SYNTHETIC IL-10 ANALOGUES

Abstract: The invention relates to the use of a substance or polypeptide according to the formula X1-X2-X3-Thr-X4-Lys-X5-Arg-X6 (SEQ ID NO:22), wherein X1 is Ala or Gly, X2 is Tyr or Phe, X3, X4 and X5 are independently selected from the group consisting of Met, Ile, Leu and Val; and X6 is selected from the group consisting of Asp, Gln and Glu, optionally at least one of X1, X2, X3, X4, X5 and X6 is independently substituted with a non-natural or unusual amino acid and/or the peptide is cyclized and/or the peptide is stabilized and/or the amino terminal amino acid residue is acylated and/or the carboxy terminal amino acid residue is amidated, and peptidomimetics modelled on the basis of the above formula for the preparation of a pharmaceutical composition for the reduction of TNF alpha production and/or for the prophylaxis or treatment of pancreatitis and/or for the prophylaxis or treatment of viral infections such as acquired immunodeficiency syndrom (AIDS) or cutaneous HPV-infection. In particular, the invention relates to analogues of peptides of the above formula wherein at least one of X1, X2, X3, X4, X5 and X6 is independently substituted with a non-natural or unusual amino acid and/or the peptide is cyclized and/or the peptide is stabilized and/or the amino terminal amino acid residue is acylated and/or the carboxy terminal amino acid residue is amidated, and peptidomimetics moldelled on the basis of the above formula.

Description: SYNTHETIC IL-10 ANALOGUES FIELD OF INVENTION The present invention relates to the pharmaceutical use of substances which are interleukin 10 (IL-10) agonists. In par- ticular, the invention relates to the use of a substance of the invention for the manufacture of a pharmaceutical compo¬ sition for the reduction of TNFα production and/or the pro¬ phylaxis or treatment of pancreatitis, arthritis urica (gout) , allergy of the skin, allergic reactions in the skin, tissue damage as a result of hypoxia/ischemia (infarction, reperfusion) , inflammatory reactions due to virus infections, and/or for the manufacture of a conceptive agent. BACKGROUND OF THE INVENTION Pharmaceutical compositions comprising hIL-10 or vIL-10, and the use of hIL-10 or vIL-10 for the manufacture of a pharma¬ ceutical composition for the treatment of various conditions have been disclosed in e.g. WO 93/02693 and WO 94/04180, and certain IL-10 agonists have been disclosed in WO 96/01318. SUMMARY OF THE INVENTION The present invention relates to the use of a substance or polypeptide according to the formula X 1 -X 2 -X 3 -Thr-X 4 -Lys-X 5 -Arg-X 6 (SEQ ID NO:22), wherein X x is Ala or Gly, X 2 is Tyr or Phe, X 3 , X 4 and X 5 are independently selected from the group con¬ sisting of Met, lie, Leu and Val; and X 6 is selected from the group consisting of Asp, Gin and Glu, optionally at least one of X l7 X 2 , X 3 , X 4 , χ 5 and X 6 is inde¬ pendently substituted with non-natural or unusual amino acids and/or the peptide is cyclized and/or the peptide is stabili¬ zed and/or the amino terminal amino acid residue is acylated and/or the carboxy terminal amino acid residue is amidated, and peptidomimetics modelled on the basis of the above for¬ mula for the preparation of a pharmaceutical composition for the reduction of TNFα production and/or for the prophylaxis or treatment of pancreatitis. Further, the invention relates to a substance or polypeptide having the formula X 1 -X 2 -X 3 -Thr-X 4 -Lys-X 5 -Arg-X 6 (SEQ ID NO:22) , wherein X x is Ala or Gly, X 2 is Tyr or Phe, X 3 , X 4 and X 5 are independently selected from the group con¬ sisting of Met, He, Leu and Val; and X 6 is selected from the group consisting of Asp, Gin and Glu, wherein at least one of X 1# X 2 , X 3 , X 4 , X 5 and X 6 is indepen- dently substituted with non-natural or unusual amino acids and/or the peptide is cyclized and/or the peptide is stabi¬ lized and/or the amino terminal amino acid residue is acyla¬ ted and/or the carboxy terminal amino acid residue is amidat¬ ed, and peptidomimetics modelled on the basis of the above formula, said substance or polypeptide having at least one of the following properties: a) induces inhibition of spontaneous IL-8 production by human monocytes, b) induces inhibition of IL-10 induced IL-8 production by human peripheral blood mononuclear cells (PBMC) , c) induces production of interleukin-l receptor antagonis¬ tic protein (IRAP) by human monocytes, d) induces chemotactic migration of CD8+ human T lymphocy¬ tes in vitro, e) desensitizes human CD8+ T cells resulting in an unre- sponsiveness towards rhIL-10, f) suppresses the chemotactic response of CD4+ human T lymphocytes towards IL-8, g) suppresses the chemotactic response of human monocytes towards MCAF/MCP-1, h) inhibits class II MHC molecule expression on human monocytes stimulated with IFN-7, i) induces the production of IL-4 by cultured normal human CD4+ T cells, j) reduces the TNFα production in human mixed leukocyte reaction, k) downregulates TNFα and IL-8 production in a rabbit model of bile acid induced acute pancreatitis and reduces neutrophil infiltration in the lungs of the treated rabbits. It is contemplated (as described in detail in the following description of immunological mechanisms) that the action mechanism is via interference with the action of mediators of the immune system, in particular cytokines such as monokines, lymphokines, chemokines and monokine-receptor antagonists, i.e. that the substance of the invention interferes with/suppresses the production and/or action of certain cytokines and thus inhibits pathological processes leading to tissue damage, and that the substance of the invention induces the production of natural monokine-receptor antago¬ nists thus interfering with/suppressing the action of certain cytokines such as TNFα or IL-1 and thereby inhibiting patho¬ logical processes which lead to tissue damage. An important embodiment of the present invention thus relates to a pharmaceutical composition comprising, as the active ingredient, a substance of the invention. In a further aspect, the present invention relates to the use of a substance of the invention for the manufacture of a phar¬ maceutical composition for substantially inhibiting a biolo¬ gical effect related to a cytokine, i.e. the use of a sub- stance of the invention as an IL-l receptor antagonist pro- tein/peptide, lymphokine, monokine, interleukin, interferon, chemokine or colony-stimulating factor. Another aspect rela¬ tes to the use of a substance of the invention for the manu¬ facture of a pharmaceutical composition for the prophylaxis or treatment of a condition related to the disturbance of a cytokine system, i.e. the IL-l receptor antagonist protein/- peptide, lymphokine, monokine, interleukin, interferon, chemokine or colony-stimulating factor system. In another aspect, the invention also relates to a method of treating a condition in a human related to a disturbance in a cytokine system which method comprises administering to the subject an effective amount of a substance of the invention. The cellular immune system takes part in the development of such disorders as infectious, inflammatory and neoplastic diseases. Immunocompetent cells and their products may play important roles in the initiation, progression and possible chronic nature of development of inflammatory conditions. These disorders are often without known etiology and includes common diseases such as diabetes mellitus, rheumatoid arthri- tis, inflammatory diseases of the gastro-intestinal tract and of the skin. Apart from these examples, cell-mediated immuni¬ ty or pro-inflammatory mediators, however, contribute to many other inflammatory and proliferative diseases (see Table 1) . TABLE 1 Some diseases where macrophages/T-lymphocyte-mediated immune reactions are considered pathogenetically important Skin diseases : Psoriasis Atopic dermatitis Contact dermatitis Cutaneous T cell lyrtvphoma (CTCL) Sezary syndrome Pemphigus vulgaris Bullous pemphigoid Erythema nodosum Scleroderma Auto -immune (including rheumatic) diseases: Uveitis Bechet's disease Sarcoidosis Boeck Sjδgren' s syndrome Rheumatoid arthritis Juvenile arthritis Reiter's syndrome Gout Osteoarthrosis Systemic lupus erythematosis Polymyositis Myocarditis Primary biliary cirrhosis Crohn's disease Ulcerative colitis Multiple sclerosis and other demyelinating diseases Aplastic anaemia Idiopathic thrombocytopenic purpura Multiple myeloma and B cell lymphoma Simmons' panhypopituitarism Graves' disease and Graves' opthalmopathy Subacute thyreoditis and Hashimoto's disease Addison's disease Insulin-dependent diabetes mellitus (type 1) Other diseases Various clinical syndromes with vasculitis (e.g. polyarteri- tis nodosa, Wegener's granulomatosis, Giant cell arteritis Fever, malaise Anorexia (e.g. in acute and chronic inflammatory and infec¬ tious diseases) Disseminated intravascular coagulation (DIC) Arteriosclerosis (atherosclerosis) Shock (e.g. in gram-negative sepsis) Cachexia (e.g. in cancer, chronic infectious and chronic in¬ flammatory diseases) Transplant rejection and graft vs. host disease Prevention of spontaneous abortion JL-10 activi ty on cytokine production: hIL-10 inhibits the production of a number of cytokines including interferon-γ (IFN-γ) , Tumor Necrosis Factor-o; (TNF-α) , Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), Granulocyte-CSF (G-CSF), IL-lα, IL-13, IL-2, IL-6, IL-8 and Monocyte Chemotactic polypeptide-l (MCP-l/MCAF) by monocytes/macrophages and/or T lymphocytes (4, 5) . IL-10 also inhibits the ability of monocytes to migrate as a response to the chemokine MCP-l/MCAF (75) . Further, hIL-10 induces the production of an endogenous, natural interleukin-1 receptor antagonist (IRAP) (6), which inhibits IL-lo; and IL-lS by competing with receptor binding. Since IL-8 is strongly inducible by IL-lα and by IL-1/3, IL-10 exerts part of its inhibitory effect on IL-8 production by stimulating the pro- duction of the IL-l-receptor antagonist IRAP. This last mechanism is of considerable importance for the present in¬ vention as described and exemplified in the following. IRAP has anti-inflammatory activities (9) , and its therapeutic effect in rheumatoid arthritis has been suggested (10) . Also, IRAP proved to be effective in the treatment of sepsis syn¬ drome and a dose-dependent, 28-day survival benefit was asso¬ ciated with IRAP treatment (p = 0.015) in a study by Fisher et al. (11). IRAP may exert parts of its anti-inflammatory effects by inhibiting chemokine-production such as the pro- duction of IL-8. IL-10 and antigen expression : IL-10 inhibits the expression of class II MHC expression on human monocytes (8) . Constitutive and IL-4 or IFN-7 induced expression of HLA-DR/DP and DQ was inhibited by hIL-10 (12) . In addition, monocytes pre-incubated with IL-10 are refrac¬ tory to subsequent induction of class II MHC expression by IL-4 or IFN-γ. IL-10 inhibits class II expression by human monocytes following activation by LPS (12, 76) . BALB/c mice given 1 to 10 mg of IL-10 concomitantly with a lethal dose of LPS were protected from death (6) . IL-10 inhibits nitrogen intermediates and superoxide anions. IL-10 also inhibits reactive nitrogen intermediate (NO) as well as reactive oxygen intermediates (H 2 0 2 ) by macrophages following activation by IFN-γ (13) . IL- 10 and T cell activi ty: IL-10 has also modulatory effects on T cell functions/acti¬ vity. Thus, hIL-10 is a potent chemotactic factor to CD8+ T lymphocytes, while hIL-10 does not show chemotaxis towards CD4+ T cells (14) . Additionally, IL-10 suppresses the capa¬ city of CD4+ T cells to respond to the chemotactic signals of the β-chemokine RANTES as well as the α-chemokine IL-8. hIL-10 also directly inhibits the proliferation of human peripheral blood T cells and CD4+ T cell clones (14) . Therapeutic considerations : These in vivo results/data and other data summarized e.g. in WO 96/01318 strongly suggest a homeostatic role of IL-10 in controlling cell-mediated and monokine-amplified immune inflammation and indicate the wide-ranged therapeutical applications of IL-10 or a drug with IL-10-like activity in the treatment of diseases which are characterized by a decreased/insufficient production and/or activity of IL-10. Tables l and 2 list some diseases where an immune-modulator like IL-10 or an immune-modulator with IL-10-like activity is considered to have therapeutic importance: TABLE 2 Some diseases where an immune-modulator with IL-10-like activity, due to its induction of IRAP production and/or inhibition of cytokine-production and/or activity may have therapeutic importance (ref. 20-74 + 109) Pre-term labour caused by infection or other conditions Rheumatoid arthritis Lyme's arthritis Gout Sepsis syndrome Hyperthermia Ulcerative colitis or enterocolitis Osteoporosis Cytomegalovirus Periodontal diseases Glomerulonephritis Chronic, non-infectious inflammation of the lung (e.g. sar- coidosis and smoker's lung) Granuloma formation Fibrosis of the liver Fibrosis of the lung Transplant rejection Graft vs. host disease Chronic myeloid leukaemia Acute myeloid leukaemia Other neoplastic diseases Asthma bronchiale Diabetes mellitus, type I (insulin dependent) Arteriosclerosis/atherosclerosis Psoriasis Chronic B lymphocyte leukaemia Common variable immunodeficiency Side-effects using other biological response modifiers Disseminated intravascular coagulation Systemic sclerosis Encephalomyelitis Lung inflammation Hyper IgE syndrome Enterocolitis Cancer metastasis and growth Adoptive immune therapy Acquired respiratory distress syndrome Sepsis Reperfusion syndrome Postsurgical inflammation Organ transplantation Alopecia AIDS Cutaneous HPV-infection DETAILED DESCRIPTION OF THE INVENTION Development of an IL- 10 -homologous nonapeptide wi th IL-10 - like activi ty: Partial sequences of hIL-10 having a length of 9 amino acids was chosen according to the principle that the sequences should possess high homology between vIL-10 and hIL-10, but as low homology to m.IL-10 as possible. It was found that a synthetic nonapeptide, IT9302, possessed some immuno-suppres- sive activities which mimic those of hIL-10 as described in further detail in the following examples. IT9302 corresponds to a nonapeptide sequence from the C-terminal end of hIL-lO with the following amino