in pancreases of rats receiving GAD-specific T cells. The pathogenic PI peptide-specific T cells are CD4 + /CD8" and secrete TH like cytokines in response to antigen. The results described herein demonstrate that an MHC class II binding motif can be used to predict a pathogenic T cell epitope of rat proinsulin. This example further provides a novel, antigen-specific model of autoimmune insulitis by T cells specific for a peptide fragment of proinsulin. The following methodologies were used in this example: MATERIALS AND METHODS Animals, DA(RP) rats, with the MHC type RT1.A U B -D -E/Ca, were used in these studies. This rat strain develops neither spontaneous insulitis nor diabetes. DA(RP) strain rats were originally obtained from Dr. Heinz Kunz (Department of Pathology, University of Pittsburgh, Pittsburgh, PA), and a breeding colony was maintained in the Animal Research Facility of the Dartmouth Medical School, Lebanon, NH. Both male and female DA(RP) rats were used in experiments between the ages of 50-70 days. All procedures and animal care were in accordance with the National Institutes of Health guidelines on laboratory animal welfare. MHC Class II Binding Motif Peptide Synthesis. Sequences of the PI and GAD peptides containing the binding motif were synthesized by standard F-moc chemistry using the RapidAmide Multiple Peptide Synthesis (RaMPS) system (NEN-Dupont, Wilmington, DE). Given that MHC Class Il-restricted T cells typically recognize peptides between 13-25 amino acids in length (Zamvil, S. et al. (1986) Nature 224:258-260; Wraith, D.C. et al. (1989) Cell 52:247-255), GAD and PI peptides were extended by four to six amino acids on each end of the motif, and synthesized to yield 17-amino acid long peptides (designated GAD412, GAD520- and PI). Moreover, peptides were N-terminally acetylated to encourage α-helix formation and MHC interaction (Mains, R. et al. (1983) Trends Neurosci. 6:229-235). Generation of Peptide-specific T Cell Lines and Adoptive Transfer. Individual T cell lines were generated against GAD412, GAD520 and PI peptides. To initiate T cell lines, peptides were emulsified in complete Freund's adjuvant (CFA) supplemented with 5 mg/ml H37RA (DIFCO, Detroit, MI) and injected intradermally in the hind footpads of DA(RP) rats in a final concentration of 200 μg peptide. After nine days, rats were sacrificed via Fluothane anesthesia (Ay erst Laboratories, New York, NY) to obtain popliteal lymph nodes. Lymph nodes were mechanically dissociated with forceps into a single cell suspension, washed two times in phosphate buffered saline (PBS), and resuspended in initiation medium with 50 μg/ml peptide. Initiation proliferation medium consisted of RPMI 1640, 1 % autologous rat serum, 5 % NCTC-109 (BioWhittaker Products, Walkersville, MD), 2 mM glutamine, 100 U/ml penicillin, 100 μg/ml streptomycin, 100 μg/ml fungizone (ICN Biomedicals, Costa Mesa, CA), and 5 x 10' 5 M 2-mercaptoethanol (Sigma, St. Louis, MO). After three days, T-lymphoblasts were collected by density centrifugation using Histopaque- 1.077 (Sigma), washed two times in PBS, and resuspended in medium containing 10 % fetal calf serum and 5 % IL-2-rich supernate from concanavalin A-stimulated spleen cells. Peptide-specific T cell lines were allowed to come to a resting state 7-10 days after the initiatial in vitro stimulation with peptide, then restimulated with irradiated thymocytes (2000 rad) and 20 μg/ml peptide. For adoptive transfer studies, anti-GAD and anti-PI T cells were stimulated with either peptide (20 μg/ml) or the mitogenic lectin concanavalin-A (5 μg/ml) for 72 hr prior to intravenous (i.v.) injection into naive recipients. Ten days following i.v. transfer of peptide-specific T cells (ranging in concentrations from 25 - 120 x 10^), rats were sacrificed under ether anesthesia to obtain the pancreas. Tissue was fixed in 10 % formalin, embedded in paraffin, sectioned (6 microns), mounted and stained with hematoxylin and eosin. Antigen Specificity and MHC Restriction of Peptide-specific T Cell Lines. Peptide-specific T cells were collected and co-cultured in triplicate (5-7 x lO^/well) with or without peptide (5-20 μg/ml), irradiated (2000 rad) thymocytes (5 x 10-Vwell) as antigen presenting cells (APC), OX-3, OX-6 or OX-17 (anti-RTl.B and D) antibodies, or W3/25 (anti-CD4), OX-8 (anti-CD8) antibodies for 72 hr, including a final 18 hr pulse with -1H-Thymidine (0.5 μCi/well). -^H-Thymidine incorporation was measured by liquid scintillation counting (Wallac, Gaithersburg, MD) and the results expressed as stimulation indices ± one standard deviation (SD) for triplicate cultures. Cytokine Production Profile of Peptide-specific T cells. Proinsulin-specific T cells were tested for cytokine production in response to PI peptide. Proinsulin peptide specific levels of interleukin 2 (IL-2) and interleukin 4 (IL-4) were measured in a bioassay using IL-2-dependent HT-2 cells, and IFN-γ production was measured with an ELISA specific for rat IFN-γ (GIBCO BRL, Gaithersburg, MD). Briefly, 100 μl aliquots of supernatant were collected from in vitro cultures of Pi-specific T cells, PI peptide, APC + anti-MHC Class II antibodies at 40 hr for IL-2 and IL-4 assay, and 72 hr for IFN-γ. Interleukin-2 containing supernates were cultured with 1 x 10-^ HT-2 cells for 48 hr, including a pulse with -1H-Thymidine for the final 12 hr of culture. Interleukin-4 containing supernates were cultured with 1 x 10-^ HT-2 cells which had been preincubated with an IL-2 receptor antibody (PC 61.5.3, ATCC, Rockville, MD). After 48 hr, HT-2 cells were harvested and -1H-Thymidine uptake measured by liquid scintillation counting. Flow Cytometric Analyses of Peptide-specific T Cell Lines. Pl-specific and GAD-specific T cells were stimulated with 20 μg/ml peptide or 5 μg/ml concanavalin A for 72 hr prior to determinations of surface antigen expression. Samples of 1 x 10^ anti-PI T cells each were stained with primary antibody (OX- 19 (CD5); W3/25 (CD4); OX-8 (CD8); R7.3 (αβ T cell receptor); OX-3, OX-6, OX-17 (RT1.B and RT1.D); OX-22 (CD45RC); 12.5-20 μg/ml protein from ascities; Harlan Bioproducts for Science, Indianapolis, IN) for 30 min on ice, washed twice, then incubated with fluorescein isothiocyanate (FΙTC)-conjugated goat anti-mouse F(ab)'2 antibody (Cappel-Orginon Teknika, West Chester, PA) for 30 minutes on ice, washed twice and fixed with 1 % paraformaldehyde/PBS. Control staining consisted of cells stained with an IgGl isotype control antibody (MOPC 21, Sigma, St. Louis, MO) in place of primary antibody, in addition to unstained cells and cells stained with secondary antibody only. Cells were analyzed on a FacScan flow cytometer (Becton-Dickinson, Lincoln Park, NJ). RINm5F Insulinoma Cells. RINm5F insulinoma cells (Gadzar, A. et al. (1980) Proc. Natl. Acad. Sci. USA 22:3519-3523) were obtained from Dr. Walter Hsu, Iowa State University. RIN cells were cultured in RPMI 1640 medium supplemented with 10 % heat-inactivated fetal calf serum (Hyclone), 100 μg/ml streptomycin, 100 U/ml penicillin, and 2mM L-glutamine (Bio Whittaker). Exhausted RIN cell supernatant was collected after 5 days of growth, 50-70 % confluency of RIN cells. Supernates were centrifuged, sterile filtered and stored at -20 °C until use in Pi-specific T cell assays. RIN cell supernate was added in a 20 % v/v concentration to Pi-specific T cells in vitro. RESULTS Proinsulin (PI) and GAD peptides containing the MHC Class II binding motif were synthesized and used to generate T cell lines. Table V lists the amino acid sequences of the synthetic PI and GAD peptides. Figure 3 represents a diagram of the proximal relationship between the amino acid sequence of rat preproinsulin, the MHC Class II binding motif, and the cleavage products of insulin and C-peptide. TABLE V Amino Acid Sequences of Synthetic Peptides containing the MHC Class II (RT1.B--) Binding Motif a) rat PROINSULIN * * PROINSULIN I 47 G F F Y T P K S R E V E D P Q V 63 (SEQ ID NO: 18) PROINSULIN II 47 G F F Y T P M S R R E V E D P Q V 63 (SEQ ID NO: 19) b) rat islet GAD412 4 _ 2 L L Q c s I L V K E K G I Q G 428 (SEQ ID NO: 20) c) rat islet GAD520 520 γ I p Q s L R G v P D S P E R R E 536 (SEQ ID NO: 21) *represents cleavage site during processing of proinsulin to insulin; Arg- Arg residues are released as a dipeptide at the separation of the insulin B-chain and C-peptide. Proinsulin-specific and GAD-specific T cell lines were adoptively transferred to DA(RP) rats by i.v. tail vein injection. Ten days following transfer of peptide-specific T cells, pancreases were obtained and examined for signs of histopathology by staining with hematoxylin and eosin. No detectable insulitis was observed in pancreases of rats receiving GAD412- or GAD52fj-specific T cells (range = 3.0-12.0 x 10? cells/rat) relative to untreated pancreas. In contrast, the intravenous injection of 3.0-7.0 x lθ ' * 7 T cells/rat specific for PI peptide caused insulitis in all DA(RP) rats (n=l 8). The average inflammatory involvement of islets per pancreas section/per rat was 40 + 6 % (range 21-62 % per pancreas section) by day 10 post-transfer of Pl-specific T cells. Within pancreas sections, the severity of islet involvement ranged from no involvement to early peri-insular inflammation, to marked insulitis. Immunohistochemical analysis revealed that Pi-induced insulitis