acid sequence: NH 2 -Ala-Tyr-Met-Thr-Met-Lys-Ile-Arg-Asn-COOH (SEQ ID N0:1) The nonapeptide IT9302 is very potent to induce different functions and is very stable, and it is presumed that it can¬ not be incorrectly coupled to receptors. A nonapeptide has been chosen because generally a 9 amino acid polypeptide sequence is unique for a protein. However, it is to be noted that the 6 amino acids at the very end of hIL-10 seem to be the most important ones. Within the scope of the present in¬ vention is thus a substance or polypeptide comprising a sub- sequence of the amino acid sequence Ala-Tyr-Met-Thr-Met-Lys- Ile-Arg-Asn (SEQ ID N0:1). It is considered likely that some amino acid substitutions will not have adverse effects on the hIL-10 agonist activity as defined herein as long as the threonine, the lysine and the arginine are present and with one amino acid placed inbetween. The present invention in particular relates to the use of a substance or polypeptide according to the formula: X 1 -X 2 -X 3 -Thr-X 4 -Lys-X 5 -Arg-X 6 (SEQ ID NO:22), wherein X x is Ala or Gly, X 2 is Tyr or Phe, X 3 , X 4 and X 5 are independently selected from the group con¬ sisting of Met, He, Leu and Val; and X 6 is selected from the group consisting of Asp, Gin and Glu, optionally at least one of X 1# X 2 , X 3 , X 4 , X 5 and X 6 is inde¬ pendently substituted with non-natural or unusual amino acids and/or the peptide is cyclized and/or the peptide is stabi¬ lized and/or the amino terminal amino acid residue is acylat- ed and/or the carboxy terminal amino acid residue is amidat¬ ed, and peptidomimetics modelled on the basis of the above formula for the preparation of a pharmaceutical composition for the reduction of the IL-l-induced TNFα production presum¬ ably by the blocking of the IL-l receptor with IRAP and/or for the prophylaxis or treatment of pancreatitis. Examples of specific polypeptides which are presumed to be useful for the reduction of TNFo; production and/or the pro¬ phylaxis or treatment of pancreatitis are as follows: I. NH 2 -Ala-Tyr- et-Thr-Ile- ys- et-Arg-Asn-COOH (SEQ ID N0:2) 2. NH 2 -Ala-Phe-Met-Thr-Leu-Lys-Leu-Arg-Asn-COOH (SEQ ID NO:3) 3. lrø 2 -Ala-Tyr-Met-Thr-Met-Lys-Val-Arg-Glu-cθOH (SEQ ID NO:4) 4. NH 2 -Gly-Tyr-Met-Thr-Met-Lys-Ile-Arg-Asp-COOH (SEQ ID N0:5) 5. NH 2 -Ala-Phe-Met-Thr-Met-Lys-Ile-Arg-Asp-COOH (SEQ ID NO:6) 6. NH 2 -Ala-Tyr-Ile-Thr-Met-Lys-Ile-Arg-Asp-COOH (SEQ ID N0:7) 7. NH 2 -Ala-Tyr-Leu-Thr-Met-Lys-Ile-Arg-Asp-COOH (SEQ ID NO:8) 8. NH 2 -Ala-Tyr-Val-Thr-Met-Lys-Ile-Arg-Asp-COOH (SEQ ID NO:9) 9. NH 2 -Ala-Tyr-Met-Thr-Ile-Lys-Ile-Arg-Asp-COOH (SEQ ID NO:10) 10. NH 2 -Ala-Tyr-Met-Thr-Leu-Lys-Ile-Arg-Asp-COOH (SEQ ID NO:ll) II. NH 2 -Ala-Tyr-Met-Thr-Val-Lys-Ile-Arg-Asp-COOH (SEQ ID NO: 12) 12. NH 2 -Ala-Tyr-Met-Thr-Met-Lys-Ile-Arg-Asp-COOH (SEQ ID NO:13) 13. NH 2 -Ala-Tyr-Met-Thr-Met-Lys-Met-Arg-Aεp-COOH (SEQ ID NO:14) 14. NH 2 -Ala-Tyr-Met-Thr-Met-Lys-Val-Arg-Asp-COOH (SEQ ID NO:15) 15. NH 2 -Ala-Tyr-Met-Thr-Met-Lys-Ile-Arg-Gln-COOH (SEQ ID NO:16) 16. NH 2 -Ala-Tyr-Met-Thr-Met-Lys-Ile-Arg-Glu-COOH (SEQ ID NO:17) The present invention in particular relates to a polypeptide having the formula Thr-X 4 -Lys-X 5 -Arg-X 6 (SEQ ID N0:19), a polypeptide having the formula X 3 -Thr-X 4 -Lys-X 5 -Arg-X 6 (SEQ ID NO:20), a polypeptide having the formula X 2 -X 3 -Thr-X 4 -Lys-X 5 -Arg-X 6 (SEQ ID NO:21) , and a polypeptide having the formula X 1 -X 2 -X 3 -Thr-X 4 -Lys-X 5 -Arg-X 6 (SEQ ID NO:22) , wherein X χ is Ala or Gly, X 2 is Tyr or Phe, X 3 , X 4 and X 5 are independently selected from the group con¬ sisting of Met, He, Leu and Val; and X 6 is selected from the group consisting of Asp, Gin and Glu, wherein one or more amino acids are substituted with non- natural or unusual amino acids and/or the peptide is cyclized and/or the amino terminal amino acid residue is acylated and/or the carboxy terminal amino acid residue is amidated, and peptidomimetics modelled on the basis of the above for¬ mula, said analogues having at least one of the following properties: a) induces inhibition of spontaneous IL-8 production by human monocytes, b) induces inhibition of IL-13 induced IL-8 production by human peripheral blood mononuclear cells (PBMC) , c) induces production of interleukin-1 receptor antagonis¬ tic protein (IRAP) by human monocytes, d) induces chemotactic migration of CD8+ human T ly phocy- tes in vitro, e) desensitizes human CD8+ T cells resulting in an unre- sponsiveness towards rhIL-10, f) suppresses the chemotactic response of CD4+ T human lymphocytes towards IL-8, g) suppresses the chemotactic response of human monocytes towards MCAF/MCP-1, h) inhibits class II MHC molecule expression on human monocytes stimulated by IFN-7, i) induces the production of IL-4 by cultured normal human CD4+ T cells, j ) reduces the TNFα production in human mixed leukocyte reaction, k) downregulates TNFα and IL-8 production in a rabbit model of bile acid induced acute pancreatitis and reduces neu- trophil infiltration in the lungs of the treated rab¬ bits. By use of the term "at least one biological activity of IT9302" in the present specification and claims, reference is meant to be to at least one of the above mentioned pro¬ perties. Any of the contemplated peptides of the invention can have an amino terminal amino acid residue which is acylated such as acetylated or benzoylated. Also, any of the contemplated peptides can have a carboxy terminal amino acid residue which is amidated. The present invention further contemplates analogues of peptides formed by other conservative amino acid substitu¬ tions than the specific substitutions proposed above, sub¬ stitutions of unusual or non-natural amino acids, stabili¬ zation of peptides, cyclization of peptides, and peptidomi- metics modelled on the identified IL-10 agonist peptides. The principle behind conservative amino acid substitution is that certain amino acid pairs have compatible side chains such that, when one is substituted for the other, there will be only minimal changes in the tertiary structure and the binding affinity of the peptide. Rules for conservative substitution are explained in (78) . "Conservative" as used herein means (i) that the alterations are as conformationally neutral as possible, that is, design¬ ed to produce minimal changes in the tertiary structure of the mutant polypeptides as compared to the native protein, and (ii) that the alterations are as antigenically neutral as possible, that is designed to produce minimal changes in the antigenic determinants of the mutant polypeptides as compared to the native protein. Conformational neutrality is desirable for preserving biological activity, and antigenic neutrality is desirable for avoiding the triggering of immunogenic responses in patients or animals treated with the substances of the invention. Although it is difficult to select with absolute certainty which alternatives will be conformational- ly and antigenically neutral, rules exist which can guide those skilled in the art to make alterations that have high probabilities of being conformationally and antigenically neutral, see e.g. (77) and (78) . Some of the more important rules include (1) replacement of hydrophobic residues is less likely to produce changes in antigenicity because they are likely to be located in the protein's interior, e.g. Berzof- sky (cited above) and Bowie et al. (cited above); (2) repla¬ cement of physicochemically similar, i.e. synonymous, resi- dues is less likely to produce conformational changes because the replacing amino acid can play the same structural role as the replaced amino acid; and (3) alteration of evolutionarily conserved sequences is likely to produce deleterious confor¬ mational effects because evolutionary conservation suggests sequences may be functionally important. In addition to such basic rules for selecting mutein sequences, assays are avail¬ able to confirm the biological activity and conformation of the engineered molecules. Changes in conformation can be tested by at least two well known assays: the microcomplement fixation method, e.g. (79) and (80) used widely in evolution¬ ary studies of the tertiary structures of proteins; and affinities to sets of conformation-specific monoclonal anti¬ bodies, e.g. (81) . Biological assays for the substances of the invention are described more fully in the examples: Inhibition of spontaneous IL-8 production by human monocytes is tested as outlined in Example 1 using the synthesized substance or peptide instead of IT9302. If the IL-8 produc¬ tion is suppressed to be no more than 50% when 1 ng/ml of the substance or peptide is used, then the substance or peptide is within the scope of the present invention. Inhibition of IL-lβ induced IL-8 production by human periphe¬ ral blood mononuclear cells (PBMC) is tested as outlined in Example 2 using the synthesized substance or peptide instead of IT9302. If the percent inhibition of IL-8 production is at least 50% when 1 ng/ml of the substance or peptide is used, then the substance or peptide is within the scope of the present invention. Production of interleukin-1 receptor antagonistic protein (IRAP) by human monocytes is tested as outlined in Example 3 using the synthesized substance or peptide instead of IT9302. If the induction of IRAP is at least 30 ng/ml when 10 ng/ml of the substance or peptide is used, then the substance or peptide is within the scope of the present invention. Induction of chemotactic migration of CD8+ human T lymphocy- tes in vi tro is tested as outlined in Example 4 using the synthesized substance or peptide instead of IT9302. If the potency of the substance or peptide when a concentration of 10 ng/ml is used is present, i.e. 2 or more, then the sub¬ stance or peptide is within the scope of the present inven- tion. Desensitization of human CD8+ T cells resulting in an unre- sponsiveness towards rhIL-10 is tested as outlined in Example 5 using the synthesized substance or peptide instead of IT9302. If preincubation of cells with the substance or peptide results in a substantially totally suppressed respon¬ siveness of the CD8+ cells towards hrIL-10, i.e. giving a value of about 1, such as 0.8 to 1.2, at a concentration of the substance or peptide of 10 ng/ml, then the substance or peptide is within the scope of the present invention. Suppression of the chemotactic response of CD4+ human T lymphocytes towards IL-8 is tested as outlined in Example 6 using the synthesized substance or peptide instead of IT9302. If addition of the substance or peptide to a suspension of human CD4+ T lymphocytes results in a substantially total inhibition of the response of the CD4+ cells towards IL-8, i.e. giving a value of about 1, such as 0.8 to 1.2, at a concentration of the substance or peptide of 10 ng/ml, then the substance or peptide is withm the scope of the present invention. Suppression of the chemotactic response of human monocytes towards MCAF/MCP-1 is tested as outlined in Example 7 using the synthesized substance or peptide instead of IT9302. If addition of the substance or peptide to a suspension of human monocytes results in a substantially total inhibition of the chemotactic response of the monocytes towards MCAF/MCP-1, i.e. giving a value of about 1, such as 0.8 to 1.2, at a concentration of the substance or peptide of 10 ng/ml, then the substance or peptide is within the scope of the present invention. Inhibition of class II MHC molecule expression on human mono¬ cytes stimulated with IFN-7 is tested as outlined in Example 8 using the synthesized substance or peptide instead of IT9302. IFN-7 upregulated MHC II antigen expression in the cell population from 36.8% to 58.4%, and this stimulation was blocked or downregulated to 25.2% by 10 ng/ml rhIL-10 and to 31.2% by 1 ng/ml IT9302 (Fig. 12) . If a substance or peptide blocks or downregulates class II MHC expression on monocytes to the unstimulated level, when added in an amount of 1-10 ng/ml, then the substance or peptide is within the scope of the present invention. If addition of the substance or peptide is capable of block¬ ing the effect of the IFN7 stimulation at a concentration of the substance or peptide of 10 ng/ml, then the substance or peptide is within the scope of the present invention. Induction of the production of IL-4 by cultured normal human CD4+ T cells is tested as outlined in Example 9 using the synthesized substance or peptide instead of IT9302. If addi¬ tion of the substance or peptide induces the production of IL-4 in CD4+ T lymphocytes at a concentration of the sub¬ stance or peptide of 10 ng/ml, then the substance or peptide is within the scope of the present invention. Reduction of the TNFα production in human mixed leukocyte reaction is tested as outlined in Example 10 using the syn- thesized substance or peptide instead of IT9302. If addition of the substance or peptide significantly reduces the produc¬ tion of TNFα in human mixed leukocyte reaction within 24 hours at a concentration of the substance or peptide of 10 ng/ml, then the substance or peptide is within the scope of the present invention. Downregulation of TNFα and IL-8 production in a rabbit model of bile acid induced acute pancreatitis and reduction of neu- trophil infiltration in the lungs of the treated rabbits is tested as outlined in Example 14 using the synthesized sub¬ stance or peptide instead of IT9302. If addition of the sub¬ stance or peptide significantly reduces the mortality of the test animals, when the substance or peptide is added at a concentration of 100 μg/kg, then the substance or peptide is within the scope of the present invention. An important embodiment of the present invention thus relates to a polypeptide in which at least one amino acid residue has been substituted with a different amino acid residue and/or in which at least one amino acid residue has been deleted or added so as to result in a polypeptide comprising an amino acid sequence being different from the amino acid sequence or a subsequence of said amino acid sequence as defined in the following, but essentially having hIL-10 agonist activity as defined above. Analogues of synthetic peptides can also be made by substitu¬ ting individual residues with non-natural or unusual amino acids. Sequences of bioactive peptides are originally derived from proteins which are made up of the naturally occurring twenty L-amino acid residues. However, the process of chemi- cal synthesis used to construct synthetic peptides allows for the substitution of alternate residues including D-amino acids, β-amino acids, N-substituted amino acids, infrequently occurring natural amino acids, or non-natural synthetic amino acid analogues (93) . Non-limiting examples of amino acids useful in the present invention are: Aad 2-Aminoadipic acid bAad 3-Aminoadipic acid bAla beta-Alanine, beta-Aminopropionic acid Abu 2-Aminobutyric acid 4Abu 4-Aminobutyric acid, piperidinic acid Acp 6-Aminocaproic acid Ahe 2-Aminoheptanoic acid Aib 2-Aminoisobutyric acid bAib 3-Aminoisobutyric acid Apm 2-Aminopimelic acid Dbu 2,4-Diaminobutyric acid Des Desmosine Dpm 2,2' -Diaminopimelic acid Dpr 2,3-Diaminopropionic acid EtGly N-Ethylglycine EtAsn N-Ethylasparagine Hyl Hydroxylysine aHyl allo-Hydroxylysine 3Hyp 3-Hydroxyproline 4Hyp 4-Hydroxyproline Ide Isodesmosine alle allo-Isoleucine MeGly N-Methylglycine, sarcosine Melle N-Methylisoleucine MeLys 6-N-Methyllysine MeVal N-Methylvaline Nva Norvaline Nle Norleucine Orn Ornithine Further and non-limiting examples of infrequently occurring, non-natural amino acids or building blocks are listed as follows: Novabiochem 1994/95 Catalog (Calbiochem-Novabiochem AG, Weidenmattweg 4, CH-4448 Laufelfingen/Switzerland) , pp. 65-125; Bachem Feinkemikalien AG 1995 Catalog (Bachem Fein- kemikalien AG, Hauptstrasse 144, CH-4416 Bubendo t/Switzer- land) , pp. 753-831; Neosystem Laboratoire Catalogue 1997/98 (Neosystem Laboratoire, 7 rue de Boulogne, 67100 Strasbourg, France), pp. 131-176. The above described alternate residues can be used (a) to replace chemically reactive residues and improve the stabili- ty of the synthetic peptide towards e.g. enzymatic and pro- teolytic degradation, (b) to provide analytic labels useful in the detection of the synthetic peptide, and (c) to modula¬ te the bioactivity of the synthetic peptide by increasing or decreasing the binding affinity of the peptide for the IL-10 receptor, e.g. by introduction of conformational constraints which reduce the rotational freedom for specific chemical bonds. Within the scope of the present invention are further sub¬ stances wherein one or more of the residues Thr, Lys or Arg in the above formula is substituted with non-natural or unusual amino acids as proposed above. All polypeptide se¬ quences in the present specification and claims are, also when not explicitly stated, written from the N-terminal to the C-terminal end in the conventional format. The method of choice for synthesis of the peptides and their analogues is solid-phase peptide synthesis (SPPS) . This method was introduced by Merrifield (100) in 1963, and nume¬ rous peptides have been synthesized since then with this technique. An excellent review of the current chemical syn- thesis of peptides and proteins is given by S.B.H. Kent (101) . In practice, peptides are assembled by stepwise SPPS. The C- terminal amino acid in the form of an N-alfa-protected, if necessary side chain-protected reactive derivative, is co- valently coupled either directly or by means of a suitable linker to a solid support, e.g. a polymeric resin, which is swollen in an organic solvent. The N-alfa-protective group is then removed and the succeeding protected amino acids accord¬ ing to the desired sequence are added in a stepwise manner. After assembly of the complete peptide chain, the side chain- protective groups are removed, and the peptide is cleaved from the resin, which may be done simultaneously or in sepa¬ rate steps. Among the several different coupling strategies which have emerged over the years, two are currently in general use, based on the different N-alfa-protective groups and matching side chain-protective groups. Merrifield used tert.butyloxy- carbonyl (Boc) as the N-alfa-protective group, while 9-fluor- enylmethoxycarbonyl (Fmoc) was introduced by Carpino and Han (102) . The practical application of these two strategies including the choice of solid supports, side chain-protecting groups, activation procedures, cleavage procedures, instru¬ mentation, and analytical and monitoring techniques have been given in several monographs among which should be mentioned the following: Stewart and Young (103) , Atherton and Sheppard (104) , and Pennington and Dunn (105) . Peptides and their analogues with unusual or non-natural amino acids in the present invention are conveniently synthesized according to these protocols. Analogues of synthetic linear peptides can be made by chemi¬ cally converting the structures to cyclic forms. Cyclization of linear peptides can modulate bioactivity by increasing or decreasing the affinity of binding of the peptide by the target protein (94) . Linear peptides are very flexible and tend to adopt many different conformations in solution. Cyclization acts to constrain the number of available confor¬ mations and thus favour the more active or inactive struc¬ tures of the peptide. The immunogenicity of synthetic pepti- des has been correlated with the experimentally observed conformational preferences in solution (95) . Differences in immunogenicity may be indicative of differences in binding affinity of specific antibodies for cyclic peptides. Cyclization of linear peptides is accomplished either by forming a peptide bond between the free N-terminal and C- terminal ends (homodetic cyclopeptides) or by forming a new covalent bond between amino acid backbone and/or side chain groups (heterodetic cyclopeptides) (93) . The latter cycliza- tions use alternate chemical strategies to form covalent bonds, e.g. disulfides, lactones (both also present in natu¬ ral peptides), ethers, or thioethers. Linear peptides of more than five residues can be cyclized relatively easily. The propensity of the peptide to form a beta-turn conformation in the central four residues facilitates the formation of both homo- and heterodetic cyclopeptides. The presence of proline or glycine residues at the N- or C-terminal ends also facili¬ tates the formation of cyclopeptides, especially from linear peptides shorter than six residues in length. Examples of protocols for the formation of disulfide bonds and for other cyclization reactions of peptides are given in Pennington and Dunn (105) , chapters 7 and 11. Peptidomimetics technology is the design of molecular mimics of peptides. The ability to successfully design such molecu¬ les depends on the understanding of the properties of the linear peptide sequence and the conformation in which it is presented to the IL-10 receptor. The synthesis of mimetics can provide compounds exhibiting greater biological activity, improved solubility, and stability (96) . As an example, the following peptidomimetic has been derived on the basis of the α-helical templates in C-terminal peptide mimetics of cytokines disclosed in US 5,446,128 (97) in com¬ bination with the knowledge that the C-terminal of IL-10 exists as an α-helix (98) . By this attachment of a small molecule at the N-terminal of the peptide, an a-helical structure of the synthetic peptide is stabilized, and the peptide is made more resistant to pro- teolytic degradation. Other peptidomimetics may be derived on the basis of the disclosure in US 5,446,128. Such substances wherein substitution has taken place at other residues than X λ and/or substitution has taken place with other molecules than the N-terminal molecule shown in the formula above are within the scope of the present invention. In accordance with the present invention, the term "an ana¬ logue of the peptide" comprises any pharmaceutically active and acceptable compound derived on the basis of the above formulae and exhibiting at least one biological activity similar to IT9302, including derivatives of such analogues, especially pharmaceutically acceptable salts, esters and solvates thereof. The following terms: "cytokine", "lymphokine", "interleukin", "monokine", "chemokine", "interferon", "colony-stimulating factor", and "polypeptide" are used as defined in WO 96/01318. An interesting embodiment of the invention relates to a poly¬ peptide of the invention where the number of amino acids amount in total from 6, 7, 8, 9 or 10 up to about 100 amino acids, e.g. 11, 12, 13, 14 or 15 amino acids, or even larger such as 20 amino acids or 30 amino acids. In a preferred embodiment of the invention, the substance or polypeptide is used in substantially pure form. To obtain this, purification of the polypeptide may be required. Examp¬ les of the procedures employed for the purification of poly- peptides are: (i) immunoprecipitation or affinity chromato¬ graphy with antibodies, (ii) affinity chromatography with a suitable ligand, (iii) other chromatography procedures such as gel filtration, ion exchange or high performance liquid chromatography or derivatives of any of the above, (iv) elec- trophoretic procedures like polyacrylamide gel electrophore- sis, denaturating polyacrylamide gel electrophoresis, agarose gel electrophoresis and isoelectric focusing, (v) any other specific solubilization and/or purification techniques. Within the scope of the present invention is also a pharma¬ ceutical composition comprising a substance or polypeptide of the invention and a pharmaceutically acceptable excipient. The composition may comprise e.g. purified synthesized pro¬ tein or a purified recombinant polypeptide. The IL-10 agonist used in this invention may be prepared as formulations in pharmaceutically acceptable media, for example, saline, phosphate buffered saline (PBS), Ringer's solution, dextrose/saline, Hank's solution, and glucose. The compositions may contain pharmaceutically acceptable auxili- ary substances as required to approximate physiological con¬ ditions, such as buffering agents, tonicity adjusting agents, wetting agents, detergents, and the like. Additives may also include additional active ingredients, e.g. bactericidal agents, or stabilizers. The amount administered to the patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the host, the manner of administration, and the like. The pharmaceutical compositions are typically intended for transcutaneous or parenteral administration, e.g. intrave¬ nously, subcutaneously, or intramuscularly. Orally admini¬ strable forms are also desired and can be provided by modify¬ ing the composition to bypass the stomach environment. The composition can be used for prophylactic and/or therapeutic treatment. Pharmaceutical compositions of the invention suitable for topical administration may e.g. be creams, ointments, lotions, liniments, gels, solutions, suspensions, pastes, sticks, sprays, or powders. The composition may be impreg- nated or distributed onto e.g. pads, plasters or strips and is conveniently applied 1-10 times a day. The topical compositions will generally comprise 1-80% of the active compound by weight, based on the total weight of the preparations, such as 0.001-25% w/w of the active compound, e.g., 0.1-10%, 0.5-5%, or 2-5%. The composition may be formu¬ lated in accordance with conventional pharmaceutical practice with pharmaceutical excipients conventionally used for topi¬ cal applications. Vehicles other than water that can be used in compositions can include solids or liquids such as emol¬ lients, solvents, humectants, thickeners and powders. The pH of the composition may in principle be within a very broad range such as 3-9, although a pH of about 4 to 8 is preferred. Conventional buffering agents may be used to obtain the desired pH. As an example, a composition for transcutaneous administra¬ tion can contain 1 mg of substance (IT9302) dissolved in 1 g of cream basis such as Moistion's neutral cream with 0.05% salicylic acid (the pharmacy of Arhus Kommunehospital) and be applied in amount of 0.4-0.5 mg under plastic on the skin. This composition is used in Examples 16 and 17. Pharmaceutical compositions may alternatively be administered intravenously. Thus, the invention provides compositions which comprise an IL-10 agonist substance dissolved or sus- pended in an acceptable carrier, preferably an aqueous car¬ rier. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The IL-10 agonist may also be administered with a second biologically active agent, such as a standard chemotherapeutic agent. Such agents include but are not limited to vincristine, daunorubi¬ cin, L-asparaginase, mitoxantrone and amsacrine. In therapeutic applications, the pharmaceutical compositions are administered to a patient in an amount sufficient to produce the desired effect, defined as a "therapeutically effective dose". The therapeutically effective dose of an IL-10 agonist will vary according to, for example, the par¬ ticular use for which the treatment is made, the manner of administration, the health and condition of the patient, and the judgment of the prescribing physician. For example, the dose for continuous infusion will typically be between 500 ng/kg/day and 50 μg/kg/day. This dose is calculated on the basis of a randomized controlled trial of IL-10 in humans (90) . The concentration of IL-10 agonist in the pharmaceutical formulations can vary widely, i.e. from about 10 μg to about 5 mg/ml, preferably between about 100 μg and about 2 mg/ml. The concentration will usually be selected primarily by fluid volumes, viscosities, etc., in accordance with the particular mode of administration selected. Thus, a typical pharmaceu¬ tical composition for intravenous infusion could be made up to contain 250 ml of dextrose/saline solution and 2.5 μg of IL-10 agonist. For solid compositions, conventional non-toxic solid carriers may be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium sac- charin, talcum, cellulose, glucose, sucrose, magnesium carbo¬ nate, and the like. For oral administration, a pharmaceuti¬ cally acceptable non-toxic composition is formed by incorpo¬ rating normally employed excipients, such as those carriers previously listed, and generally 10-95% of active ingredient, that is, an IL-10 agonist substance, preferably 25-75%. For aerosol administration, the IL-10 agonist is preferably supplied in finely divided form along with a surfactant and propellant. Typical percentages of IL-10 agonist are 0.01-20% by weight, preferably 1-10%. The surfactant must, of course, be non-toxic, and preferably soluble in the