consisted primarily of CD4 + T cells and macrophages, an infiltrate typical of delayed type hypersensitivity and autoimmune reactions in the rat. The phenotypic and functional characteristics of the GAD and Pi-specific T cell lines were investigated to determine antigen specificity and MHC restriction. Figure 4 shows -1H-Thymidine incorporation assay results for anti-GAD and anti-Pi T cell lines and their MHC Class II restriction patterns. The stimulation index (S.I.) is defined as the mean cpm of the experimental sample divided by the mean cpm of control wells (medium only). -1H- thymidine incorporation assays were replicated 2-3 times for cells of each line at the time of the second in vitro stimulation with peptide. GAD and Pi-specific T cells responded to their respective peptides and did not crossreact with other peptides containing the class II binding motif. Proliferation of both GAD T cell lines containing the S-E binding motif was inhibited by the addition of anti-RTl.B antibody (Ox-3 & Ox-6), but not anti-RTl.D (Ox-17) antibody (Figure 4, panel A: GAD412; panel B: GAD520)- Proliferation of Pi-specific T cells to 20 μg/ml PI peptide could be partially inhibited by antibodies against RT1.B (54-67 %) and RT1.D (22-25 %) molecules individually, and significantly inhibited by the addition of RT1.B and D antibodies together (>90%) (Figure 4, panel C). This inhibitory effect of anti-MHC Class II antibodies followed the same pattern irrespective of the antigen presenting cell (APC) source used (i.e., DA(RP) or the RTl.B/Dl congenic Lewis strain rat). In addition, Pi-specific T cells proliferated in response to a insulin/proinsulin-containing supernatant from the rat insulinoma cell line, RINm5F, and this proliferation could be blocked by the addition of anti-RTl.B antibody. Both GAD-specific and Pl-specific cell proliferation was abrogated by monoclonal antibodies against CD4, but not CD8, indicating that only CD4 positive T cells responded to GAD and PI peptides. Pl-specific T cells were monitored in vitro for cytokine production in response to PI peptide with or without MHC Class II blocking antibody. Pl-specific T cells secreted marked amounts of both IL-2 and IL-4 in response to PI peptide, even in the presence of antibodies to MHC Class II that inhibited proliferation. Furthermore, Pl-specific T cells secreted IFN-γ in response to PI peptide alone (22.5 + 0.2 ng/ml) as measured by an ELISA specific for rat IFN-γ (GIBCO). IFN-γ production in response to PI peptide in combination with individual class II antibodies (Ox-3 and Ox-17) averaged 23.8 + 0.3 ng/ml, and then dropped to 12.5 + 0.2 ng/ml in cultures where ^H-Thymidine incorporation in response to PI peptide was significantly inhibited by the addition of Ox-3 and Ox- 17 together (Figure 4, C). Cell surface antigen expression of the T cell lines was defined by flow cytometric analysis using a FACScan (Becton-Dickinson) and is shown in Figure 5. Pl-specific T line cells were positive for TcRαβ, were predominantly of the CD4 + /CD8" phenotype, and exhibited negligible expression of CD45RC (<1 %). The cell surface phenotype exhibited by cells specific for GAD 4 ι 2 and GAD 52 o lines was similar. Depletion of the Pl-specific T cell line of the small number of CD8 + cells (using magnetic beads; DYNAL, Lake Success, NY) neither abolished the ability of the remaining CD4 + /CD8" cells to respond vigorously to the PI peptide, nor inhibited the ability of the CD4 + cells to adoptively transfer insulitis. Therefore, in DA(RP) rats, it appears that CD4 + T cells specific for a peptide fragment of PI can mediate the adoptive transfer of insulitis, rather than T cells specific for comparable GAD peptides, even though all peptides result in vigorous, antigen-specific CD4 + T cell proliferation. In order to assess the persistence of antigen specificity of GAD- and Pl-specific T cell lines in vivo, spleens were removed from rats injected with either GAD- or Pl-specific T cells 18 days post-transfer. Splenocytes from rats injected with Pl-specific cells exhibited the ability to respond specifically to PI peptide, but not GAD, as measured by -1H-Thymidine incoφoration (anti-PI T cell line response to PI peptide stimulation index (S.I.) = 41.9 vs. response to GAD = 1.9). Similarly, splenocytes from rats injected with GAD-specific T cells were found to proliferate markedly to GAD peptide (S.I. = 21.6) but not PI peptide (S.I.= 1.3). Moreover, the islets of rats which received Pl-specific T cells exhibited more severe insulitis at day +18 than at day +10 (63 ± 10 % involvement of islets). Pancreases from rats injected with GAD-specific T cells still showed no evidence of insulitis 18 days post-transfer. Of particular interest is the finding that the pathogenic T cell epitope identified in proinsulin spans the endogenous cleavage site between the B-chain and C-peptide of insulin. Under normal enzymatic processing of proinsulin to the insulin B-chain and C-peptide, the exact area which contains the two overlapping binding motifs (as shown in Table V) is cleaved so that both motifs are destroyed (see Figure 3). The aforementioned area of proinsulin would exist intact in significant quantities only in islet β-cells or in their vicinity where proinsulin is processed in an alternative manner. These results demonstrate that pathogenic T cell epitopes can be located in portions of molecules which are subsequently degraded during normal enzymatic processing. Since proinsulin is found in highest concentrations in the β-cells of pancreatic islets, it is possible that this molecule, and not its individual degradation products (i.e., insulin and C-peptide) may serve as an autoantigen in the pathogenesis of Type I diabetes. Almost 99 % of proinsulin is destined to become insulin via a regulated-release pathway from the β-cell granule, however, residual proinsulin travels in secretory vesicles along a constitutive release pathway (see Sizonenko, S. et al. (1991) Biochem. J. 22£:621-625; Sizonenko, S. et al. (1993) Diabetes 42:933-936; Hutton, J.C. et al. (1989) Diabetologia 22:271-281; Halban, P.A. et al. (1991) Diabetologia 24:767-778). Of interest relative to the clinical onset of Type I diabetes is the finding that circulating proinsulin levels can be more than two times greater in recently diagnosed diabetics than in nondiabetics (Heaton, D. et al. (1988) Diabetologia 21:182-184; Heding, L. et al. (1981) Acta. Med. Scand. Suppl. 656:509). In this example, it was possible to use both GAD and PI peptides to successfully generate peptide-specific T cell lines, the majority of which were CD4 + and MHC Class Il-restricted in recognition of their respective peptides in vitro. Both Pl-specific and GAD-specific T cells were found to persist at least three weeks in the spleen following transfer and retain their antigen specificity. However, adoptive transfer experiments revealed that only Pl-specific T cells were capable of mediating insulitis in vivo. Although splenocyte responses to GAD occur prior to detectable insulitis and suggest a role for GAD in the pathogenesis of autoimmune insulitis in NOD mice (see Kaufman, D.L. et al. (1993) Nature 266:69-72; Tisch, R. et al. (1993) Nature 266:72-75), the present studies found that rat T cells specific for selected GAD peptides do not produce islet lesions. The present study has identified another potentially significant autoantigen in addition to GAD by demonstrating that proinsulin-reactive T-cells are sufficient to yield insulitis. It has been shown that insulitis precedes diabetes by 2-3 weeks in BB rats (see Colle, E. (1990) Clin. Immunol. Immunopathol. 52:1-9). Given that circulating insulin levels in humans and mice with Type I diabetes are not significantly reduced until >95% of the islets are destroyed (Katz, J.D. et al. (1993) Cell 24:1089-1100), ongoing studies are monitoring insulitis and blood glucose levels for extended periods in rats given Pl-specific T cells to determine if overt diabetes ensues as islets are increasingly involved by inflammatory cells. EXAMPLE 3: Cardiac myosin (CM) has been implicated as an autoantigen in the induction of experimental allergic myocarditis (EAM), although no myocarditogenic peptides of CM have been identified to date. In this example, a peptide of CM heavy chain was identified that, when used to immunize Lewis rats, induces the development of EAM. This peptide was selected by scanning the amino acid sequence of CM alpha and beta heavy chains looking for peptides that fulfilled two criteria. The first criterion was that selected peptides must contain a class II binding motif of the MHC class II molecule RT1.B 1 . This binding motif consists of serine and glutamic acid residues separated by five intervening amino acids (S-x-x-x-x-x-E) (SEQ ID NO: 1). Nine peptides were found that fulfilled this first requirement. The second criterion was that the amino acid sequences of these CM peptides ought to be unique to CM and not shared with skeletal muscle myosin. This second requirement is based on the observation that skeletal myosin does not induce myocarditis. Three S-E containing peptides fulfilled this second criterion and correspond to a.a. 1309-1315, a.a. 1544-1550, and a.a. 1845-1851. Synthetic peptides corresponding to a.a. 1304-1320 (CM #1), a.a. 1539-1555 (CM #2), and a.a. 1840-1856 (CM #3) of rat CM alpha heavy chain were prepared. The CM peptides were synthesized in both nonacetylated and N-terminally acetylated forms, since it has previously been observed that the immune response to peptides derived from self antigens can in some instances be enhanced by the acetylation of the N-terminal amino acid (see e.g., Rothbard, J.B. et al. (1989) Phil. Trans. R. Soc. Lond. 222:553). The ability of CM #1, CM #2 or CM #3 (either acetylated or nonacetylated) to induce EAM, either by direct immunization or by adoptive transfer of T cells from immunized animals, was examined. The results demonstrate that animals immunized with acetylated CM #2 emulsified with complete Freund's adjuvant develop active myocarditis. Furthermore, T cell lines specific for either acetylated CM #2 or nonacetylated CM #2 were able to adoptively transfer EAM to normal Lewis rat recipients. Additionally, lymph node cells specific for acetylated CM #1 could mediate the transfer of EAM to normal recipients. Thus, an MHC class II binding motif can be used as a basis for identification of self reactive peptides of cardiac myosin. The following methodologies were used in this example: MATERIALS AND METHODS Experimental Animals. Female Lewis rats, 6 to 8 weeks of age, were purchased from Charles River Laboratory, Wilmington, MA. DA(RP) rat strain is bred and maintained by the animal research facility at Dartmouth Medical School. The Lewis (RT11) and DA(RP) rat strains are syngeneic at the RT1.B and RT1.D locus and disparate at other MHC loci (RT11 and RT1 U respectively). All rats were housed in the animal research facility of Dartmouth Medical School and were cared for according to NIH guidelines on laboratory animal welfare. Peptide synthesis. Synthetic peptides corresponding to amino acids 1304-1320 (CM #1), a.a. 1539-1555 (CM #2), and a.a. 1840-1856 (CM #3) of rat CM alpha heavy were prepared. All peptides were synthesized with a primary structure based on the amino acid sequence of the alpha chain of rat CM heavy chain (disclosed in McNally, E.M. et al. (1989) J. Mol. Biol. 2U_:665) using the RaMPS Multiple Peptide Synthesis System (NEN-DuPont, Wilmington, DE) according to the manufacturer's instructions. Peptides were synthesized on a RapidAmide resin (p-methylbenzhydrylamine resin) with Fmoc as the protecting group for the terminal amino acid on the lengthening peptide. In the production of identical peptides varying only by N-terrninal acetylation, the peptide resin was divided into two portions following the addition of the N-terminal amino acid to the peptide, and one half of the peptide-resin compound was N-terminally acetylated while half was not. The carboxy terminal amino acid of all peptides was amidated, a byproduct of standard RaMPS peptide synthesis. Completed peptides were cleaved from the resin by treatment with trifluoroacetic acid and phenol. Following standard diethyl ether extractions and peptide solubilization in water, the peptides were lyophilized and stored at -80°C After synthesis all peptides were shown to contain one major peak on HPLC Immunization and lymph node cell preparation. CM peptides were dissolved in PBS at a concentration of 2 mg/ml and emulsified with equal volume of complete Freund's adjuvant supplemented with 5 mg/ml of Mycobacterium tuberculosis H37RA (DIFCO, Detroit, MI). To produce actively induced EAM, rats received a single immunization at four subcutaneous sites on the flanks with a total of 0.4 ml of emulsion for each rat, thus yielding an immunizing dose of 400 μg of CM peptide per rat. To produce T-lymphocyte lines for in vitro study and adoptive transfer of EAM, 0.1 ml of the same CM-CFA emulsion were injected intradermally in the skin of the lateral lower legs of Lewis rats (200 μg of antigenic peptide per animal). Nine days later, draining popleteal lymph nodes were isolated, the lymphocytes dissociated and cultured in the presence of the immunizing peptide at 20 μg/ml. The medium employed to initiate the T cell lines and for proliferation assays (termed "initiation medium") was composed of RPMI- ϊ 640 supplemented with 1 % rat serum, 5 % NCTC-109, 5 x 10 ~ 5 M 2-mercaptoethanol, 2 mM glutamine, 100 μg/ml penicillin, 100 μg/ml streptomycin and 100 μg/ml Fungizone. After 3 days in culture, the cells were separated by specific density using Histopaque 1.077 (Sigma, St. Louis, MO). The T-lymphoblasts suspended at the density phase interface were collected, washed with PBS, and cultured in a medium identical to initiation medium, except that rat serum was replaced by 10 % fetal bovine serum (HyClone Labs., Logan Utah). The medium was supplemented with 5 % supernatant of rat splenocytes cultured for 48 hours in the presence of 5.0 μg/ml Con A. Ten days later, the cells were used for antigen specificity assays or they were restimulated with their specific antigen for further in vitro passage and subsequent adoptive transfer studies. All of the T-lymphocyte lines were propagated for extensive periods by cyclical restimulation with antigen in the presence of irradiated syngeneic antigen presenting cells, and expanded in a medium supplemented with 5 % cytokine enriched supernatant from Con A stimulated splenocytes. EAM induction. Actively induced EAM was produced by a single immunization of the rat with flank injections of an antigen-adjuvant emulsion, as noted above. Adoptive transfer of EAM was initiated by the intravenous injection of CM peptide specific T-lymphoblasts that had been stimulated in vitro for 3 days with CM peptide at 20 μg/ml or Con A at 5.0 μg/ml in the presence of accessory cells. For adoptive transfer, rats received between 5 to 45 million T cells based on the specific experiment's protocol. Following adoptive transfer (unless otherwise stated) recipient animals were examined for the presence of histological signs of myocarditis on day 11 post cell transfer. Antigen Specificity Assays. The T-lymphocyte line cells were cultured in triplicate in 0.2 ml of "initiation medium" at 5 x 10^ cells per well in 96-well microtiter plate. 2.5 x 10^ irradiated (2000 rads) mixed lymph node and thymus cells from Lewis rat were added to each well as antigen presenting cells. Appropriate peptide antigens were added to the culture wells at varying concentrations. At 48 hours each well received 0.5 μCi [-1H] thymidine in a volume of 50 μl. The cells were harvested after additional 16 hr of culture using 1295-001 Cell Harvester (LKB-Wallac Inc., Gaithersburg, MD). Counts per minute were determined by liquid scintillation counting as an indicator of cell proliferation. Histological studies. For all rats employed in the study of peptide cardiac inflammatory potential, the hearts were removed postmortem and fixed in 10 % formalin. Paraffin embedded tissues were cut and stained with hematoxylin-eosin for histological examination. Severity of inflammation in the biventricular cardiac cross sections was graded as follows: 0, no inflammation; 1, rare scattered small foci of inflammation; 2, multiple isolated foci of cell infiltration; 3, multiple foci with inflammatory confluence; and, 4, foci of necrosis and or neutrophilic infiltration. Giant cell formation was also noted, when present, but did not effect the histological grading system. Immunohistochemistry. The heart was removed without prior fixation and cut into three transverse sections, the middle section was snap frozen in O.C.T. Compound (Miles Inc., Elkhart, IN). Cryostat sections 6 μm thick were cut and mounted on glass slides for immunohistochemical staining according to the protocol described in Hickey, W.F. et al. (1983) J Immunol. 121:2805. In brief, following a 30 sec. exposure to absolute methanol at -20 °C and extensive rinsing in 0.5 M Tris buffer (pH 7.6), the sections were incubated with appropriate primary antibodies at 4 °C over night. After further buffer washes, the slides were incubated with biotinylated secondary anti-murine IgG antibodies for 40 min., washed in buffer, and then incubated with avidin-biotinylated horse radish peroxidase complex (Vector laboratories, Burlingame, CA) for 2 hrs. The chromatic reaction was developed by incubating slides with 3,3'-diaminobenzidine in the presence of 0.03 % H2O2. Following dehydration and mounting of coverslips, the slides were assessed histologically. The antibodies used in this experiment were all murine monoclonal antibodies specific for immunologically important rat molecules. These reagents were purchased from Harlan-Bioproducts for Science, Indianapolis, IN. The antibodies and their specificities were: OX-6, anti-RTl.B (rat MHC class II, I-A) (McMaster, W.R. and Williams, A.F. (1979) Eur. J. Immunol. 