propellant. Re- presentative of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic poly- hydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arbitol, mannitol, sorbitol, the hexitol anhydrides derived from sorbitol, and the polyoxyethylene and polyoxypropylene derivatives of these esters. Mixed esters, such as mixed or natural glycerides may be employed. The surfactant may constitute 0.1-20% by weight of the compo¬ sition, preferably 0.25-5%. The balance of the composition is ordinarily propellant. Liquified propellants are typically gases at ambient conditions, and are condensed under pres- sure. Among suitable liquified propellants are the lower al- kanes containing up to 5 carbons, such as butane and propane; and preferably fluorinated or fluorochlorinated alkanes. Mix¬ tures of the above may also be employed. In producing the aerosol, a container equipped with a suitable valve is filled with the appropriate propellant, containing the finely divi¬ ded polypeptide(s) and surfactant. The ingredients are thus maintained at an elevated pressure until released by action of the valve. To enhance the serum half-life, the IL-10 agonist may be en- capsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended lifetime of the polypep¬ tides. Thus, in certain embodiments, the IL-10 agonist may be encapsulated in a liposome. A variety of methods are avail- able for preparing liposomes, as described in, e.g., (83), (84) , (85) and (86) . As described above it has been found that IT9302 and ana¬ logues and variants thereof are useful for preventing effects of cytokines known to be pathogenetically involved in the previously described pathological conditions. Therefore, the potentials of therapy by using the polypeptide of the invention or analogues or derivatives thereof is con¬ templated and should be investigated in all diseases where a therapeutic effect of hIL-10 and/or IRAP is expected (see above, Tables 1 and 2) . LEGENDS TO FIGURES Fig. 1 is a diagram showing that IT9302 inhibits spontaneous IL-8 production by purified cultured human monocytes. Fig. 2 is a diagram showing that IT9302 inhibits IL-l induced (1 ng/ml) IL-8 production by human peripheral blood mono¬ nuclear cells. Fig. 3 illustrates IRAP production by IT9302-stimulated human monocytes. Fig. 4 illustrates IRAP production by IL-10-stimulated human monocytes. Fig. 5 illustrates the chemotactic activity of IT9302 on CD8+ T cells Fig. 6 illustrates the desensitization of DC8+ T cells by IT9302, resulting in unresponsiveness of CD8+ T cells towards IL-10 (10 ng/ml) induced chemotaxis. Fig. 7 illustrates the suppression of IL-8 activity on CD4+ T cells by IT9302. Fig. 8 is a diagram showing that IT9302 inhibits MCAF/MCP-1 induced monocyte chemotaxis. Fig. 9 shows IL-4 production in CD4+ T cell cytosolic frac¬ tions by ECL - Western Blotting. Fig. 10 shows TNF-α production in human mixed lymphocyte cul¬ ture cytosolic fractions by ECL - Western Blotting. TNF-α Western Blotting was carried out as the IL-4 described in Materials and Methods, but using a rabbit anti-human TNF-α antibody (Pepro Tech. Inc., London, England) and a horse¬ radish peroxidase-labelled secondary antibody (Cat.no. P 217, Dako, Denmark) . Fig. 11 shows regulation of T cell proliferation by IL-10 and IT9302. Fig. 12 shows HLA-DR expression on human monocytes (flow cytometry) . Fig. 13 shows that LPS induced shock and leukopenia are modulated by IT9302, shown by total leukocyte counting. Fig. 14 shows that injection of murine IT9302 into rabbits before induced pancreatitis prevented leukopenia. EXAMPLES Materials and Methods Cytokines and chemoattractants Recombinant hIL-lO was obtained from Pepro Tech Inc., NJ. (Cat.No. 200 10) . Recombinant hIL-lβ and recombinant hIL-8 were a kind gift from Dainippon Pharmaceutical Company, Osaka, Japan. The culture medium was RPMI 1640 GIBCO, LPS- free according to the Limulus Amoebocyte Lysate assay (Sigma E-TOXATE Kit Cat.No. 210-A1) . rhMCAF/MCP-1 was a kind gift from professor Kouji Matsushima, Kanazawa, Japan. LeuJeocyte chemotaxis assay T cell chemotaxis CD4+ and CD8+ T lymphocyte subsets characterized by expres¬ sing either CD4 or CD8 antigens were purified from hepari- nized blood of normal donors. Thus, peripheral blood mono¬ nuclear cells (PBMC) were purified from the heparinized blood by diluting 100 ml of the blood with Hanks balanced salt solution (HBSS) 1:1 and then separated by layering the cells on Lymphopac™ (Nycomed Pharma, Oslo, Norway) followed by gra- dient centrifugation at 2000 rpm for 20 minutes. The mononu¬ clear cells were washed 3 times in HBSS and the cell pellet was diluted in 4 ml of HBSS containing 1% fetal calf serum and sorted at 4°C by using Dynabeads coated with monoclonal antibody towards CD4 or CD8 antigen (Dynabeads M-450 CD4 Cat.No. 111.16, Dynabeads M-450 CD8 Cat.No. 111.08, DETACHaBEAD Cat.No. 125.04). The bead:cell ratio was 10:1 and the incubation time 1 hour. The beads were detached by adding polyclonal anti-mouse antibody according to the manufactu¬ rer's instructions. The chemotaxis assay was a 48-well microchamber technique (Neuroprobe, Rockville, MD) as previously described (74; see ref. 3 and ref. 14) . Chemoattractants were diluted in RPMI 1640 (GIBCO Cat.No. 61870-010) with 1% sterile filtered fetal calf serum and placed in the lower 25 μl chamber. In the case of determining T cell chemotaxis, T cells (5 x 10 6 /ml) were suspended in medium and 50 μl was placed in the upper chamber separated from the lower chamber by a 5 μm pore-size poly¬ carbonate, polyvinylpyrrolidone-free filter (Nucleopore Corp., Pleasanton, CA) coated with type IV collagen (Sigma Cat.No. C 0543) . Cells were allowed to migrate for 2 hours at 37°C at 5% C0 2 . The filters were then carefully removed, fixed in 70% methanol, and stained for 5 minutes in Coomas- sie's Brilliant Blue. Cells attached to the lower surface of the filter were counted by measuring their area using a video camera on the microscope connected to a computer system for digital analysis and supported by software for objective determination of chemotactic migration. Approximately 5% of the T cells will migrate spontaneously corresponding to between 12,000 and 13,000 cells; this may vary from day to day, but very little in the same day's experiments. As has been described earlier (ref. 3 and ref. 14), it was therefore chosen to report the results as a ratio between number of cells migrating in the sample and in the negative control, which reflects spontaneous migration. This ratio is referred to as the chemotactic index (CI) . All samples were analyzed in triplicates and cell migration in each well was measured in three fields before the median value of area was estima¬ ted. In some experiments the chemotaxis membrane was not coated with collagen, and in the present assay system migra¬ ting cells will therefore drop to the bottom of the lower well of the chemotaxis chamber. In one experiment, the chemotactic activity of IT9302 on CD8+ T cells was performed by testing serial dilutions of IT9302 added to the lower chamber and evaluating chemotaxis as described above. In a second experiment, the ability of IT9302 to desensitize the migration of CD8+ T cells as a response to rHIL-10 (10 ng/ml) was studied by adding IT9302 to the target cells 30 minutes before chemotaxis. IT9302 was added in serial concentrations and the chemotactic response of rhIL-10 was evaluated as described above. In a third experiment, the ability of IT9302 to suppress the chemotactic response of CD4+ T cells towards rhIL-8 (10 ng/ml) was studied by adding IT9302 to the target cells 30 minutes before performing chemotaxis. IT9302 was added in serial concentrations and the chemotactic response of rhIL-8 was evaluated as described above. Monocyte chemotaxis Monocyte chemotaxis was measured using the same Boyden cham¬ ber equipment as described for T cells above. The chemo- attractant MCAF/MCP-1 was diluted in RPMI 1640 medium with 0.5% BSA and added to the lower chamber at a concentration of 10 ng/ml. Monocytes, purified by the standard plastic adhe¬ rence technique, from normal human PBMC, obtained as descri¬ bed above were suspended in RPMI 1640 medium with 0.5% BSA and then incubated for 30 minutes in the presence of IT9302 at different concentrations. Subsequently, the cells were added to the upper chemotaxis chambers at a concentration of IO 6 cells/ml. The upper and lower chambers were separated by an 8 μm pore size polyvinyl pyrrolidone-free polycarbonate filter (Nucleopore, Pleasanton, CA) . The chamber was incuba- ted at 37°C for 90 minutes. The membranes containing migra¬ ting cells were treated as described above and a chemotactic index calculated according to the technique described above. Production of IL- 8 by normal human peripheral mononuclear cells (PBMC) PBMC was purified from heparinized blood of normal human donors. Following gradient centrifugation with Lymphoprep™ (Nycorned Pharma, Oslo, Norway) , the mononuclear cells were diluted to 2 x IO 6 cells/ml in LPS-free RPMI 1640 medium (Gibco Cat.No. 6187-010) containing 1% sterile filtered heat- inactivated fetal calf serum and penicillin (10,000 IE/ml) , streptomycin (10 mg/ml) and gentamycin (2.5 mg/ml). Cells were cultured in 24 wells Nunc Micro Plates (Nunc, Denmark) and in the presence of different concentration of IT9302 (0, 1 μg, 100 ng, 10 ng, 1 ng, 0.1 ng, 0.01 ng/ml) for 24 hours. Following 24 hours of incubation, another dose of IT9302 was added once more, and 1 hour later r-hlL-lβ (1 ng/ml) was added to the cell cultures. Supernatants were collected after a total of 48 hours of incubation, and the concentration of the secreted IL-8 was measured by IL-8 ELISA by using an IL-8 ELISA Kit (Dainippon Pharmaceutical Co. Ltd, Osaka, Japan) . Briefly, standards and cell supernatants were incubated for one hour and in duplicates at 20°C on a micro-plate shaker. Then after washing, a second antibody was added for one hour, followed by one hour of incubation with peroxidase-labelled goat anti-rabbit IgG. After washing, the reaction was deve¬ loped with 0-phenylenediamine. Thirty minutes later the reac¬ tion was stopped with 1.6 N sulphuric acid. Optical density (OD) was measured in an ELISA reader at 490 nm. IL-8 concen¬ tration was calculated by a calibration curve of absorbance of unknown vs concentrations of IL-8 standards. Determination of IRAP concentration PBMC was purified as described above. PBMC was cultured in RMPI 1640, 10% sterile heat-inactivated fetal calf serum (including penicillin 10,000 IE/ml, streptomycin 10 mg/ml, gentamycin 2.5 mg/ml) and the cell concentration was 5 x IO 6 cells/ml. The monocytes were then purified by standard plast¬ ic adherence technique. Monocytes were then cultured in RPMI 1640 with 2% FCS (2.5 x IO 6 cells/ml) and with different dilutions of rhIL-10 or IT9302. The cells were stimulated for 24 hours and the supernatants were collected for IRAP deter¬ mination. IRAP ELISA was carried out by using Human IL-lra Quantikin Immunoassay Kit from R&D Systems Europe Ltd. (Cat.No. DRA 00, Abingdon, Oxon, UK) . Determination of T cell proliferation Proliferation assay. PBMCs (2 x IO 5 ) were cultivated in 200 μl of RPMI medium with 10% FCS for 72 hours with PHA 0.5 μl/ml and rhIL-10 (1, 10, 100 ng/ml) or IT9302 (0.1, 1, 10 ng/ml) in triplets. The last 18 hours 3 H-thymidine was added with 0.5 μCi/well (Amersham, Denmark). The cells were harvested on a filter (Glass Microfibre Filters, Whatman, Cat.No. 1822 849) and scintillation fluid (Ultima, Gold MV, Packard) was added. The scintillation counting was made on Tri-Carb model 1600 TR, Packard. Determination of class II MHC antigen expression on monocytes HLA-DR expression on human monocytes. The monocytes were iso¬ lated from fresh, heparinized blood by adherence to plastic at 37°C in RPMI 1640 containing 10% FCS. After incubation, the supernatant was removed, Hank's solution (4°C with 1% FCS) was added, and the cells were detached by cooling at -20°C for 15 minutes and gentle banging to the table. Monocytes were stimulated (2 x IO 6 cells/ml) in RPMI 1640 added 2% FCS, with IFN-7 (10 ng/ml), or rhIL-10 (100, 10, 1 ng/ml) added before IFN-7, or IT9302 (10, 1, 0.1 ng/ml) added before IFN-7 for 40 hours. The cells were detached from the wells by cooling as before. Fresh, non-fixed cells were used for surface typing by antihuman antibody for HLA-DR. The cells were resuspended in Hank's solution with 1% FCS, 1 x IO 6 cells/ml and FITC conjugated mouse-anti-human HLA DR, DP, DK antibodies were added (F 0817, DAKO Denmark) for 45 mi¬ nutes. The cells were washed three times in Hank's solution and a FACS analysis was performed on a Coulter-Epics XL-MCL flow cytometer at a wavelength of 488 nm. Non-specific bind- ing was determined with a non-relevant Fitch conjugated antibody (mouse anti goat DAKO F 479) . Alternatively cells were fixed in 10% DMSO, 40% RPMI 1640 and 50% sterile FCS, and stored at -80°C and used for DNA typing. Determination of apoptosis in monocytes DNA typing of the stimulated monocytes. The fixed cells were incubated in 70% ethanol for 60 minutes and washed twice in Hank's solution. 1 x IO 6 cells were resuspended in 250 μl of RNase 1 μg/ml in 1.12% sodium citrate, pH 8.4 (Ribonuclease A, Pharmacia No. 17-0442-01) and incubated at 37°C for 3 minutes. Thereafter, 250 μl of propidiumiodide (50 μg/ml in Hank's solution) was added, and cells were incubated in the dark for 30 minutes. After this the cells were washed twice in Hank's solution (Jensen et al. , (110)). The DNA content was measured by flow cytometry on a Coulter-Epics XL-MCL at a wavelength of 550 nm. Resul ts Regulation of T cell proliferation by IL-10 and IT9302 PBMC's were stimulated with PHA as described above and rhIL-10 and IT9302 were added for 72 hours, and the 3 H- thymidine incorporation was measured for the last 18 hours. Both rhIL-10 and IT9302 downregulated cell proliferation in an optimum concentration of 100 ng/ml rhIL-10 and 10 ng/ml IT9302, as seen in Fig. 11. HLA -DR expression on human monocytes The monocytes were purified as described above and stimulated for 40 hours by IFN-7 (10 ng/ml) and/or rhIL-10 and/or IT9302 added 30 minutes before IFN-7. MHC II antigen expression was studied by incubation with FITC conjugated mouse-anti-human HLA DR, DP, DK antibody. The expression of MHC II antigen was upregulated by IFN-7 as seen in Fig. 12, and 10 ng/ml rhIL-10 and l ng/ml IT9302 downregulated the MHC II antigen expres¬ sion in a similar way. DNA typing of the stimulated monocytes The IFN-7 stimulated monocytes from above were incubated with propidium iodide and the DNA content was measured by flow cytometry. The fraction of cells expressing DNA in G or G 2 phase of cell proliferation was measured and also the frac¬ tion expressing apoptosis. As seen in Fig. 12, non-stimulated monocytes were expressing 6.6% apoptosis, IFN-7 stimulation downregulated apoptosis to 4.1%, while both IL-10, IFN-7 and IT9302 + IFN-7 stimulation of the cells induce the apoptosic fraction to 10.3% and 9.3%, respectively. Determination of IL-4 production by CD4+ T lymphocytes Cell cul tures CD4+ T lymphocytes were purified from heparinized normal human blood. Following Lymphoprep™ (Nycomed Pharma, Oslo, Norway) gradient centrifugation, the mononuclear cells were further sorted at 4°C using Dynabeads (Dynal AS, Norway) coated with monoclonal anti-CD4 antibodies. The beads were detached by adding polyclonal anti-mouse antibody (Dynal AS, Norway) . The purity of the positively selected cells were higher than 99% as judged by FACS analysis. When examining the de novo production of IL-4 by IL-8-stimulated T cells, T cells were cultures, 5 x IO 6 cells/ml in LPS-free RPMI 1640 (Gibco Cat.no. 61870-010) containing 1% sterile-filtered, heat-inactivated fetal calf serum (FCS), penicillin (10,000 IU/ml) , streptomycin (10 mg/ml) and gentamycin (2.5 mg/ml). T cells were stimulated for 3 days using rIL-8 (100 ng/ml), rIL-10 (100 ng/ml), IT9302 (10 ng/ml) and IFN-7 (10 ng/ml). Recombinant human IL-8 (rh IL-8) was a kind gift from Dainip- pon Pharmaceuticals Co. Ltd., Osaka, Japan), and IFN-7 was purchased from Boehringer Ingelheim Am Rhein, Germany. To obtain specific inhibition of IL-8 stimulation, a neutrali¬ zing monoclonal anti-IL-8 antibody (WS.4) was used (a kind gift from Dr. K. Matsushima, Japan) . Recombinant IL-10 was purchased from Pepro Tech. Inc. (London, England) . Preparation of cell material and cul ture supernatant for gel elec trophoresi s Cultured T cells and culture media were separated by centri¬ fugation at 2000 rpm for 5 minutes. The supernatants were freeze-dried and then dissolved in 100 μl of lysis buffer. The cells were resuspended directly in 100 μl of gel lysis buffer (9) . The material was kept at -80°C until further examination. ECL-Western blotting of CD4+ T cell derived proteins Cells or freeze-dried cell culture supernatants were used for IL-4 protein content determination. Proteins from one-dimen¬ sional 15% SDS-PAGE gels were transferred by blotting onto Hybond-ECL nitrocellulose membranes (Amersham RPN 2020D, UK) and blocked with 5% bovine serum albumin (Sigma) in Tris buffer saline pH 7.8 containing 0.1% Tween-20. The blots were then incubated with a polyclonal goat anti-human IL-4 anti¬ body (R&D Systems, UK) followed by a horseradish peroxidase- labelled secondary antibody (Cat.no. RPN 2106 ECL, Amersham, UK) , and the immunostaining was detected by exposing a film (Kodak X-OMAT-S, USA) for 90 seconds. EXAMPLE 1 Inhibi tion of spontaneous IL- 8 production by human monocytes The test was performed as described in "Production of IL-8 by normal human peripheral mononuclear cells (PBMC)". Monocytes were purified by plastic adherence technique and 3.0 x IO 6 cells/ml were stimulated for 40 hours. As shown in Fig. l, IT9302 inhibited the production of IL-8 by monocytes, and at 0.1 ng/ml of IT9302 the IL-8 production was suppressed to 35% of the spontaneous production in vi tro . The viability of cells always exceeded 80% after l day in culture and the addition of IT9302 did not in this or in the following exam¬ ples affect viability at any concentration of IT9302 between 0.1 and 1000 ng/ml (IT9302 MW: 1,127 dalton, rhIL-10 predict- ed MW: 18,400 dalton). EXAMPLE 2 Inhibi tion of IL-lβ induced IL- 8 production by human peri ¬ pheral blood mononuclear cells (PBMC) The test was performed as described in "Production of IL-8 by normal human peripheral blood mononuclear cells (PBMC)". As shown in Fig. 2, IT9302, in a dose dependent manner, inhi¬ bited the IL-lβ induced production of IL-8 by human periphe¬ ral blood mononuclear cells in vi tro . The suppression of IL-8 production plateaued at IT9302 concentrations between 0.01 and 100 ng/ml. EXAMPLE 3 Production of interleukin-1 receptor antagonist protein (IRAP) by human monocytes The test was performed as described in "Determination of IRAP concentration". As shown in Fig. 3, IT9302 dose-dependently induced the production of IRAP by human monocytes. The pro¬ duction drastically increased when using concentrations of IT9302 above 10 ng/ml. Fig. 4 shows the induction of IRAP by rhIL-10 and since hIL-10 is approximately 20 times larger than IT9302, 5 ng/ml of IT9302 equals 100 ng/ml of IL-10 in molarity. Therefore the potencies of IT9302 and rhIL-10 are comparable and approximately equal with respect to the induc¬ tion of IRAP at lower concentrations. At IT9302 concentra¬ tions exceeding 10 ng/ml, the induction of IRAP increased and reached a maximum level of 60 ng/ml. Further, the specificty of this induction by the antibody which is specifically di¬ rected against IT9302 was tested. In a separate experiment where the monocytes spontanously produced 3.5 ng/ml IRAP and they were induced by 1-10 ng/ml IT9302 to a maximum IRAP pro¬ duction of 10.6 + 0.6 ng/ml, this production could be blocked by a polyclonal antibody for IT9302, 2 μg/ml added 30 minutes before 10 ng/mg IT9302, so the level of IRAP was downregu¬ lated to 2.9 + 0.3 ng/ml. This results is in contrast to the result obtained with the antibody directed against IL-10, 19F1, which added in the same way (2μg/ml 30 minutes before 10 ng/ml IT9302) did not block IRAP production but on the contrary upregulated this to 22 ng/ml. This result can be explained by that this antibody is able to neutralize endo¬ genous IL-10 but not IT9302. The spontaneously produced IL-10 in the cell culture has a negative autoregulatory effect on IRAP production by IT9302. EXAMPLE 4 The chemotactic effect on human CD8+ T lymphocytes The experiment was carried out as described in "Leukocyte chemotaxis assay". As shown in Fig. 5, IT9302 induced the chemotactic migration of CD8+ human T lymphocytes in vitro, while there was no effect on CD4+ T cells (data not shown) . Again, the potency of IT9302 shown in this experiment is comparable with that of rhIL-10 shown previously (14) . EXAMPLE 5 Desensiti zation of human CD8+ T cells resulting in an un- responsiveness towards rhIL-10 The experiment was carried out as described in "Leukocyte chemotaxis assay" . IT9302 was added to a suspension of CD8+ T cells 30 minutes before these cells were tested towards their chemotactic response to rhIL-10. As shown in Fig. 6, the pre- incubation of cells with IT9302 results in a suppressed responsiveness of the CD8+ T cells towards hrIL-10. This indicates that IT9302 may affect the binding of rhIL-10 to the IL-10 receptor. EXAMPLE 6 Suppression of the chemotactic response of CD4+ T lymphocytes towards IL- 8 The experiment was carried out as described in "Leukocyte chemotaxis assay". As shown in Fig. 7, IT9302, in a dose- dependent manner and added to a suspension of human CD4+ T lymphocytes, inhibits the response of the CD4+ T cells to- wards IL-8. EXAMPLE 7 Suppression of the chemotactic response of human monocytes towards MCAF/MCP-1 The experiment was carried out as described in "Monocyte chemotaxis". As shown in Fig. 8, IT9302, in a dose-dependent manner and added to a suspension of human monocytes, inhibits the chemotactic response of the monocytes towards MCAF/MCP-1. EXAMPLE 8 Inhibi tion of class II MHC molecule expression on human monocytes when stimulated with IFN In a new experimental model (flow cytometry) , it has been shown that monocytes stimulated with IFN-7 upregulate their expression of MHC II antigen, and this induction can be blocked by IL-10 and IT9302 in a similar way. At the same time, both peptides upregulate the number of cells showing apoptosis in the monocytes (see Fig. 12) . These experiments indicate that IL-10 and IT9302 can inhibit monocyte/macro- phage dependent T cell proliferation by diminishing the anti- gen presenting capacity of monocytes via the downregulation of Class II MHC expression (see 12) . PMBC's stimulated by PHA start to proliferate as shown by 3 H- thymidine incorporation, which can also be downregultaed by IL-10 and IT9302. PHA stimulates T cell proliferation through activation of Ca 2+ dependent channels. Ca 2+ fluxes in human T cell clones were diminished when cells were preincubated with IL-10 (Taga, K. et al. , 1992) . The present experiment shows that T cell proliferation is downregulated by IT9302 also by the control of the Ca 2+ dependent channels. Discussion related to the experiments The present data demonstrate a dose-dependent inhibitory effect of the synthetic nonapeptide, IT9302, on processes which reflect pro-inflammatory activity, including IL-8 pro- duction and monocyte and/or T cell migration. Thus, IT9302 was able to suppress the spontaneous production of IL-8 by human monocytes cultured overnight. This could be explained by a direct inhibitory effect on IL-8 mRNA production and/or subsequent protein production and or release. Another mecha- nism could be explained by the fact that monocytes cultured in vi tro will express and produce IL-l, which then in turn induces the production of IL-8. This is supported by the fact that it has been demonstrated that IT9302 potently induces the production of IRAP from monocytes. IT9302 may therefore also inhibit spontaneous IL-8 production by interfering with the activity of IL-l. The observed IRAP induction by IT9302 appears to induce a biologically active IRAP, since IT9302 added to the cultures counteracts IL-l-induced IL-8 produc¬ tion, but only when added at least 16 hours before adding IL-l to the cultures. This could mean that IT9302 inhibits IL-l-induced IL-8 production by inducing the production of IRAP, which then in turn blocks the activity of IL-l through its receptor. If IT9302 directly inhibited IL-8 production, it would have been expected that addition of IT9302 to the cultures 1 hour before adding IL-l should inhibit IL-8 pro- duction, which was not the case (data not shown) . Therefore, the observed inhibition of IL-8 production of IT9302 is likely to be due to an induction of IRAP production rather than a direct inhibition of IL-8 production. IT9302 speci- fically blocks the IL-l receptor by the induction of IRAP, and thereby the induction of other cytokines which are induced by IL-l, like TNFα;, IL-8 and probably many other cytokines and factors. The specificity of the induction was confirmed by that our antibody for IT9302 could block the induction of IRAP. Another IL-10 antibody 19F1 did not block IT9302-induced IRAP production. IT9302 also mimics IL-10 activity by suppressing the ability of CD4+ T cells to migrate as a response to IL-8. Since IL-8 is related to many different states of inflammation and since CD4+ T cells appear early in the infiltrate of T cell-medi¬ ated immune inflammation such as allergy of the skin, this feature may prove to have significant therapeutic value for the control of T cell-mediated immune inflammation. The demonstrated CD8+ T cell chemotactic activity of IT9302 is also parallel to that of IL-10, and IT9302 may thus acti¬ vate T cell populations with suppressor activity contributing to the ending of T cell-mediated immune inflammation. There¬ fore IT9302 according to the examples which are demonstrated above, possesses therapeutic value in diseases where IL-10 and/or IRAP may also have therapeutic value. Additionally, IT9302 may have therapeutic value in diseases where IL-8 and/or MCAF and/or IL-l are believed to have pathogenetic roles. The present invention describes analogues of IT9302, i.e. substances or peptides having at least some of the above-described properties. EXAMPLE 9 Induction of the production of IL-4 in CD4+ T lymphocytes Background Like IL-10, IL-4 is a product of CD4+ T cells of T H 2 type. It was observed that recombinant human IL-10 induces the produc¬ tion of IL-4 by cultured human CD4+ T cells. This means that IL-10, in addition to its own immunosuppressive functions, also induces the production of another immunosuppressive cytokine, IL-4. It was therefore tested whether IT9302 also induces the production of IL-4 by CD4+ T cells. Thus, CD4+ T cells, purified as described in "Methods for T cell chemotaxis", and cultured as described in the section "Determination of IL-4 production by CD4+ T lymphocytes", were stimulated for 3 days with IT9302 (10 ng/ml) or IL-10 (100 ng/ml) . Cytosolic fractions were collected and analyzed for their IL-4 content using Western blotting (Fig. 9) and a goat anti-human IL-4 polyclonal antibody. As demonstrated in Fig. 9, it was observed that IL-10 as well as IT9302 induce the production of IL-4 by cultured normal human CD4+ T cells. EXAMPLE 10 Inhibition of the production of TNF-αι during a mixed leuko ¬ cyte reaction (MLR) It has been demonstrated that the mixed leukocyte reaction is partly dependent on the production of TNF-OJ during the reac¬ tion. It has been shown that IT9302 does not significantly reduce the MLR, but it was found that there is a significant reduction in the production of TNF-α; during the MLR. Thus, MLR was performed by purifying human leukocytes and then culturing 1 million cells/ml from allogeneic donors for 4 days. Before establishing the cultures, one group of cells was irradiated for 2 minutes using beta irradiation. Cyto- solic protein fractions were purified as described in the section "Determination of IL-4 production by CD4+ T lymphocy¬ tes", and Western blotting was performed using a rabbit anti- human TNF-α; antibody. As demonstrated in Fig. 10, a significant reduction in the production of TNF-α; was observed during a human mixed leuko¬ cyte reaction. EXAMPLE 11 The modulation of the LPS induced shock and leukopenia in swine Since it was found that IT9302 modulates cytokine production, including TNF-α; and IL-8, and supported by the published sequence of porcine IL-10 (88) , it was tested whether IT9302 was able to modulate the course