2:426); OX-8, anti-rat CD8 (Mason, D.W. et al. (1983) Immunol. Rev. 24:57); W3/25, anti-rat CD4 (Mason, D.W. et al. (1983) Immunol. Rev. 24:57; and Jefferies, W.A. et al. (1985) J. Exp. Med. 162:117); OX-19, anti-rat CD5 (Mason, D.W. et al. (1983) Immunol. Rev. 24:57); and R7.3, anti-rat alpha-beta T-cell receptor (Hunig, T. et al. (1989) J. Exp. Med. 169:73 ,. Surface phenotype of peptide stimulated cell lines. The following procedure was used as an indirect staining method for determining the phenotype of peptide stimulated cell lines. All primary antibodies used were mouse monoclonal antibodies (IgGl isotype) directed against various rat surface markers: OX-19 (pan-T), W3/25 (CD4), OX-8 (CD8), OX-3 (MHC class II RT1.B 1 ), OX-17 (MHC class II RT1.D), and OX-22 (CD45RO leukocyte common antigen). To remove debris, peptide stimulated Ac-CM #2 specific T-lymphocytes were placed on a ficoll gradient followed by 2 washes in DPBS and resuspended in RPMI or DPBS with 1 % autologous rat serum. Aliquots of 0.5-1.0 x 10^ were placed into 12 x 75 mm polypropylene tubes and the cells were pelleted by centrifugation and resuspended in 100 μl of each primary antibody. Tubes were placed on ice for 30 min. after which they were washed twice with DPBS/1 % rat serum. After the second wash, the pellets were resuspended in 100 μl of the secondary FITC-labeled antibody (diluted 1 :20 in DPBS/1 % rat serum), vortexed, placed on ice for 30 minutes. Cells were then washed twice with DPBS/1 % rat serum and then resuspended in 1 ml of DPBS/1 % paraformaldehyde solution to fix the cells. RESULTS Identification of peptides derived from CM heaw chain that mav potentiallv be myocarditic. The amino acid sequence of rat CM alpha and beta heavy chains were scanned to identify peptides that contain serine and glutamic acid residues separated by five amino acids (the amino acid sequences of rat CM alpha and beta heavy chains are disclosed in McNally, E.M. et al. (1989) J. Mol. Biol. 21__:665). This serine, glutamic acid (S-x-x-x-x-x-E) (SEQ ID NO: 1) motif is one pattern thought to be important in binding of peptides to the rat class II (RT1.B1) molecule. Both the cardiac myosin alpha and beta heavy chains were found to contain eight peptides that have this class II binding motif. These corresponded to a.a. 14-30, a.a. 168-184, a.a. 318-334, a.a. 839-855, a.a. 863-879, a.a. 1196-1212, a.a. 1539-1555 and a. a. 1840- 1856 of CM alpha heavy chain. A ninth peptide was found only in the alpha chain (a.a. 1309-1316). The amino acid sequence of CM heavy chain when compared to skeletal myosin is highly conserved (see Strehler, E.E. et al. (1986) J Mol. Biol. 120:291-317). However, it has been shown experimentally that CM does not induce inflammation of skeletal muscle (myositis) (Neu, N. et al. (1987) J. Immunol. 122:3630); similarly, skeletal myosin does not cause inflammation of the cardiac muscle (Neu, N. et al. (1990) J. Immunol. 145:4094: Rosenberg, N.L. et al. (1987) Clin. Exp. Immunol. 6£:117). As a result, it was reasoned that peptides derived from CM capable of eliciting myocarditis would be unique to CM and would not be present in skeletal myosin. Therefore, the amino acid sequence of rat skeletal muscle was scanned for peptides that are identical or similar to CM peptides. CM peptides that were identical to or similar to skeletal myosin were not considered for further study. There are three peptides that contain the S-E motif which are unique to CM alpha chain. These peptides are shown below in Table VI. Furthermore, all three of the unique peptides are found in the rod portion of CM heavy chain (a.a. 831-1940) which is highly alpha helical in confirmation. Table VI Peptide Amino Acid Sequence Location in CM α-chain CM #1 TRGKL SYTQQME DLKRQ a.a. 1304-1320 SEQ ID NO: 22 CM #2 KLELQ SALEEAE ASLEH a.a. 1539-1555 SEQ ID NO: 23 CM #3 KGMRK SERRIKE LTYQT a.a. 1840-1856 SEQ ID NO: 24 Induction of experimental allergic myocarditis following immunization with synthetic CM heavy chain peptides. The immunization regimen used for the induction of EAM by CM peptides consisted of a single injection of CM peptide-CFA. Animals injected with CM peptides-CFA failed to develop clinical signs of myocarditis. The lack of clinical signs associated with CM peptide-CFA immunization is similar to what is seen with whole CM-CFA immunization in which only the development of histological inflammation has been reported (see Smith, S.C. and Allen, P.M. (1992) Cir. Res. 2Q:856). As can be seen in Table VII, animals receiving acetylated CM #2 developed histological signs of myocarditis. Inflammatory infiltrates were found to develop approximately 5 weeks following the single immunization. It is of interest that nonacetylated CM #2 peptide failed to induce either clinical or histological signs of myocarditis. Ac-CM #1 and Ac-CM #3 failed to generate clinical or histological signs of myocarditis following active immunization. TABLE VII Kinetics of induction of experimental allergic myocarditis following immunization with cardiac myosin peptides in adjuvant emulsion Active EAM Peptides Day Post Immunization 21 28 35 42 _____ CM#2 a.a. 1539-1555 0/1 a 2/4 2/2 Average Histological Score 0 0.75 2 CM #2 Nonacetylated 0/2 0/3 0/4 Average Histological Score 0 0 0 CM#1 a.a. 1304-1320 0/1 0/1 0/1 0/1 0/1 Histological Score 0 0 0 0 0 CM#3 a.a. 1840-1856 0/1 0/2 0/1 0/1 Histological Score 0 0 0 0 a. Number of animals with histological signs of myocarditis versus number of animals immunized. Induction of experimental allergic myocarditis following the adoptive transfer of T lymphocytes specific for CM peptides. Although acetylated CM #2 was the only peptide that was effective in the induction of active EAM, it was not the only peptide of CM that could mediate adoptively transferred EAM. As can be seen in Table III, T-lymphocytes directed against both acetylated and nonacetylated CM #2 peptide following in vitro activation with the respective peptide mediated the transfer of adoptive EAM. It should be noted that mitogenic stimulation with Con A also could activate acetylated CM #2 specific T-lymphocytes to mediate the adoptive transfer of EAM. Although immunization with acetylated CM #1 did not lead to the development of actively induced EAM, T-lymphocytes obtained from animals immunized with acetylated CM #1 peptide could transfer EAM following in vitro activation with Con A. Nevertheless, the long term culture of T-lymphocytes generated against acetylated CM #1 and #3 peptides has not been possible because of the lack of a reliable proliferative response to their respective peptides. Ac-CM #3 produced neither actively induced nor adoptively transferred EAM. We were unable to induce clinical signs of illness in rats with either T-lymphocytes specific for acetylated or nonacetylated CM #2 peptide, and T-lymphocytes specific for acetylated CM #1 peptide. Following the adoptive transfer of 4.5 x 10? Con A stimulated acetylated CM #2 peptide specific T-lymphocytes, severe histological myocarditis develops apparent by day 8 post transfer, similar to kinetics reported by other investigators (Kodoma, M. et al. (1992) Circulation £5:1 18), yet the rats show no overt illness. As can be seen in Table VIII, the histological severity of myocarditis is directly proportional to the number of cells adoptively transferred. TABLE VIII Adoptive transfer of EAM by T-lymphocytes specific for cardiac myosin peptides In Vitro No. of cells Adoptive EAM Peptide Activation Transferred No. Animal Day Histological Sacrificed Score Ac-CM #1 Con A 1.7 X 107 11 4 ConA 6.8x106 11 2 Ac-CM#2 ConA 4.5 x 107 Ac-CM #2 Con A 2.0 x 107 11 2 14 2 Ac-CM#2 Ac-CM#2 3.0 x 107 15 4 18 2 2.0 x 107 15 4 18 2 1.0 x 107 15 4 18 2 0.5x 106 15 2 18 2 CM #2 CM #2 3.0 x107 14 4 (No-Ac) (No-Ac) 18 4 Ac-CM#2 Ac-CM#2 3.0 x 107 14 4 18 2 Moφhologic and histological features of actively induced and adoptively transferred experimental myocarditis. Animals receiving at least 1 x 10? T-lymphocytes specific for Ac-CM #2 (stimulated with either Ac-CM #2 peptide or Con A), exhibited pericardial effusion; furthermore, macroscopic examination of the myocardium showed numerous geographic white plaques distributed over the epicardial surface of both ventricles. Animals receiving less than 5 x 10^ cells did not exhibit macroscopic signs of myocarditis. Grossly observable evidence of myocarditis was limited to animals receiving adoptively transferred T-lymphocytes and was not seen in actively immunized rats. Histopathological examination of transverse sections of hearts obtained from animals receiving either Con A or Ac-CM #2 peptide stimulated T-lymphocytes frequently exhibited transmural inflammation. This infiltrate consisted primarily of lymphocytes, macrophages, and scattered giant cells, associated focally with destruction of myocardial fibers. Itnmunohistological findings of CM peptide #2 induced adoptively transferred experimental allergic myocarditis. Frozen transverse sections of cardiac tissue were stained with a panel of monoclonal antibodies to characterize the subpopulations of inflammatory cells. The iriflammatory cells found in the lesions were predominantly CD4 positive T cells and monocytes/macrophages, and to a lesser extent CD8 positive T cells were also present. The macrophages were prevalent in and around the lymphocytic aggregates. MHC class II expression was extensive and appeared to be more extensive than what can be accounted for by merely class II positive macrophages. Peptide specificity of T-lvmphocvte lines generated against Ac-CM #2 peptide. Representative results of the proliferative response of Lewis T-lymphocyte lines generated against Ac-CM #2 and an irrelevant peptide are shown in Table IX (Part A). As can be seen, the anti-AcCM #2 T-lymphocyte line responds in a dose dependent manner to Ac-CM #2 peptide. Furthermore, this proliferative response is peptide specific. Ac-CM #2 specific T-lymphocyte lines do not proliferate to an irrelevant CM peptide, Ac-CM #3, even though this peptide also contains an S-E