of LPS induced leukopenia in swine (Fig. 13) . In a preliminary experiment, it was tested how the intra¬ venous injection of IT9302 0.1 mg/kg modulated the effect of intravenous injection of 2 μg/kg LPS in swine (N = 3) . IT9302 was injected 30 minutes before injection of LPS, and blood samples were drawn as described in Fig. 13. Total leukocyte count as well as differential cell count were determined, and the total number of neutrophilic leukocytes was calculated on the basis of these results. As demonstrated, it was observed that injection of LPS caused a transient leukopenia. Injection of IT9302, however, preven- ted leukopenia as demonstrated in the figure. EXAMPLE 12 The effect of murine IT9302 homologous to human IT9302 on TNF-oi release in plasma after LPS administration in mice It has been demonstrated in animals that recombinant murine IL-10 can protect mice from lethal endotoxemia (89) and in addition, it has been demonstrated that IL-10 administrated in humans has inhibitory effects on T-cells and suppresses production of proinflammatory cytokines (90) . The aim of the study was to test whether IT9302 can suppress production of TNF-α in mice exposed to endotoxin-induced shock after admi¬ nistration of LPS (Fig. 14) . Eight week old BALB/C mice were used (obtained from Centre for Research Animals, Bomholtgaard, Bomholtvej 10, DK-8680 Ry, Denmark) . LPS from E. coli was from Sigma (batch 3444114) and murine IT9302 was from Schafer-N, Lersø Parkalle 42, DK-2100 Copenhagen 0, Denmark. Mice were injected intraperitoneally with 100 μg of LPS in 1 ml of 0.9 M NaCl. 60 minutes prior to LPS injection mice were given murine IT9302 equivalent to 0.1 μg, 1 μg and 10 μg of human IL-10. Groups of 5 animals were anaesthetized (Imo- bilon, Pherrovet, Malmδ, Sweden) after 1, 2, 3 and 4 hours, respectively, after which a maximum of whole blood was drawn through cardiac puncture. The blood was centrifuged in the cold and sera were collected and stored at -70°C for subse- quent analysis of TNF-α content by ELISA (TNF-α Mouse Immuno Assay Diagnostic kits, Genzyme, Cambridge, MA, USA) . As demonstrated, it was observed that 10 μg of murine IT9302 clearly suppressed TNF-α in mouse sera compared to the con¬ trol group not treated with mIT9302 (see Table 3) . TABLE 3 m-TNF-α ng/ml + SEM in serum of mice Murine IT9302 equivalent to hIL-10 added 60 minutes before LPS 0 0.1 μg μg 10 μg 1 h 2.48±0.16 1.92±0.48 2.64±0.38 1.84±0.16 2 hs 1.43±0.17 1.68±0.27 1.16±0.21 0.62±0.14 3 hs 0.48±0.04 0.05±0.02 0.18±0.05 0.0 4 hs 0.09±0.06 0.06±0.02 0.20±0.04 0.05±0.01 EXAMPLE 13 The modulation of acute pancreatitis induced by bile acid using murine IT9302 Rodents, mice and rabbits are often used in animal models, and recently Genzyme Diagnostics has advertized with Cross- reactivity Kits for Cytokine Research Products. Especially, it was possible to measure rabbit TNF-α and IFN-7 by mouse Immunoassay Kits. As we were working on a rabbit model, studying the pathophysiological role of IL-8 in experimental acute pancreatitis, we investigated the effect of the murine IT9302 on induced leukopenia (Fig. 14) . Our hypothesis was that even IL-10 could be identical in mice and rabbits and might have effects on IL-8-induced leukocyte invasion in the pancreas during acute pancreatitis. Experimental model New Zealand white rabbits (Oryctolagus cuniculus) weighing 1.7-4.0 kg were fasted for 18-24 hours. The operative proce¬ dures according to Banerjee et al. , 1994 (91) and Hong et al., 1962 (92) were followed, and acute pancreatitis was induced in rabbits by 5% bile acid given into the pancreatic duct. Murine IT9302 (100 μg/kg) was given through a central vein 30 minutes before the bile and subcutaneously in a dose of 100 μg/kg rabbit immediately afterwards. Plasma samples were collected according to Fig. 14. As demonstrated, it was observed that injection of murine IT9302 into rabbits before induced pancreatitis prevented leukopenia as demonstrated in the Figure. EXAMPLE 14 The modulation of acute pancreatitis in rabbi ts induced by bile acid using human IT9302 The same experimental model was used as in Example 13 with the exception that the murine IT9302 was exchanged by human IT9302. Acute pancreatitis was induced by intraductal injec- tion of 2.0 ml of 5% chemodeoxycholin bile acid (10 animals). Another group of animals was treated with human IT9302 (8 animals) , the first dose (100 μg/kg) being injected subcuta¬ neously and the second dose (100 μg/ml) intravenously, half an hour before the induction of acute pancreatitis. Serum samples were collected for cytokine measurements with time intervals, 0, l, 3, 6, and 12 hours after the induction of acute pancreatitis. Methods for the TNF-α and IL- 8 measurements in rabbit serum Genzyme mouse TNF-α ELISA kit code No. 80-3807-00 was used in a modified version for TNF-α measurements in the serum of rabbits. This kit is built up by a solid-phase monoclonal hamster anti-mouse TNF-α antibody which captures the TNF-α present in serum, and a peroxidase-conjugated polyclonal goat anti-mouse TNF-α antibody, substrate and chromagen TMB. The incubation time for serum and standard TNF-α was extended for 4 hours and the development time for substrate incubation was 30 minutes. Rabbit IL-8 measurements in rabbit serum were carried out by a special IL-8 ELISA kit, a gift from Professor Kouji Matsu- shima, Tokyo, Japan. Briefly, monoclonal anti-IL-8, guinea pig anti-rabbit IL-8 and alkaline phosphatase-conjugated rabbit anti-guinea pig immunoglobulin G antibodies were employed as capture, second and detection antibodies, respec¬ tively. For methods, see Ikeda et al. (106) . Resul t TABLE 4 Acute pancreatitis in rabbit, by 5% bile acid, content of TNF-α in serum (pg/ml ± SEM) 0 1 3 6 9 12 1210±396 1206±239 1918±374 1662±357 1884±698 915±431 Acute pancreatitis, treated with human IT9302, 30 minutes before 5% bile acid, content of TNF-α in serum (pg/ml ± SEM) 12 347±77 739+339 697±146 658±156 872±594 463±203 TABLE 5 Acute pancreatitis, by 5% bile acid, content of IL-8 in serum (pg/ml ± SEM) 0 1 3 6 9 12 1154±351 780±153 2210±459 2690±468 2196±1058 1833+1114 Acute pancreatitis, treated with human IT9302, 30 minutes before 5% bile acid, content of IL-8 in serum (pg/ml ± SEM) 0 1 3 6 9 12 875±181 695±205 900±178 1037±244 1207±210 1087±216 Summary Maximum TNF-α induction was achieved at 3 hours, and maximum IL-8 at 6 hours. Both TNF-α and IL-8 levels in the blood circulation were markedly downregulated for 0 to 12 hours. The levels of pancreatic enzymes in the blood were also measured (amylase, lipase and tryptase) and they all showed peaks after 3-6 hours after induction of acute pancreatitis, but none of these enzymes appeared to be affected by trea - ment with IT9302. Histologically similar pancreatic changes were observed in the two groups while there was a significant reduction in interstitial neutrophil infiltration in the lungs. Conclusion IT9302 downregulates TNF-α and IL-8 production in a model of bile acid induced acute pancreatitis, and blocks neutrophil infiltration in lungs of these treated rabbits, thereby preventing the development of ARDS-like syndrome in these animals, resulting in a reduction of mortality from 60% to 0% after 12 hours. Interleukin iβ is regarded as an important inducer of acute pancreatitis (see ref. 107) and thereby sup¬ porting our hypothesis that IT9302 can block all IL-l indu- cible effects. The reason why human IT9302 can be used in a rabbit model could be explained by the observation made by Dan Gaur et al. and published this year in Nature (108) where he showed that rabbit (Lagomorpha) proteins are phylogenti- cally more close to primates (human) proteins than to other rodents (mouse, rat, ...) proteins. EXAMPLE 15 IT9302 as a treatment of cancer and in the prevention of metastasis It was recently demonstrated (111) that systemic administra- tion of cellular IL-10 induces an effective, specific and long-lived immune response against established tumours in mice in vivo . It was suggested that this effect is partially explained by the renowned effects of IL-10 on diverse cell types, including co-stimulation of T cell proliferation, chemoattraction of CD8+ T cells, and stimulation of lympho¬ kine-activated killer cell activity. They also observed that human IL-10 can reverse the local immunosuppressive effect of viral IL-10. Another research group confirmed the potential therapeutic role of IL-10 administration in cancer (112) since they observed that IL-10 inhibits metastasis through a natural killer cell-dependent mechanism in an in vivo experi¬ ment with mice having different tumours, including etastasizing malignant melanoma. Kundu et al. (1996) (113) reported that IL-10 exerts anti-metastatic and anti-tumour effects in a murine model of human breast cancer. These observations indicate a potential role for human IL-10 and for IT9302 administration in the biological therapy of cancer. EXAMPLE 16 IT9302 as an immune adjuvant in the treatment of viral infec¬ tions IL-10 is known to possess certain anti-viral capacities. Thus, Kollmann et al. (1996) (114) found that IL-10 inhibits acute in vivo HIV infection of SCID mice with human fetal thymus and liver. We observed that two of the applicants/- researchers, when applying IT9302 in a cream formulation (total dose 400 to 500 μg) under plastic wrapping occlusion on the skin of the back for 24 hours, developed an increase in their total number of CD8+ T cells (60% and 90%, respec¬ tively) and an increase in serum IRAP concentration from 1 ng/ml to 2 ng/mml. In seven non-treated volunteers, the IRAP concentration never exceed 1.1 ng/ml. As an accidental and unexpected observation, both researchers observed that common warts (due to cutaneous HPV infection) showed clear signs of inflammation with redness and itching around the warts 3 to 4 days after the application of the IT9302-con- taining cream. The inflammatory reaction occurred synchron¬ ously on several fingers for one of the test persons, while the other person only had one wart on a finger. In both cases the warts quickly and gradually decreased in size during the following 4 to 7 days so that there were no clinical signs of remaining wart infection after 10 to 11 days. At a follow-up control 2 months later, there were no signs of recurrence of the infection. We therefore find that IT9302, possibly through a systemic activation of NK cells and/or cytotoxic CD8+ T cell activity, is able to evoke a latent immune response against cutaneous HPV infection, eventually resulting in clinical remission of the virus infection. Thus, IT9302 is a possible therapeutic alternative for the treatment of virus infections such as HIV and HPV infections. EXAMPLE 17 IT9302 as an immune adjuvant in the treatment of inflammatory joint diseases (arthri tis) Anti-IL-l therapy as well as anti-TNFα therapy appear to have significant clinical potential in the treatment of arthritis (Maini, 1996) (115) . As described elsewhere in this document, we have found IT9302 to be an inhibitor of TNFα production as well as a stimulator of IRAP (IL-l receptor antagonist pro¬ tein) from human mononuclear cells. Thus, IT9302 is a poten¬ tial treatment modality of arthritis. This was supported by an observation of one of the applicants of this invention who, after applying IT9302 (approximately 500 μg) in a cream basis on the skin for 24 hours, observed a strong reduction in chronic joint pains due to arthritis. This observation was made three times and in each case the symptoms gradually recurred during the following week after removal of the IT9302 application. We are thus finding in vivo support of the arguments for using IT9302 in the treatment of acute or chronic inflammatory reactions such as arthritis or other auto-immune diseases. REFERENCES 1. Bendtzen K. Lymphokines in inflammation. Inflammation Basic Mechanisms Tissue Injuring Principles and Clinical Models (P Venge & A Lindbom eds) 1985; Almqvist & Wiksell International. Stockholm: 187-217. 2. Bendtzen K. Interleukin-1, Interleukin-6, and tumor ne¬ crosis factor in infection, inflammation and immunity. Immunol Lett 1988;19:183-192. 3. Larsen C.G. Leukocyte activating and chemotactic cyto- kines in cell-mediated immune reactions of the human skin. Acta Dermatovenerol. 1991; Suppl. 160:1-48 4. Fiorentino D. F. , M. W. Bond, and T. R. Mosmann. 1989. Two types of mouse helper T cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Thl clones. J. Exp. Med., 170:2081. 5. Viera P., R. de Wall-Malefyt, M.-N. Dang, K. E. Johnson, R. Kastelein, D. F. Fiorentiono, J. E. de Vries, M.-G. Roncarolo, T. R. Mosmann, and K. W. Moore. 1991. Isola¬ tion and expression of human cytokine synthesis inhibi- tory factor (CSIF/IL-10) cDNA clones: homology to Ep¬ stein-Barr virus open reading frame BCRFI. Proc. Natl. Acad. Sci. (USA), 88:1172. 6. Moore, K.W. , O'Garra A., de Waal Malefyt R. , Vieira, Mosmann T.R. 1993. Interleukin-10, Annu Rev. Immunol, 11:165-90. 7. Kim, J.M., Brannan, C.I. Copeland N.G., Jenkins, N.A. , Khan, T.A. , Moore, K.W. 1992. Structure of the mouse interleukin-10 gene and chromosomal localization of the mouse and human genes. J. Immunol 148:3618-23. 8. Carter, D.B., Deibel, M.R-Jr, Dunn, CJ. et al. 1990. Purification, cloning, expression and biological charac¬ terization of an interleukin-1 receptor antagonist pro¬ tein. NATURE 344:633-638. 9. Hannum, C.H., Wilcox, C.J. , Arend, W.P. et al . 1990. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343:336-40. 10. Firestein, G.S., Boyle, D.L., Yu, C, et al. 1994. Synovial interleukin-1 receptor antagonist and inter¬ leukin-1 balance in rheumatoid arthritis. Arthritis Rheum 37:644-652. 11. Fisher, C.J. -Jr. ,Slotman, G.J. , Opal, S.M., Pribble, J.P. et al . 1994. Initial evaluation of recombinant inter¬ leukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. The IL-1RA Sepsis Syndrome Study Group. Crit-Care-Med. 22:12-21. 12. de Waal-Malefyt, R., Haanen J. , Spits, H., et al. 1991. IL-10 and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen- presenting capacity of monocytes via down-regulation of class II MHC expression. J. Exp. Med. 174:915-24. 13. Gazzinelli, R.T., Oswald, I.P., James, S.L., S er, A., 1992. IL-10 inhibits parasite killing and nitric oxide production by IFN-\-activated macrophages. J. Immunol. 148:1792-96. 14. Jinquan, T. , Larsen, C . G . , Gesser, B., Matsushima, K., Thestrup-Pedersen, K. 1993. Human IL-10 is a chemo- attractant for CD8+ T lymphocytes and an inhibitor of IL-8- induced CD4+ T lymphocyte Migration. Journal of Immunology, 151:4545-4551. 15. Rousset F., E. Garcia, T. Defranee, C. Peronne, D.-H. Hsu, R. Kastelein, K. W. Moore, and J. Banchereau. 1992. IL-10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc. Natl . Acad. Sci. USA, 175:671. 16. Howard, M. , O'Garra, A., Ishida, H. , de Waal Malefyt, R. , de Vries, J. 1992. Biological properties of Interleukin- 10. J. Clin. Immunol 12:239-47. 17. Kuhn, R. , Lohler, J., Rennick, D., Rajewsky, K., Mul- ler, W. 1993. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75: 263-74. 18. Sher, A., Fiorentino, D.F., Caspar, P., Pearce, E., Mosmann, T. 1991. Production of IL-10 by CD4+ lymphocy¬ tes correlates with down-regulation of Thl cytokine synthesis in helminth infection. J. Immunol. 147:2713- 16. 19. Clerici, M. , Shearer, G.M. 1993 Immunology Today. 14:107-111. 20. Bry, K. , Lappalainen, U. 1994. Interleukin-4 and trans¬ forming growth factor-beta 1 modulate the production of interleukin-1 receptor antagonist and prostaglandin E2 by decidual cells. Am-J-obstet-Gynecol 170 (4) : 1194- 1198 21. Firestein, G., S., Boyle, D. L., Yu, C, Paine, M. M. , Whisenand, T. D., Zvaifler, N. J. , Arend, W. P. 1994. Synovial interleukin-1 receptor antagonist and inter¬ leukin-1 balance in rheumatoid arthritis. Arthritis- Rheum, 37/5: 644-652 22. Roberge, C. J., De-Medicis, R. , Dayer, J. M. , Rola- Pleszcyczynski, M. , Naccahe, P. H. , Poubelle, P. E. 1994. Crystal-induced neutrophil activation: V. Diffe¬ rential production of biologically active IL-l receptor antagonist. J. Immunol 152/11: 5485-5494 23. McCall, R. D. , Haskill, S., Zimmermann, E. M. , Lund, P. K., Thompson, R. C, Sartor, R. B. 1994. Tissue inter¬ leukin 1 and interkeukin-1 receptor antagonist expres¬ sion in entercolitis in resistant and susceptible rats. Gastroenterology (4) : 960-72 25. Kimble, R. B., Vannice, J. L, Bloedow, D. C, Thompson, R. C, Hopfer, W. , Kung, V. T. , Brownfield, C, Paci- fici, R. 1994. Interleukin-1 receptor antagonist de- creases bone loss and bone resorption in ovariectomized rats. J. Clin Invest. 93/5: 1959-1967 26. Kline, J. N. , Geist, L. J. , Monick, M. M. , Stinski, M. F., Hunninghake, G. W. , 1994. J. Immunol. 152 (5) : 2351-7 27. Tompkins, R. G. 1994. Human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome (editorial; comment) . Crit-Care-Med. 22 (1) : 3, 22 (1) :12-21 28. Everaerdt, B., Brouckaert, P., Fiers, W. 1994. Recombi¬ nation IL-l receptor antagonist protects against TNF- induced lethality in mice. J. Immunol. 152/10: 5041- 5049 29. Fischer, C. J. Jr., Slotman, G. J., Opal, S. M. , Pribble, J. P., Bone, R. C. , Emmanuel, G. , Ng, D., Bloedow, D. C. , Catalano, M. A. 1994. Initial evalu¬ ation of human recombination interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a ran¬ domized, open-label, placebo-controlled multicenter trial. The IL-1RA Sepsis Syndrome Study Group (see comments) . Crit-Care-Med. 22(1) : 12-21, 22(1) : 3 30. Gomez-Reino-Carnoto, J. J. 1994. New terapies in rheu¬ matoid arthritis. Med-Clin 543-545. 32. Nishihara, T. , Ohsaki, Y., Ueda, N. , Saito, N. , Mundy, G. R. 1994. Mouse interleukin-l receptor antagonist induced by actinobacillus actinomycetemcomitans lipo- polysaccharide blocks the effects of interleukin-l om bone resorption and osteoclast-like cell formation. Infect-Immun. 62(2) : 390-7 33. Simon, C, Frances, A., Piquette, G. N. , el-Danasouri, I., Zurawski, G. , Dang, W. , Polan, M. L. 1994. Embryo¬ nic implantation in mice is blocked by interleukin-l receptor antagonist (see comments) . Endocrinology. 134(2) : 521-8, 134(2) : 519-20 34. Baergen, R. , Benirschke, K. , Ulich, T. R. , 1994. Cyto¬ kine expression in the placenta. The role of inter¬ leukin 1 and interleukin 1 receptor antagonist expres- sion in chorioamnionitis and parturition. Arch-Pathol- Lab-Med. 118(1) : 52-5 35. Tang, W.W. , Feng, L., Vannice, J. L., Wilson, C. B. 1994. Interleukin-l receptor antagonist ameliorates experimental antiglomerular basement membrane antibody- associated flomeulonephritis. J. Clin-Invest. 93(1) : 279-9. 36. Cassatella, M. A., Meda, L., Gasperini, S., Calzetti, F., Bonara, S. 1994. 37. Interleukin 10 (IL-10) upregulates IL-l receptor anta¬ gonist production from lipopolysaccharide-stimulated human polymorphonuclear leukocytes by delaying mRNA degradation. J. Exp-Med. 179/5: 1695-1699 38. Mancini, R. , Bendetti, A., Jezequel, A. M. 1994. An interleukin-l receptor antagonist decreases fibrosis induced by dimethylnitrorsamine in rat liver. Virchows- Arch. 424/1: 25-31 39. Lukacs, N. W. , Kunkel, S. L. , Burdick, M. D. , Lincoln, P. M. , Strieter, R. M. 1993. 40. Interleukin-l receptor antagonist blocks chemokine production in the mixed lymphocyte reaction. Blood. 82 (12) : 3668-74 41. Bandara, G. , Mueller, G. M. , Galea-Lauri, J. , Tindal, M. H. , Georgescu, H. I., Suchanek, M. K. , Hung, G. L. , Gloriso, J. C. , Robbins, P. D. , Evans, C. H. 1993. 42. Intraarticular expression of biologically active inter¬ leukin 1-receptor-antagonist protein by ex vivo trans¬ fer. Proc-Natl-Acad-Sci-U-S-A. 90(22) : 10764-8 43. Dinarello, C. A. 1994. Anti-interleukin-l strategies in the treatment of the septic shock syndrome. Can-J-in- fect-Dis. 5(suppl. A) : 9A-16A 44. Oelmann, E., Topp, M. S., Reufi, B., Papadimitriiou, C, Koeningsmann, M. , Oberberg, D., Thiel, E., Berdel, W. E. 1994. Int-J-Oncol. 4/3: 555-558 45. Estrov, Z. 1993. Interruption of autocrine and paracri¬ ne growth-stimolatory mechaisms: a new therapeutic stratefy for chronic myelogenous leukemia. Semin-Hema- tol. 30 (3 suppl 3) : 35-6 46. Wooley, P.H., Whalen, J.D., Chapman, D.L., Berger, A.E., Richard, K.A. , Aspar, D.G. , Staite, N.D. 1993. The effect of an interleukin-l receptor antagonist protein on type II collagen-induced arthritis and antigen-induced arthritis in mice. Arthritis Rheum. 36 (9) : 1305-1314 47. Peterson, CM., Hales, H.A. , Hatasaka, H.H., Mitchell, M.D., Rittenhouse, L., Jones, K.P. 1993. Interleukin-l beta (IL-l beta) modulates prostaglandin production and the natural IL-l receptor antagonist inhibits ovulation in the optimally stimulated rat ovarian perfusion model. Endocrinology 133 (5) : 2301-2306 48. Estrov, Z., Kurzrock, R. , Talpaz, M. 1993. Role of interleukin-l inhibitory molecules in therapy of acute and chronic myelogenous leukemia. Leuk. Ly phoma 10 (6) : 407-418 49. Chensue, S.W., Bienkowski, M. , Eessalu, T.E., Warming- ton, K.S., Hershey, S.D., Lukacs, N.W. , Kunkel, S.L. 1993. nous IL-l receptor antagonist protein (IRAP) regulates schistosome egg granuloma formation and the regional lymphoid response. J. Immunol. 151 (7) : 3654- 3662 50. Bowyer, J.F., Davies, D.L., Schmued, L., Broening, H.W., Newport, G.D., Slikker, W Jr., Holson, R.R. 1994. Further studies of the role f hyperthermia in metha - phetamine neurotoxicity. J. Pharmacol. Exp. Ther. 268/3: 1571-1580 51. Cole, O.F., Sullivan, M.H.F., Elder, M.G. 1993. The 'interleukin-l receptor antagonist' is a partial ago- nist of prostaglandin synthesis by human decidual cells. Prostaglandins 46/6: 493-498 52. Jenkins, J.K., Arend, W.P. 1993. Interleukin l receptor antagonist production in human monocytes is induced by IL-lalpha, IL-3, and IL-4 and GM-CSF. Cytokine 5/5: 407-415 53. Coceani, F., Lees, J., Redford, J. , Bishai, I. 1992. Interleukin-l receptor antagonist: effectiveness against interleukin-l fever. Can. J. Pharmacol. 70 (12) : 1590-1596 54. Schiro, R. , Longoni, D. , Rossi, V., Maglia, 0., Doni, A., Arsura, M. , Carrara, G. , Masera, G. , Vannier, E., Dinarello, CA. , Rambaldi, A., Biondi, A. 1994. Sup¬ pression of juvenile chronic myelogenous leukemia co¬ lony growth by interleukin-l receptor antagonist. Blood 83/2: 460-465 55. Watson, M.L., Smith, D., Bourne, A.D., Thompson, R.C, Westwick, J. 1993. Cytokines contribute to airway dys¬ function hyperreactivity, pulmonary eosinophil accumu¬ lation and tumor necrosis factor generation by pre- treatment with an interleukin-l receptor antagonist. Am. J. Respir. Cell Mol. Biol. 8 (4): 365-369 56. Abhyankar, S., Gilliland, D.G. , Ferrara, J.L.M. 1993. Interleukin-l is a critical effector molecule during cytokine dysregulation in graft-versus-host disease to minor histocompatibility antigens. Transplantation 56/6: 1518-1523 57. Lan, H.Y. , Nikolic Paterson, D.J. , Zarama, M. , Vannice, J.L., Atkins, R.C. 1993. Suppression of experimental crescentic glomerulonephitis by the interleukin-l receptor antagonist. Kidney Int. 43 (2): 479-485 58. Herve, P. 1993. Prevention and treatment of acute GvHD - New modalities. Nouv. Rev. Fr. Hematol. 35/3: 295-297 59. Conti, P., Panara, M.R., Barbacane, R.C, Placido, F.C, Bongrazio, M. , Reale, M. , Dempsey, R.A. , Fiore, S. 1992. Blocking the interleukin-l receptor inhibits leukotriene B4 and prostaglandin E2 generation in human monocyte cultures. Cell Immunol. 145 (1): 199-209 60. Kristensen, M. , Deleuran, B., Eedy, D.J., Feldmann, M. , Breathnach, S.M., Brennan, F.M. 1992. Distribution of interleukin-l receptor antagonist protein (IRAP) , interleukin-l receptor, and interleukin-l alpha in normal and psoriatic skin, Decreased expression of IRAP in psoriatic lesional epidermis. Br. J. Dermatol. 127 (4) : 305-311 61. Romero, R. , Sepulveda, W. , Mazor, M. , Brandt, F., Cot¬ ton, D.B., Dinarello, C : , Mitchell, M.D. 1992. The natural interleukin-l receptor antagonist in term and pre-term parturition. Am. J. Obstet. Gynecol. 167 (4 Pt 1) : 863-872 62. Dinarello, CA. 1992. Reduction of inflammation by decreasing production of interleukin-l or by specific receptor antagonism. Int. J. Tissue. React. 14 (2) : 65- 75 63. Conti, P., Panara, M.R. , Barbacane, R.C, Bongrazio, M: , Dempsey, R.A. , Reale, M. 1993. Human recombinant IL.l receptor antagonist (IL-lRa) inhibits leukotriene B4 generation from human monocyte suspensions stimu¬ lated by lipopolysaccharide (LPS) . Clin. Exp. Immunol. 91/3: 526-531 64. DeForge, L.E., Tracey, D.E., Kenney, J.S., Remick, D.G. 1992. Interleukin-l receptor antagonist protein inhibits interleukin-8 expression in lipopolysacchari- de-stimuled human whole blood. Am. J. Pathol. 140 (5) : 1045-1054 65. Porat, R. , Poutsiaka, D.D., Miller, L.C., Granowitz, E.V., Dinarello, CA. 1992. Interleukin-l (IL-l) recep¬ tor blockade reduces endotoxin and Borrealia burgdor- feri-stimulated IL-8 synthesis in human monoclear cells. Faseb. J. 6 (7) : 2482-2486 66. Boermeester, M.A. , van Leeuwen, P.A.M., Schneider, A.J. , Houdijk, A.P.J., Ferwerda, CC, Wesdorp, R.I.C 1993. Interleukin-l receptor antagonist: A new thera¬ peutic agent in the treatment of septic syndrome. Ned. Tijdschr. Geneesks. 137/7: 337-342 67. Smith, R.J., Chin, J.E., Sam, L.M. , Justen, J.M. 1991. Biologic effects of an interleukin-l receptor antago¬ nist protein on interleukin-l-stimulated cartilage erosion and chondrocyte responsiveness. Arthsitis Rheum. 34 (1) : 78-83 68. Conti, P. Barbacane, R.C, Panara, M.R. , Reale, M. , Placido, F.C, Fridas, S., Bongrazio, M. , Dempsey, R.A. 1992. Human recombinant interleukin-l receptor antago- nist (hrlL-lra) enhances the stimulatory effect of interleukin-2 on natural killer cell activity against MOLT-4 target cells. Int. J. Immunopharm. 14/6: 987-993 69. Selig, W. , Tocker, J. 1992. Effect of interleukin-l receptor antagonist on antigen-induced pulmonary responses in guinea pigs. Eur. J. Pharmacol. 213/3: 331-336 70. McCarthy, P.L. Jr., Abhyankar, S., Neben, S., Newman, G., Sieff, C, Thompson, R.C, Burakoff, S.J., Ferrara, J.L.M. 1991. Inhibition of interleukin-l by an inter¬ leukin-l receptor antagonist prevents graft-versus-host diseases.Blood 78/8: 1915-1918 71. Estrov, Z, Kurzrock, R. , Wetzler, M. , Kantarjian, H. , Blake, M. , Harris, D. , Gutterman, J.U. , Talpaz, M. 1991. Suppression of chronic myelongenous leukemia colony growth by interleukin-l (IL-l) receptor antago¬ nist and soluble IL-l receptors: A novel application for inhibitors of IL-l activity. Blood 78/6: 1476-1484 72. Thomas, T.K., Will, P.C, Srivastava, A., Wilson, C.L., Harbison, M. , Little, J., Chesonis, R.S., Pignatello, M. , Schmolze, D., Symington, J., Kilin, P.L., Thompson, R.C. 1991. Evaluation of an interleukin-l receptor antagonist in the rat acetic acid-induced colitis model. Agents Actions 34/1-2: 187-190 73. Carter, D.B. , Deibel, M.R. Jr., Dunn, C.J., Tomich, C.S.C, Laborde, A.L., Slightom, J.L., Berger, A.E., Bienkowski, M.J., Sun, F.F., McEwan, R.N. , Harris, P.K.W., Yem, A.W. , Waszak, G.A. , Chosay, J.G. , Sieu, L.C, Hardee, M.M. , Zurcher Neely, H.A., Reardon, I.M., Heinrikson, R.L. et al . 1990. Purification, cloning expression and biological characterization of an inter¬ leukin-l receptor antagonist protein. Nature 344/6267: 633-638 74. Larsen C . G, Anderson A.O, Apella E., Oppenheim J.J. , Matsushi a K. , 1989. Science 243:1464; 75. Larsen C.G. , Jinquan T. , Deleurant B. , Thestrup-Peder- sen K. 1993, IL-10 is a potent regulator of the chemotactic response of mononuclear cells, but not of granulocytes. J. Invest. Dermatol. Vol 100, No 6 76. Sankoff and Kruskal in chapter 1 of "Time Warps, String Edits, and Macromolecules: The Theory and Practice of Sequence Comparison" (Addison-Wesley, Reading, Mass. 1983) . 77. Berzofsky, Science 229, (1985) 932-940 78. Bowie et al . , Science 247, (1990) 1306-1310 79. Wasserman et al. , J. Immunol . 87, 1961, 290-295 80. Levine et al. , Methods in Enzymology 11, 1967, 928-936 81. Lewis et al . , Biochemistry 22, 1983, 948-954 82. Rene de Waal Maletyt, John Abrahams, Bruce Bennet, Carl G. Figdor and Jan E. de Vries (1991) , Interleukin 10 (IL-10) Inhibits Cytokine Synthesis by Human Monocytes: An Autoregulatory Role of IL-10 Produced by Monocytes. J. Exp . Med. 174, 1209-1220 83. Szoka et al . , Ann. Rev. Biophys . Bioeng. 9, 1980, 467 84. US Patent No. 4,235,871 85. US 4,501,728 86. US 4,837,028. 