motif. To examine the influence of acetylation on T-lymphocyte recognition, Ac-CM #2 T- lymphocyte lines were stimulated with either acetylated or nonacetylated CM #2 peptide (Table IX Part B). As can be seen, acetylation of CM #2 peptide is not required for T-lymphocyte recognition, although at lower peptide concentration the proliferative response to acetylated peptide is greater than nonacetylated peptide. In order to determine if the Ac-CM #2 peptide is presented by MHC class II molecules, we made use of Lewis and DA(RP) antigen presenting cells to present Ac-CM #2 peptide to Lewis derived Ac-CM #2 peptide specific T-lymphocytes. As shown in Table IX (Part A), both DA(RP) and Lewis APC are capable of presenting Ac-CM #2 peptide to Lewis derived Ac-CM #2 peptide specific T-lymphocytes. TABLE IX Antigen responsiveness of Lewis anti Ac-CM #2 T-lvmuhocvtes Peptide Lewis APC DAΓRP . APC Concentration Ac-CM #2 Ac-CM #3 Ac-CM #2 Part A 10.0 μg/ml 41.1 ± 20.7 a 2.2 ± 2.2 25.7 ± 3.1 5.0 μg/ml 34.5 ± 4.4 2.7 ± 1.6 19.3 ± 11.6 2.0 μg/ml 11.1 ± 7.8 2.0 ± 2.8 6.9 ± 0.2 1.0 μg/ml 9.4 ± 4.7 3.2 ± 1.6 4.8 ± 2.0 0.5 μg/ml 11.5 ± 7.4 2.2 ± 3.2 3.1 ± 1.9 0.0 μg/ml 1.0 ± 0.4 1.0 ± 0.1 1.0 ± 0.9 Par B Ac-CM #2 Non Ac-CM #2 16.7 μg/ml 52.0 ± 4.0 47.9 ± 5.7 3.3 μg/ml 35.3 ± 3.4 22.0 ± 1.5 0.7 μg/ml 9.4 ± 1.4 4.8 ± 0.5 0.0 μg/ml 1.0 ± 0.4 1.0 ± 0.4 a. The proliferative response of T-lymphocyte lines to peptides is represented by the stimulation index defmed by the magnitude of the proliferative response (^H-Thymidine incorporation generated counts per minute) for specific antigens compared to a baseline incorporation of ^H-Thymidine without antigen. The ability of DA(RP) thymocytes to present Ac-CM #2 peptide to peptide specific T- lymphocytes suggests that Ac-CM #2 peptide is efficiently presented by the RT1.B1 and/or RT1.D class II molecules. The ability of DA(RP) thymocytes to present antigen to Lewis cells suggests that the Ac-CM #2 peptide may itself be a CM T-cell epitope in the DA(RP) rat. To test this premise DA(RP) animals were immunized with Ac-CM #2 peptide/CFA to obtain lymph node cells for the establishment of a T-lymphocyte line. A DA(RP) derived, Ac-CM #2 specific T-lymphocyte line was established. The response to Ac-CM #2 peptide is shown in Table X. The Ac-CM #2 DA(RP) derived cell line responds in a dose dependent manner to peptide concentration, and similarly the DA(RP) derived cell line responds to specific peptide when presented by either DA(RP) or Lewis derived antigen presenting cells. TABLE X Antigen responsiveness of DA(RP, derived anti CM #2 T-lymphocytes Peptide Ac-CM #2 Peptide Concentration DArRP ) APC Lewis APC 50.0 μg/ml 56.8 ± 5.6 a 50.8 ± 28.6 20.0 μg/ml 47.8 ± 17.8 42.6 ± 3.6 10.0 μg/ml 47.4 ± 16.2 33.2 ± 2.4 5.0 μg/ml 29.5 ± 5.3 26.9 ± 9.3 2.0 μg/ml 15.4 ± 3.0 7.2 ± 2.3 1.0 μg/ml 9.6 ± 5.1 5.1 ± 3.0 0.5 μg/ml 7.3 ± 2.3 3.9 ± 2.2 0.0 μg/ml 1.0 ± 0.5 1.0 ± 0.2 a. The proliferative.response of T-lymphocyte lines to peptides is represented by the stimulation index defined by the magnitude of the proliferative response (-^H-Thymidine incorporation generated counts per minute) for specific antigens compared to a baseline incorporation of --Η-Thymidine without antigen. Phenotvpic characterization of anti-Ac-CM #2 cell lines. Following peptide stimulation of the Ac-CM #2 cell line, the responding cells were characterized by FACS analysis. Phenotypically, 91 % of the cells were found to be T-lymphocytes (OX- 19, Pan T-cell). The majority of the cells (83.9 %) were CD4 positive (W3/25, T-helper/Macrophage) and 8.5 % were positive for CD8 (OX8, T-cell cytotoxic/suppressor). Only 8 % of the cells were positive for CD45RO (OX-22, Leukocyte common antigen) which is consistent with the T-lymphocyte line consisting predominantly of memory T-lymphocytes. A minority (21.2%) of the cells express the RT1.B class II molecule and all cells are negative for expression of RT1.D class II molecule (OX-17). Ac-CM #2 peptide is presented by both RTI .BI and RTl.PJ Class II Molecules. Ac-CM #2 specific T-lymphocyte lines were placed in culture with syngeneic antigen presenting cells in the presence of OX-3 (anti-RTl.B u cross reacts with the 1 haplotype), OX-6 (RT1.B) and OX-17 (RT1.D) monoclonal antibodies. Ac-CM #2 peptide was then added at graded concentrations. As can be seen in Table XI, the addition of RT1.B blocking antibodies was able to inhibit the proliferation of Ac-CM #2 specific T-lymphocyte lines. Furthermore, the addition of RT1.D blocking antibodies was also able to substantially reduce the proliferation of Ac-CM #2 Tlymphocyte lines to peptide. These results suggest that the Ac-CM #2 peptide can be efficiently presented by both RT1.B^ and RT1.D^ class II molecules. TABLE XI The Class II Restriction Elements for the Presentation of Ac-CM #2 Peptide Percent Inhibition Peptide Stimulationa OX-3 OX-6 OX- 17 Concentration Index Anti RTI.BI Anti RT1.B Anti RTl.D 20 μg/ml 128.1 ± 9.7 32% 35% 38% 10 μg/ml 96.6 ± 29.4 16% 24% 32% 5 μg/ml 93.1 ± 11.6 25% 39% 55% 2 μg/ml 47.5 ± 8.6 31% 36% 63% 0.0 μg/ml 1.0 ± 0.9 a. The proliferative response of T-lymphocyte lines to peptides is represented by the stimulation index defined by the magnitude of the proliferative response ( -Thymidine incorporation generated counts per minute) for specific antigens compared to a baseline incorporation of -'H-Thymidine without antigen. EXAMPLE 4: The medical literature describes a rare autoimmune disease targeted to the anterior pituitary gland in humans, termed lymphocytic hypophysitis (see Goudie, R. and Pinkerton, P. (1962) J. P thol. & Bacteriol. £2:584-585; Pestell, R. et al. (1990) Clin. Endocrinol. 22:457-466). A similar phenomenon has been reproduced in Lewis rats after inoculation with anterior pituitary tissue in adjuvant (see Levine, S. (1967) Science 15£:1190-1191). This indicates that the pituitary contains an autoantigen(s) potentially pathogenic for the hypophysis. To date, the identity of the antigen responsible for hypophysitis is unknown. This example examines the possibility that peptide hormones secreted by the hypothalamic- pituitary-adrenal axis may be T cell targets for autorecognition. In this example, an MHC class II binding motif (S-x-x-x-x-x-E) (SEQ ID NO: 1) was used as a template for selecting and synthesizing peptide fragments of the neuroendocrine hormones, corticotropin-releasing hormone (CRH) and pro-opiomelanocortin (POMC) that may serve as T cell epitopes. T cell lines were generated specifically against 17 amino acid CRH or POMC peptides. The results described herein indicate that the normal T cell repertoire of the rat contains elements which can recognize and specifically proliferate to self proteins of the hypothalamic-hypophyseal axis and, moreover, that an MHC class II binding motif can be used to predict autoreactive peptide fragments of CRH and POMC. The following methodologies were used in this example: MATERIALS AND METHODS Animals. Viral antibody-free, female Lewis strain (RTll) rats were obtained from Charles River Laboratory (Wilmington, MA). Rats were group housed (n =2-3/cage) and maintained on a 12 hr light/dark cycle, with access to food and water ad libitum. All procedures and animal care were in accordance with NIH guidelines on laboratory animal welfare. POMC/ CRH peptide synthesis. The POMC 17-mer peptide was synthesized based on the primary amino acid sequence of unprocessed, anterior pituitary-derived POMC (Drouin, J. and Goodman, H. (1980) Nature 2££:610-612). The portion of POMC containing the putative MHC Class II peptide binding motif (S-E motif) was found in the N-terminal fragment between residues 67-83 and synthesized as follows: ^S S A G G S A O R R A E E E T A G 83 (SEQ ID NO: 25). The CRH 17-mer peptide was synthesized according to the primary amino acid sequence of the 41 -amino acid hypothalamic hormone, human/rat CRH (Shibahara, S. et al. (1983) EMBOJ. 2:775-779). The S-E motif was found between residues 25-41 and synthesized as follows: 2* Q L A Q Q A H S N R K L M E 11 -NH 2 41 (SEQ ID NO: 26). Both POMC and CRH peptides were synthesized in N-terrninal acetylated (POMCac, CRHac) and non-acetylated (POMCnon-ac, CRHnon-ac) forms using the RaMPS (Rapid Amide Multiple Peptide Synthesis) System (NEN-Dupont, Wilmington, DE) as previously described (Trotter, J. et al. (1991) J. Neuroimmunol. 22:55-62). All CRH and POMC peptides were amidated on the carboxy-terminal amino acid, a byproduct of standard RaMPS synthesis. Both N-terminal acetylation and carboxy-terminal amidation are natural in vivo phenomena that increase the biological activity of many neuropeptides (see Mains, R. and Eipper, B. (1983) Trends Neurosci. 