87. Walter H. Gotlieb, John S. Abrams, Joanna M. Watson, Thierry J. Velu, Jonathan S. Berek, Otoniel Martinez- Meza (1992) , Presence of interleukin 10 (IL-10) in the ascites of patients with ovarian and other intra-abdo- minal cancers. Cytokine 4, No. 5, 385-390 88. Blancho G. , P. Gianello, Sh. Germana, M. Baetscher, D.H. Sachs and Chr. LeGuern (1995) , Molecular identifi¬ cation of porcine interleukin 10: Regulation of expres¬ sion in kidney allograf model. Proc. Natl . Acad. Sci . USA 92, 2800-2804 89. Howard, M. , T. Muchamuel, S. Andrade, S. Menon (1993) , Interleukin 10 protects mice from lethal endotoxemia. J. Exp . Med. 177, 1205-1208 90. Chernoff, A.E., E.V. Granowitz, L. Shapiro, E. Vannier, G. Lonnemann, J.B. Angel, J.S. Kennedy, A.R. Rabson, S. Wolff, CA. Dinarello (1995) , A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses. J. Immunol . 154, 5492-5499 91. Banerjee, A.K. , S.W. Galloway and A.N. Kingsnorth (1994) , Experimental models of acute pancreatitis. Br. J. Surg. 81, 1096-1103 92. Hong, S.S., D.S. Chin, T.S. Cho, S.E. Kim (1962) , Expe¬ rimental pancreatitis induced by alcohol and bile in rabbits. Annals of Surgery 156(6) , 929-939 93. Bodansky, M. (1984) , Principles of Peptide Synthesis, Springer-Verlag, Berlin 94. Pelton, J.T. , et al. , Proc . Natl . Acad. Sci . USA 82, 233-239 95. Dyson, H. , et al . (1988) , Annual Review of Biophysi cs and Biophysi cal Chemistry 17, 305-324) . 96. Nakanishi, H. , et al . (1993) , Peptidomimetics of the immunoglobulin supergene family - a review. Gene 137, 51-56 97. US 5,446,128 98. Walter et al. (1995) , Biochemistry 3 , 12118-25 99. Marshall, G.R. (1993) , Te trahedron 49, 3547-3558 100. Merrifield, R.B. (1963) , J. Amer. Chem. Soc . 85, 2149- 2154) 101. Kent, S.B.H. (1988) , Annu . Rev. Biochem. 57, 957-989 102. Carpino, L.A. and Han, G.Y. (1972) , J. Org. Chem. 37, 3404-3409 103. Stewart, J.M. and Young, J.D. (1983) , "Solid Phase Peptide Synthesis", Pierce Chemical Company, Rockford, Illinois 104. Atherton, E. and Sheppard, R.C. (1989) , "Solid Phase Peptide Synthesis", IRL Press at Oxford University Press 105. Pennington, M.W. and Dunn, B.M. (eds.) (1994) , "Peptide Synthesis Protocols", Humana Press, Totowa, New Jersey 106. Ikeda, N. et al. (1995) , Infection and Immuni ty, 4812- 4817 107. Fink, G.W. and Norman, J.G. (1996) , "Intrapancreatic Interleukin-ljβ Gene Expression by Specific Leukocyte Populations during Acute Pancreatitis", J " . Surgical Research 63, 369-373 108. Gaur, D. et al . (1996) , "Phylogenetic position of the order Lagomorpha (rabbits, hares and allies) ", Nature, 379, 333-335 109. Poli, G. et al. (1994) , Proc . Natl . Acad. Sci . USA 91, 108-112 110. Jensen, I.M. et al . (1993), Analyt. Cell . Pathol . 5, 213-223 111. Berman, R.M. , Suzuki, T. et al. (1996) , "Systemic admi¬ nistration of cellular IL-10 induces an effective, specific, longlived immune response against established tumors in mice", J. Immunol . 157, 231-238 112. Zheng, L.M. , Ojcius, D.M. et al. (1996) , "IL-10 inhibits tumor metastasis through an NK cell-dependent mechanism", J " . Exp . Med. 184, 579-584 113. Kundu, N. , Beaty, T.L. et al . (1996) , "Antimetastatic and anti-tumor activities of IL-10 in a murine model of breast cancer", J. Natl . Cancer Inst . 88, 479-480 114. Kollmann, T.R. , Pettoello-Mantovani, M. et al. (1996) , "Inhibition of acute in vivo HIV infection by human IL-10 treatment of SCID mice implanted with human fetal thymus and liver", Proc. Natl . Acad. Sci . USA 93, 3126- 3131 115. Maini, R.N. (1996), "A perspective on anti-cytokine and anti T cell directed therapies in rheumatoid arthri¬ tis", Clin . Exp. Rheumatol . 13, suppl . 12, S35-40 SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: (A) NAME: Steeno Research Group A/S (B) STREET: Dunbirkevej 6 (C) CITY: Odense SV (E) COUNTRY: Denmark (F) POSTAL CODE (ZIP) : 5250 (ii) TITLE OF INVENTION: Immunomodulators (iii) NUMBER OF SEQUENCES: 23 (iv) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentin Release #1.0, Version #1.30 (EPO) (2) INFORMATION FOR SEQ ID NO: 1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1: Ala Tyr Met Thr Met Lys lie Arg Asn 1 5 (2) INFORMATION FOR SEQ ID NO: 2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2: Ala Tyr Met Thr lie Lys Met Arg Asn 1 5 (2) INFORMATION FOR SEQ ID NO: " 3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE : amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: Ala Phe Met Thr Leu Lys Leu Arg Asn 1 5 (2) INFORMATION FOR SEQ ID NO: 4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4: Ala Tyr Met Thr Met Lys Val Arg Glu 1 5 (2) INFORMATION FOR SEQ ID NO: 5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5: Gly Tyr Met Thr Met Lys lie Arg Asp 1 5 (2) INFORMATION FOR SEQ ID NO: 6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE : amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6: Ala Phe Met Thr Met Lys lie Arg Asp 1 5 (2) INFORMATION FOR SEQ ID NO: 7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7: Ala Tyr lie Thr Met Lys lie Arg Asp 1 5 (2) INFORMATION FOR SEQ ID NO: 8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8: Ala Tyr Leu Thr Met Lys lie Arg Asp l 5 (2) INFORMATION FOR SEQ ID NO: 9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE : amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (11) MOLECULE TYPE: peptide (m) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9: Ala Tyr Val Thr Met Lys lie Arg Asp 1 5 (2) INFORMATION FOR SEQ ID NO: 10: (l) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 ammo acids (B) TYPE: ammo acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (i ) MOLECULE TYPE: peptide (in) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10: Ala Tyr Met Thr lie Lys lie Arg Asp 1 5 (2) INFORMATION FOR SEQ ID NO: 11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 ammo acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (n) MOLECULE TYPE: peptide (lli) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11: Ala Tyr Met Thr Leu Lys lie Arg Asp 1 5 (2) INFORMATION FOR SEQ ID NO: 12: (l) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 12 : Ala Tyr Met Thr Val Lys lie Arg Asp 1 5 (2) INFORMATION FOR SEQ ID NO: 13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13: Ala Tyr Met Thr Met Lys lie Arg Asp 1 5 (2) INFORMATION FOR SEQ ID NO: 14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14: Ala Tyr Met Thr Met Lys Met Arg Asp l 5 (2) INFORMATION FOR SEQ ID NO: 15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15: Ala Tyr Met Thr Met Lys Val Arg Asp 1 5 (2) INFORMATION FOR SEQ ID NO: 16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16: Ala Tyr Met Thr Met Lys lie Arg Gin 1 5 (2) INFORMATION FOR SEQ ID NO: 17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17: Ala Tyr Met Thr Met Lys lie Arg Glu 1 5 (2) INFORMATION FOR SEQ ID NO: 18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE : amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18: Ser Pro Gly Gin Gly Thr Gin Ser Glu 1 5 (2) INFORMATION FOR SEQ ID NO: 19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19: Thr Xaa Lys Xaa Arg Xaa 1 5 (2) INFORMATION FOR SEQ ID NO: 20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20: Xaa Thr Xaa Lys Xaa Arg Xaa l 5 (2) INFORMATION FOR SEQ ID NO: 21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21: Xaa Xaa Thr Xaa Lys Xaa Arg Xaa 1 5 (2) INFORMATION FOR SEQ ID NO: 22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 22: Xaa Xaa Xaa Thr Xaa Lys Xaa Arg Xaa 1 5 (2) INFORMATION FOR SEQ ID NO: 23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 27 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 23: GCCTACATGA CAATGAAGAT ACGAAAC 27

Claims: CLAIMS 1. Use of a substance or polypeptide according to the formula X 1 -X 2 -X 3 -Thr-X 4 -Lys-X 5 -Arg-X 6 (SEQ ID N0:22), wherein X x is Ala or Gly, X 2 is Tyr or Phe, X 3 , X 4 and X 5 are independently selected from the group con¬ sisting of Met, lie, Leu and Val; and X 6 is selected from the group consisting of Asp, Gin and Glu, optionally at least one of X 1# X 2 , X 3 , X , X 5 and X 6 is inde¬ pendently substituted with a non-natural or unusual amino acid and/or the peptide is cyclized and/or the peptide is stabilized and/or the amino terminal amino acid residue is acylated and/or the carboxy terminal amino acid residue is amidated, and peptidomimetics modelled on the basis of the above formula for the preparation of a pharmaceutical compo¬ sition for the reduction of TNFα; production. 2. Use of a substance or polypeptide according to the formula X 1 -X 2 -X 3 -Thr-X 4 -Lys-X 5 -Arg-X 6 (SEQ ID N0:22) , wherein X λ is Ala or Gly, X 2 is Tyr or Phe, X 3 , X 4 and X 5 are independently selected from the group con¬ sisting of Met, lie, Leu and Val; and X 6 is selected from the group consisting of Asp, Gin and Glu, optionally at least one of X x , X 2 , X 3 , X 4 , X 5 and X 6 is inde¬ pendently substituted with a non-natural or unusual amino acid and/or the peptide is cyclized and/or the peptide is stabilized and/or the amino terminal amino acid residue is acylated and/or the carboxy terminal amino acid residue is amidated, and peptidomimetics modelled on the basis of the above formula for the preparation of a pharmaceutical compo- sition for the prophylaxis or treatment of pancreatitis. 3. Use of a substance or polypeptide according to the formula X 1 -X 2 -X 3 -Thr-X 4 -Lys-X 5 -Arg-X 6 (SEQ ID N0:22), wherein X λ is Ala or Gly, X 2 is Tyr or Phe, X 3 , X 4 and X 5 are independently selected from the group con¬ sisting of Met, lie, Leu and Val; and X 6 is selected from the group consisting of Asp, Gin and Glu, optionally at least one of X 1# X 2 , X 3 , X 4 , X 5 and X 6 is inde- pendently substituted with a non-natural or unusual amino acid and/or the peptide is cyclized and/or the peptide is stabilized and/or the amino terminal amino acid residue is acylated and/or the carboxy terminal amino acid residue is amidated, and peptidomimetics modelled on the basis of the above formula for the preparation of a pharmaceutical compo¬ sition for the prophylaxis or treatment of viral infections such as acquired immun-deficiency syndrom (AIDS) or cutaneous HPV-infection. 4. A substance or polypeptide having the formula X 1 -X 2 -X 3 -Thr-X 4 -Lys-X 5 -Arg-X 6 (SEQ ID N0:22), wherein X x is Ala or Gly, X is Tyr or Phe, X 3 , X 4 and X 5 are independently selected from the group con¬ sisting of Met, lie, Leu and Val; and X 6 is selected from the group consisting of Asp, Gin and Glu, wherein at least one of X , X 2 , X 3 , X 4 , X 5 and X 6 is indepen- dently substituted with a non-natural or unusual amino acid, said substance or polypeptide having at least one biological activity of IT9302. 5. A substance or polypeptide having the formula X 2 -X 3 -Thr-X 4 -Lys-X 5 -Arg-X 6 (SEQ ID N0.21), wherein X 2 is Tyr or Phe, X 3 , X 4 and X 5 are independently selected from the group con¬ sisting of Met, lie, Leu and Val; and X 6 is selected from the group consisting of Asp, Gin and Glu, wherein at least one of X 2 , X 3 , X 4 , X 5 and X 6 is independent¬ ly substituted with a non-natural or unusual amino acid, said substance or polypeptide having at least one biological activity of IT9302. 6. A substance or polypeptide having the formula X 3 -Thr-X 4 -Lys-X 5 -Arg-X 6 (SEQ ID N0:20), wherein X 3 , X 4 and X 5 are independently selected from the group con¬ sisting of Met, lie, Leu and Val; and X 6 is selected from the group consisting of Asp, Gin and Glu, wherein at least one of X 3 , X 4 , X 5 and X 6 is independently substituted with a non-natural or unusual amino acid, said substance or polypeptide having at least one biological activity of IT9302. 7. A substance or polypeptide having the formula Thr-X 4 -Lys-X 5 -Arg-X 6 (SEQ ID N0:19) , wherein X 4 and X 5 are independently selected from the group consi¬ sting of Met, lie, Leu and Val; and X 6 is selected from the group consisting of Asp, Gin and Glu, wherein at least one of X 3 , X 4 , X 5 and X 6 is independently substituted with a non-natural or unusual amino acid, said substance or polypeptide having at least one biological activity of IT9302. 8. A substance or peptide according to any of claims 4-7 which is cyclized. 9. A substance or peptide according to any of claims 4-7 which is stabilized. 10. A substance or peptide according to any of claims 4-7 wherein the amino terminal amino acid residue is acylated. 11. A substance or peptide according to any of claims 4-7 wherein the carboxy terminal amino acid residue is amidated. 12. A peptidomimetic modelled on the basis of the formula X 1 -X 2 -X 3 -Thr-X 4 -Lys-X 5 -Arg-X 6 (SEQ ID N0:22) , wherein X x is Ala or Gly, X 2 is Tyr or Phe, X 3 , X 4 and X 5 are independently selected from the group con¬ sisting of Met, lie, Leu and Val; and X 6 is selected from the group consisting of Asp, Gin and Glu, said peptidomimetics having at least one biological activity of IT9302. 13. A pharmaceutical composition comprising a substance or polypeptide according to any of claims 4-12. 14. Use of a substance or polypeptide according to any of claims 4-12 for the treatment or prophylaxis of one or more of the diseases mentioned in Tables 1 and 2. 15. Use of a substance or polypeptide according to claim 4-12 for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of one or more of the diseases mentioned in Tables 1 and 2. 16. A method of treating and/or preventing one or more of the diseases mentioned in Tables 1 and 2, the method comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a substance or polypeptide according to any of claims 4-12. 17. Synthesis of a substance or peptide according to any of claims 4-12 by use of solid-phase peptide synthesis (SPPS) , the process comprising the following steps: a) covalently coupling the C-terminal amino acid in the form of an N-alfa-protected, optionally side chain-protected reactive derivative, either directly or by means of a suit¬ able linker to a solid support b) removing the N-alfa-protective group c) adding the succeeding protected amino acids according to the desired sequence in a stepwise manner d) removing the side chain-protective groups if any, e) upon assembly of the complete peptide chain cleaving the peptide from the resin, and optionally f) cyclizing and/or stabilizing the peptide and/or acylating the amino terminal amino acid residue and/or amidating the carboxy terminal amino acid residue.

Inventors: GESSER BORBALA, GROENHOEJ LARSEN CHRISTIAN, GESSER, BORBALA, GROENHOEJ LARSEN, CHRISTIAN
Applicants: GESSER BORBALA, GROENHOEJ LARSEN CHRISTIAN, STEENO RES GROUP AS, GESSER, BORBALA, GROENHOEJ LARSEN, CHRISTIAN, STEENO RESEARCH GROUP A/S
Application year: 1997
Main classification: C07K14
IPC codes: A61K31, A61K38, A61P1, A61P37, C07K14