6:229-235). POMC and CRH T Cell Line Production. POMC and CRH peptides were suspended in Dulbecco's phosphate buffered saline (DPBS, Bio Whittaker Products, Walkersville, MD) at concentrations of 2 mg/ml and emulsified in an equal volume of complete Freund's adjuvant (CFA) supplemented with 5 mg/ml H37RA (DIFCO, Detroit, MI). For each peptide, Lewis rats received 100 μg/O.lcc (200 μg total) peptide/CFA via intradermal injection into both hindfoot pads. To generate T cell lines for each peptide, rats were sacrificed by Fluothane anesthesia (Ayerst Laboratories, New York, NY) nine days following immunization to obtain the popliteal lymph nodes. Lymph nodes were mechanically dissociated with forceps into a single cell suspension in DPBS and washed twice (10 min, 450 x g, 4 °C). POMC-specific and CRHspecific cell pellets were resuspended in medium containing RPMI 1640 (Bio Whittaker Products), 1 % autologous rat serum, 5 % NCTC-109 (Bio Whittaker Products), 5 x 10~5 M 2-mercaptoethanol (Sigma Chemical Company, St. Louis, MO), 2 mM glutamine, 100 U/ml penicillin, 100 μg/ml streptomycin, 100 μg/ml fungizone (ICN Biomedicals, Costa Mesa, CA), and cultured with 50-100 μg/ml of the initiating peptide in 25 cm.2 tissue culture flasks (Corning Glass Works, Corning, NY) for 72 hr at 37 °C, 5 % CO2- T-lymphoblast cells were collected by density centrifugation using Histopaque- 1.077 (Sigma), washed two times with DPBS, and resuspended in complete medium (as above, except that the serum source was replaced by 10 % fetal bovine serum (Hyclone Laboratories, Logan, UT), and 5 % Concanavalin A (Coι_A)stimulated spleen cell supernate was included as a source of the growth factor, interleukin-2). Cells were cultured for an additional 4-7 days, at which time cell lines were either re-stimulated with peptide antigen (20 μg/ml POMC or CRH) for further in vitro passage or used in proliferation assays to test for antigen specificity. Proliferation Assay for T Cell Line Antigen Specificity. At the time cell lines achieved a resting state (7-10 days post-initiation), POMC and CRH T cell lines were harvested, washed twice with DPBS and resuspended in proliferation medium containing 1 % autologous rat serum. Cells were counted by trypan blue dye exclusion and added to 96-well U-bottom microtiter plates (Becton-Dickinson, Lincoln Park, NJ) at concentrations of 5-7 x 10^ cells per well. Syngeneic thymocytes were used as antigen presenting cells (APCs), irradiated with 2,000 rads (l- 7Cs source: Shepherd & Assoc, San Fernando, CA), and added to microtiter plates at concentrations of 5 x 10-Vwell. The mixtures of cell lines and thymocytes were incubated with or without their respective peptide antigens (POMC, CRH) at final concentrations ranging from 0.5 to 20 μg/ml. In some experiments, anti-MHC Class II antibodies were also added (Ox-3, 12.5 μg/ml; Ox-6, 20 μg/ml; or Ox-17, 20 μg/ml; Serotec). Cultures were incubated for a total of 72 hr, including a final 18 hr pulse with 0.5 μCi 3 H-TdR/well. Wells were harvested onto fiberglass filtermats using a LGB Wallac 1295-001 Cell Harvester (Wallac Inc., Gaithersburg, MD), and -1H-TdR uptake measured by a 1205-02 Betaplate liquid scintillation counter (Wallac). Data are expressed as stimulation indices (SI) ± one standard deviation (SD), and each assay was replicated 2-3 times for each cell line. POMC/CRH T Cell Line Phenotyping by Flow Cytometric Analysis. An indirect staining method was used for determining the relative percentages of cell surface molecules expressed on the surface of resting and ConA-activated POMC and CRH T cell lines. Surface markers consisted of the following mouse anti-rat monoclonal primary antibodies (all of the IgGl isotype): CD5 (OX-19), CD4 (W3/25), CD8 (OX-8), MHC Class II RT1.B (OX-3 & OX-6), MHC Class II RT1.D (OX-17), CD45RC (leukocyte common antigen, OX-22). These markers were obtained from Harlan Bioproducts for Science (Serotec), Indianapolis, IN. The isotype control antibody used was MOPC 21 (Sigma), mouse IgGl, heavy and light chain specific. The secondary antibody consisted of FITC-conjugated goat F(ab')2 anti-mouse IgG (Cappel-Organon Teknika Coφ., West Chester, PA). Cell Staining Protocol. To measure expression of cell surface markers on activated cells, POMC and CRH cell lines were stimulated with (ConA) (5 μg/ml), for 72 hr in the presence of irradiated Lewis splenocytes. After 72 hours, T cell lines were harvested and lymphoblasts separated from splenocytes by density gradient centrifugation. Aliquots of 0.5 - 1 x 10° " cells used for each primary antibody of interest, including the isotype control. A concentration of 12.5 to 20 μg/ml of each primary antibody was added to cells and incubated for 30 min on ice. Cells were then washed twice and a 1 :30 dilution of FITC-conjugated secondary antibody was then added to cells and incubation continued for another 30 min on ice. Finally, cells were fixed with DPBS/1 % paraformaldehyde. Cells were analyzed by a Becton Dickinson FACScan flow cytometer, equipped with an argon-ion laser. T cells from each line were stained a minimum of two times. Data represent the percent positive expression of each marker after 10,000 events were recorded. Antigen Processing and Presentation of Whole CRH vs, CRH peptides, T cell lines specific for acetylated CRH peptide (CRHac) and non-acetylated CRH peptide (CRHnon-ac) were tested for proliferative response to whole human/rat CRH (Sigma) and CRH peptides. Irradiated (2000 rad), syngeneic rat thymocytes served as antigen presenting cells (5 x 10^/ well). CRHac T line cells (5 x 10^/well) were cultured in the presence or absence of whole CRH (40 μg/ml), CRHac peptide (20 μg/ml), CRHnon-ac peptide (20 μg/ml), ± anti-MHC class II (Ox-3; Ox-6; Ox-17, 12.5 - 20 μg/ml) in 96-well, U bottom microtiter plates for 72 hr, including a final 18 hr pulse with 3 H-TdR (0.5 μCi/well). Self-Presentation of POMC to POMC T Cell Lines. POMC T line cells, thymocytes or T cells specific for a peptide fragment of glutamic acid decarboxylase (GAD) (3 x 10^) used as antigen presenting cells. T cells from the different sources were cultured for 30 hr in the presence of 100 nM whole rat/human CRH (Sigma) to potentially up-regulate any endogenous T cell POMC gene expression. For use in antigen presentation experiments, CRH-stimulated T cells were harvested after 30 hr, washed twice in DPBS, resuspended in medium containing RPMI and 1 % autologous rat serum, then irradiated (2000 rad). Resting POMC T line cells were then added at a concentration of 2: 1 APC to T cell ratio in 96-well, U bottom rnicroculture plates with or without POMC peptide (20 μg/ml). When irradiated thymocytes were used as APC they were added to POMC T cells at a standard ratio of 10: 1 APC to T cells. Cultures were incubated for a total of 72 hr, including a final 18 hr pulse with 3 H-TdR (0.5 μCi/well). Forty-hour culture supernates of the same APC/T cell/peptide mixtures were assayed for IL-2 production by bioassay using IL-2 dependent HT-2 cells. Supenates (100 μl) were cultured with 1 x 10 3 /well HT-2 cells for 48 hr, including a final 12hr pulse with 3 H-TdR (0.5 μCi/well). Other materials. RU38486 glucocorticoid receptor antagonist, a generous gift from Roussel UCLAF, France, was used to up-regulate endogenous CRH in a dose range of 0.03-3 mg/ml/100 gm/day i.p. in one experiment where CRH-specific T cells (20-55 x 10^) were adoptively transferred into Lewis rats (n = 5). RESULTS Antigen specificity of POMC and CRH T cell lines. Following at least one in vitro stimulation with their respective initiating antigens, the POMC- and CRH-specific T line cells were tested for antigen specificity in proliferation assays. Figure 6 represents the specificity of a T cell line generated against acetylated POMC (POMCac). Data are represented as stimulation indices: mean counts per minute (cpm) 3 H-thymidine incoφoration for triplicate microcultures of T cells plus peptide divided by mean cpm for T cells plus medium alone. Cells proliferated in response to co-culture with POMCac, but not non-acetylated POMC (POMCnon-ac) peptide, in a dose-dependent fashion. This same pattern of results was obtained for CRHac-specific cell lines. In addition, POMCac and CRHac cell lines did not cross-react with irrelevant peptides of similar size containing the S-E binding motif. As seen in Figure 7 (panel A), POMC T cells did not proliferate significantly in response to CRH peptide relative to POMC peptide, and similarly, CRH T cells did not respond to POMC peptide relative to CRH peptide (Figure 7B). In order to determine whether MHC Class II (RT1.B) antigens were presenting the S-E containing peptides to the cell lines, antibodies to MHC Class II were added to cultures of antigen presenting cells, antigen and T cell lines. Proliferative responses to peptide could be inhibited to varying degrees by the addition of anti-MHC Class II antibodies (RT1.B; Ox-3, Ox6), but not irrelevant MHC Class II antibody (RT1.D; Ox- 17). POMC/CRH cell line surface antigen phenotype bv flow cvtometric analyses. In establishing these T cell lines and predicting the antigenic epitope, the hypothesis was that the MHC Class II peptide binding motif contained in the peptides would favor the development of cells expressing the CD4 + (T helper) phenotype. ConA-activated POMC and CRH T cell lines were remarkably similar in surface antigen phenotype (Table XII). Nearly 90 % of the cells were T cells, with the majority expressing CD4. A small percentage of T cells from both cell lines were positive for the expression of CD8. Approximately 25 % of both POMC and CRH cells strongly expressed MHC Class II (RT1.B; I-A) following activation with ConA, whereas RT1.D (I-E) expression was minimal on both cell lines. Combined MHC Class II expression on resting T cells was lower than on activated T cells, but was present nonetheless (16 % + 3). As expected, CD45RC expression was found on less than 1 % of cells in both lines, consistent with their antigen-specific, activated state (Thomas, M. (1989) Ann. Rev. Immunol. 2:339-369). Surface antigen expression was similar between activated and resting T line cells with respect to CD5 (85 %), CD4 (79 %) and CD8 (18 %) expression. TABLE XH Flow Cytometric Analysis of Cell Surface Antigen Phenotype of POMC & CRH-specific T cell lines Antibody POMC CRH CD5 (Ox- 19) 89 ± 5 a 89 ± 3 CD4 (W3/25) 78 ± 2 84 ± 2 CD8 (Ox-8) 17 ± 5 14 ± 0.5 MHC Class II RT1.B polymoφhic I (Ox-3) 25 ± 2 29 ± 3 RT1.B monomoφhic(Ox-6) 23 ± 6 25 ± 3 RT1.D monomoφhi c (Ox-17) 8 ± 3 6 ± 0.1 CD45RC (Ox-22) 2 <1 a Values represent % positive expression of each cell surface marker per 20, 000 cells (mean ± SD). T line cells were stimulated with the appropriate antigen at least twice in vitro prior to staining. Non-specific antibody staining was less than 5 %. Processing and presentation of whole CRH vs. CRHac peptide to CRH T cell line. Given that whole rat/human CRH is a relatively small polypeptide (41 amino acids), it was uncertain whether this protein would be naturally processed into antigenic fragments resembling the synthetic 17-amino acid CRH peptide, or if the native protein would be capable of stimulating CRHac or CRHnon-ac cell lines. The molecular weight (MW) of CRH peptide (2295 MW) was estimated from the MW of the synthesized amino acid sequence and compared with whole human/rat CRH (4757 MW) in order to define equimolar concentrations to be used in proliferation assays. CRHac line cells proliferated maximally to CRHac peptide yielding values approximately eight times greater than the cell line's proliferation to whole CRH (S.I. of 34 vs. 4.4, respectively; Figure 8 A). Nevertheless, the cells specific for the synthetic peptide demonstrated reactivity against the native protein hormone. With the likelihood that whole CRH and its fragments would be in a non-acetylated form, another comparison was made between cell line response to CRHnon-ac peptide vs. whole CRH (Figure 8, panel B). Non-acetylated CRH peptide-specific T cells responded two times greater to non-acetylated peptide than to whole CRH. The addition of anti-MHC Class II antibody to cell lines in combination with antigen was found to inhibit presentation of whole CRH peptides similar to that observed for CRH peptides (as in Figure 7B). Self-Presentation of POMC peptide to POMC T cells. Given that both human and rat T cells express MHC Class II antigens, and that T cells themselves make POMC, an experiment was conducted to determine whether the T line cells could present POMC peptide to POMC-specific T cells. In this experiment, anti-POMC T cells, anti-GAD T cells or thymocytes were incubated with 100 nM rat human CRH (Sigma) for 30 hours, then irradiated (2000 rads) and used as antigen presenting cells (APC) by cultured with or without POMC peptide, POMC T cells and anti-MHC Class II antibody in a 72 hour 3H-thymidine incoφoration assay. The results are shown in Figure 9A-C POMC-specific T cells were able to present POMC peptide to POMC T cells, however not to the same magnitude as thymocytes (Figure 9C, S.I. 5 vs. 15, respectively), or a T cell line specific for another peptide (GAD; glutamic acid decarboxylase, Figure 9B). The addition of anti-MHC Class II antibody inhibited the proliferation response of POMC-specific T cells to POMC peptide when presented by either type of APC. Supernates taken from cultures of POMC T cells, POMC peptide and irradiated POMC T cells at 40 hours were found to contain greater amounts of IL-2 than the same culture without POMC peptide (see Figure 10). However, antigen presentation of POMC peptide to POMC T cells by thymocytes generated the greatest levels of IL-2 as measured by 3 H-TdR uptake by IL-2 dependent HT-2 cells. In summary, T cell lines were generated specifically against a 17-amino acid peptide of POMC or CRH peptide containing an MHC Class II binding motif (S-E), and the T cell lines responded vigorously upon restimulation with peptide in vitro. These T cell lines were predominantly CD4 + T cells and proliferated in an antigen-specific, MHC Class Il-restricted fashion. Furthermore, proliferation of T cell lines specific for peptide-hormones could be inhibited by anti-MHC Class II antibody. In vitro, the whole CRH protein could be processed and recognized as antigenic by CRH peptide-specific T cells. In addition, POMC-specific T cells can recognize POMC peptide presented on the membrane of MHC Class II + POMC T cells^ The data presented herein document that the rat T-cell repertoire contains cells specific for peptide fragments of the neuroendocrine hormones, CRH and POMC. The results demonstrate that an organism possesses the ability to react in T-cell mediated, "autoimmune" manner against substances produced by the neuroendocrine axis. EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: (A) NAME: Trustees of Dartmouth College (C) CITY: Hanover (D) STATE: New Hampshire (E) COUNTRY: USA (F) POSTAL CODE (ZIP) : 03755 (ii) TITLE OF INVENTION: Invariant Chain Compositions Useful for Treating Autoimmune Diseases (iii) NUMBER OF SEQUENCES: 26 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: LAHIVE & COC FIELD (B) STREET: 60 State Street, suite 510 (C) CITY: Boston (D) STATE: Massachusetts (E) COUNTRY: USA (F) ZIP: 02109-1875 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: ASCII Text (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: US 08/272,220 (B) FILING DATE: 08-JULY-199 (C) CLASSIFICATION: (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: DeConti, Giulio A., Jr. (B) REGISTRATION NUMBER: 31,503 (C) REFERENCE/DOCKET NUMBER: DCI-070PC (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (617)227-7400 (B) TELEFAX: (617)227-5941 (2) INFORMATION FOR SEQ ID NO:l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 2-5 (D) OTHER INFORMATION: /note= "Xaa is any amino acid" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l: Ser Xaa Xaa Xaa Xaa Xaa Glu 1 5 (2) INFORMATION FOR SEQ ID NO:2 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: Ser Gin Asn Leu Gin Leu Glu 1 5 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: Ser Lys Asn Ser Leu Glu Glu 1 5 (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: Ser Glu Pro Leu Asp Met Glu 1 5 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 2-7 (D) OTHER INFORMATION: /note= "Xaa is any amino acid" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: Tyr Xaa Xaa Xaa Xaa Xaa Xaa Lys 1 5 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 1 (D) OTHER INFORMATION: /note= "Xaa is Tyr, Leu, Val, He, Phe or Met" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 2-5 (D) OTHER INFORMATION: /note= "Xaa is any amino acid" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 6 (D) OTHER INFORMATION: /note= "Xaa is Thr, Ala, Ser or Gly" (Xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: Xaa Xaa Xaa Xaa Xaa Xaa 1 5 (2) INFORMATION FOR SEQ ID NO:7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 1 (D) OTHER INFORMATION: /note= "Xaa is He, Tyr, Leu, Val or Ala" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 2 (D) OTHER INFORMATION: /note= "Xaa is any amino acid" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 3 (D) OTHER INFORMATION: /note= "Xaa is He, Tyr, Leu, Val or Ala" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 4 (D) OTHER INFORMATION: /note= "Xaa is Asn, Gly, Arg, Lys, Glu, Asp, Ser or Thr" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 5 (D) OTHER INFORMATION: /note= "Xaa is any amino acid" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 6 (D) OTHER INFORMATION: /note= "Xaa is Lys, Arg or His" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: Xaa Xaa Xaa Xaa Xaa Xaa 1 5 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) -LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 1 (D) OTHER INFORMATION: /note= "Xaa is Leu, He, Val, Met, Phe, Tyr or Trp" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 2-5 (D) OTHER INFORMATION: /note= "Xaa is any amino acid" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 6 (D) OTHER INFORMATION: /note= "Xaa is Ser, Thr, Leu, He, Val Met" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8; Xaa Xaa Xaa Xaa Xaa Xaa 1 5 (2) INFORMATION FOR SEQ ID NO:9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 1 (D) OTHER INFORMATION: /note= "Xaa is He, Leu or Val" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 2-10 (D) OTHER INFORMATION: /note= "Xaa is any amino acid" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 11 (D) OTHER INFORMATION: /note= "Xaa is His, Lys or Arg" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 (2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 1 (D) OTHER INFORMATION: /note= "Xaa is Phe, He, Leu, Val or Tyr" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 2-3 (D) OTHER INFORMATION: /note= "Xaa is any amino acid" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 4 (D) OTHER INFORMATION: /note= "Xaa is Asp, Asn, Gin or Thr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: Xaa Xaa Xaa Xaa 1 (2) INFORMATION FOR SEQ ID NO:11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 1 (D) OTHER INFORMATION: /note= "Xaa is Phe, Leu or Val" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 2-8 (D) OTHER INFORMATION: /note= "Xaa is any amino acid" ( ix) FEATURE : (A) NAME/KEY: Modified-site (B) LOCATION: 9 (D) OTHER INFORMATION: /note= "Xaa is Asn, Gin, Ser or Thr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 (2) INFORMATION FOR SEQ ID NO:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 1 (D) OTHER INFORMATION: /note= "Xaa is Phe, He, Leu or Val" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 2-5 (D) OTHER INFORMATION: /note= "Xaa is any amino acid" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 6 (D) OTHER INFORMATION: /note= "Xaa is Asn, Ser or Thr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: Xaa Xaa Xaa Xaa Xaa Xaa 1 5 (2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION : 1 (D) OTHER INFORMATION: /note= "Xaa is Phe, He, Leu, Val or Tyr" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 2-4 (D) OTHER INFORMATION: /note= "Xaa is any amino acid" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 5 (D) OTHER INFORMATION: /note= "Xaa is His, Lys or Arg" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: Xaa Xaa Xaa Xaa Xaa 1 5 (2) INFORMATION FOR SEQ ID NO:14 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: Lys Val Cys Gly Ser Asn Leu Leu Ser He Cys Lys Thr Ala Glu Phe 1 5 10 15 Gin (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: Gly Ser Asn Leu Leu Ser He Cys Lys Thr Ala Glu Phe Gin Met 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: Leu Ser He Cys Lys Thr Ala Glu Phe Gin Met Thr Phe His Leu Phe 1 5 10 15 He (2) INFORMATION FOR SEQ ID NO:17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal ( i) SEQUENCE DESCRIPTION: SEQ ID NO:17: Leu Ser He Cys Lys Thr Ala Glu Phe Gin 1 5 10 (2) INFORMATION FOR SEQ ID NO:18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18: Gly Phe Phe Tyr Thr Pro Lys Ser Arg Arg Glu Val Glu Asp Pro Gin 1 5 10 15 Val (2) INFORMATION FOR SEQ ID NO:19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: Gly Phe Phe Tyr Thr Pro Met Ser Arg Arg Glu Val Glu Asp Pro Gin 1 5 10 15 Val (2) INFORMATION FOR SEQ ID NO:20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20: Leu Leu Gin Cys Ser Ala He Leu Val Lys Glu Lys Gly He Leu Gin 1 5 10 15 Gly (2) INFORMATION FOR SEQ ID NO:21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: Tyr He Pro Gin Ser Leu Arg Gly Val Pro Asp Ser Pro Glu Arg Arg 1 5 10 15 Glu (2) INFORMATION FOR SEQ ID NO:22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: Thr Arg Gly Lys Leu Ser Tyr Thr Gin Gin Met Glu Asp Leu Lys Arg 1 5 10 15 Gin (2) INFORMATION FOR SEQ ID NO:23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: Lys Leu Glu Leu Gin Ser Ala Leu Glu Glu Ala Glu Ala Ser Leu Glu 1 5 10 15 His (2) INFORMATION FOR SEQ ID NO:24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: Lys Gly Met Arg Lys Ser Glu Arg Arg He Lys Glu Leu Thr Tyr Gin 1 5 10 15 Thr (2) INFORMATION FOR SEQ ID NO:25: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: Ser Ser Ala Gly Gly Ser Ala Gin Arg Arg Ala Glu Glu Glu Thr Ala 1 5 10 15 Gly (2) INFORMATION FOR SEQ ID NO:26: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: Glu Gin Leu Ala Gin Gin Ala His Ser Asn Arg Lys Leu Met Glu He 1 5 10 15 He

Claims: CLAIMS 1. A method for treating an autoimmune disease in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising an invariant chain protein, or peptide fragment thereof, optionally with a pharmaceutically acceptable carrier. 2. The method of claim 1 , wherein the invariant chain protein, or peptide fragment thereof, is from the same species as the subject. 3. The method of claim 2, comprising administering to the subject a peptide fragment of the invariant chain protein comprising an amino acid sequence of a binding motif for a major histocompatibility complex (MHC) protein expressed by the subject. 4. The method of claim 3, wherein the peptide fragment comprises an amino acid sequence of a binding motif for an MHC class II protein. 5. The method of claim 4, wherein the peptide fragment comprises an amino acid sequence of a binding motif for a human MHC class II protein. 6. The method of claim 5, wherein the human MHC class II protein is an HLA-DR protein. 7. The method of claim 5, wherein the human MHC class II protein is an HLA-DQ protein. 8. The method of claim 5, wherein the human MHC class II protein is an HLA-DP protein. 9. The method of claim 4, wherein the peptide is 10-35 amino acids in length. 10. The method of claim 9, wherein the peptide is 10-20 amino acids in length. 11. The method of claim 10, wherein the peptide is 12- 16 amino acids in length. 12. The method of claim 1, wherein the invariant chain protein, or peptide fragment thereof, is administered intravenously. 13. The method of claim 1 , wherein the invariant chain protein, or peptide fragment thereof, is administered by a route of administration selected from the group consisting of subcutaneous, intramuscular, intraperitoneal and oral administration. 14. The method of claim 1, wherein the invariant chain protein, or peptide fragment thereof, is administered at a dosage of about 0.01 to 5 mg/kg body weight of the subject. 15. The method of claim 14, wherein the invariant chain protein, or peptide fragment thereof, is administered at a dosage of about 0.05 to 1 mg/kg body weight of the subject. 16. The method of claim 15, wherein the invariant chain protein, or peptide fragment thereof, is administered at a dosage of about 0.1 to 0.5 mg/kg of body weight of the subject. 17. The method of claim 1 , wherein the autoimmune disease is arthritis. 18. The method of claim 1 , wherein the autoimmune disease is insulin dependent diabetes mellitus. 19. The method of claim 1 , wherein the autoimmune disease is multiple sclerosis. 20. The method of claim 1, wherein the autoimmune disease is selected from the group consisting of myesthenia gravis, myocarditis, Guillan-Barre Syndrome, systemic lupus erythematosis, autoimmune thyroiditis, dermatitis, psoriasis, Sjδgren's Syndrome, alopecia areata, Crohn's disease, aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, allergy, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, drug eruptions, leprosy reversal reactions, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral progressive sensorineural hearing loss, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, polychondritis, Wegener's granulomatosis, chronic active hepatitis, Stevens- Johnson syndrome, idiopathic sprue, lichen planus, Graves ophthalmopathy, sarcoidosis, primary biliary cirrhosis, uveitis posterior, and interstitial lung fibrosis. 21. A method for preparing an invariant chain peptide fragment which can inhibit an interaction between an antigenic peptide and a major histocompatibility complex (MHC) protein expressed by an antigen presenting cell, comprising: a) identifying an amino acid sequence of a binding motif for an MHC protein expressed by the antigen presenting cell; b) selecting a region of an invariant chain protein comprising the amino acid sequence of the binding motif for the MHC protein; and c) preparing an invariant chain peptide fragment comprising said selected region of the invariant chain protein. 22. The process of claim 21 , wherein the MHC protein is an MHC class II protein. 23. The process of claim 21 , wherein the invariant chain protein is from the same species as the antigen presenting cell. 24. The process of claim 21 , wherein the invariant chain peptide fragment is prepared by synthesizing the peptide fragment. 25. The process of claim 21 , wherein the invariant chain peptide fragment is prepared by proteolytically digesting the invariant chain protein and isolating a proteolytic fragment comprising said selected region of the invariant chain protein. 26. The process of claim 21 , wherein the invariant chain peptide fragment is 10-35 amino acids in length. 27. The process of claim 26, wherein the invariant chain peptide fragment is 10-20 amino acids in length. 28. The process of claim 27, wherein the invariant chain peptide fragment is 12-16 amino acids in length. 29. A pharmaceutical composition comprising an invariant chain protein in an amount sufficient to inhibit at least one symptom of an autoimmune disease in a subject and a pharmaceutically acceptable carrier. 30. The pharmaceutical composition of claim 29, wherein the invariant chain protein is human. 31. A pharmaceutical composition comprising a peptide fragment of an invariant chain protein in an amount sufficient to inhibit at least one symptom of an autoimmune disease in a subject, wherein the peptide fragment comprises an amino acid sequence of a binding motif for an major histocompatibility complex (MHC) protein, and a pharmaceutically acceptable carrier. 32. The pharmaceutical composition of claim 31 , wherein the invariant chain protein is human. 33. The pharmaceutical composition of claim 31 , wherein the MHC protein is human. 34. The pharmaceutical composition of claim 31 , wherein the peptide fragment is is 10-35 amino acids in length. 35. The pharmaceutical composition of claim 34, wherein the peptide fragment is 10-20 amino acids in length. 36. The pharmaceutical composition of claim 35, wherein the peptide fragment is 12-16 amino acids in length.

Inventors: HICKEY WILLIAM F, HICKEY, WILLIAM, F.
Applicants: DARTMOUTH COLLEGE, HICKEY WILLIAM F, HICKEY, WILLIAM, F., TRUSTEES OF DARTMOUTH COLLEGE
Application year: 1995
Main classification: A61K38
IPC codes: A61K38, A61P1, A61P3, A61P7, A61P9, A61P13, A61P15, A61P17, A61P27, A61P29, A61P37, C07K5, C07K7, C07K14, G01N33