Methods for treating an autoimmune disease using a soluble CTLA4 molecule and a DMARD or NSAID

• US 20040022787A1
• Filed: 04/18/2003
• Published: 02/05/2004
• Est. Priority Date: 07/03/2000
• Status: Abandoned Application

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Cohen, Robert, Becker, Jean-Claude, Hagerty, David, Peach, Robert J., Carr, Suzette
• Application Number:
  US10/419,008
• Publication Number:
  US 20040022787A1
• Time in Patent Office: Days
• US Class Current: 424/144.1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/1774 Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
• CPC Class Codes: A61K 39/0008 Antigens related to auto-immune diseases; Preparations to induce self-tolerance
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 47/6811 the drug being a protein or peptide, e.g. transferrin or bleomycin
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/70521 CD28, CD152
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

The present invention relates to compositions and methods for treating immune system diseases such as rheumatic disease, by administering to a subject soluble CTLA4 molecules that block endogenous B7 molecules from binding their ligands, alone, or in conjunction with other agents including Disease Modifying Anti-Rheumatic Drugs (DMARDs).

Claims

1. A method for blocking B7 interactions with CTLA4 and/or CD28 comprising administering to a subject an effective amount of a first agent and a second agent, wherein

a) the first agent is a soluble CTLA4 molecule, and

b) the second agent is selected from a group consisting of immunosuppressive agents, corticosteroids, nonsteroidal antiinflammatory drugs, prednisone, azathioprine, methotrexate, TNFα

;

blockers or antagonists, infliximab, any biological agent targeting an inflammatory cytokine, hydroxychloroquine, sulphasalazopryine, gold salts, etanercept, anakinra, cyclophosphamide, leflunomide, collagen, dnaJ, a molecule that blocks TNF receptors, pegsunercept, a molecule that blocks cytokine function, AMG719, a molecule that blocks LFA-1 function, efalizumab, acetyl salicylic acid, choline magnesium salicylate, diflunisal, magnesium salicylate, salsalate, sodium salicylate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, nabumetone, phenylbutazone, piroxicam, sulindac, tolmetin, acetaminophen, ibuprofen, Cox-2 inhibitors, meloxicam, codeine phosphate, propoxyphene napsylate, oxycodone hydrochloride, oxycodone bitartrate and tramadol.

3. The method of claim 1 or 2, wherein cytokine production is regulated.

4. The method of claim 1 or 2, wherein ACR 20, 50 and/or 70 response rates are improved.

9. The method of claim 1, 2, 5, or 6, wherein the soluble CTLA4 molecule comprises an extracellular domain of a CTLA4 molecule, or portion thereof, which binds a B7 antigen expressed on activated B cells.

10. The method of claim 9, wherein the extracellular domain of the CTLA4 molecule comprises the amino acids shown in FIG. 23 (SEQ ID NO:

17) beginning with methionine at position 1 and or with alanine at position −

1 and ending with aspartic acid at position 124.

11. The method of claim 1, 2, 5, or 6, wherein the soluble CTLA4 molecule is a CTLA4 fusion molecule.

12. The method of claim 11, wherein the CTLA4 fusion molecule comprises an extracellular domain of a CTLA4 molecule which binds a B7 antigen expressed on activated B cells joined to a non-CTLA4 molecule.

20. The method of claim 1, 2, 5, or 6, wherein the soluble CTLA4 further comprises an amino acid sequence which permits secretion of the soluble CTLA4 molecule.

21. The method of claim 20, wherein the amino acid sequence which permits secretion comprises an oncostatin M signal peptide.

22. The method of claim 11, wherein the CTLA4 fusion molecule is CTLA4Ig.

23. The method of claim 22, wherein the CTLA4Ig is shown in FIG. 24 (SEQ ID NO:

19) beginning with methionine at position +1 or with alanine at position −

1 and ending with lysine at position +357.

24. The method of claim 1, 2, 5, or 6, wherein the soluble CTLA4 molecule is a soluble CTLA4 mutant molecule.

25. The method of claim 24, wherein the soluble CTLA4 mutant molecule binds a B7 antigen expressed on activated B cells and comprises a mutation in the extracellular domain of a CTLA4 molecule.

26. The method of claim 24, wherein the soluble CTLA4 mutant molecule comprises an extracellular domain of CTLA4,

a) wherein the extracellular domain of CTLA4 begins with methionine at position +1 or with alanine at position −

1 and ends with aspartic acid at position +124 as shown in FIG. 23 or 24 (SEQ ID NO;

17 or

     19), and

b) wherein at position +104 of the extracellular domain of CTLA4, leucine is substituted with any other amino acid.

27. The method of claim 24, wherein the soluble CTLA4 mutant molecule comprises an extracellular domain of CTLA4,

a) wherein the extracellular domain of CTLA4 begins with methionine at position +1 or with alanine at position −

1 and ends with aspartic acid at position +124 as shown in FIG. 23 or 24 (SEQ ID NO;

17 or

     19),

b) wherein at position +104 of the extracellular domain of CTLA4, leucine is substituted with glutamic acid, and

c) wherein at position +29 of the extracellular domain of CTLA4, alanine is substituted with tyrosine.

28. The method of claim 24, wherein the soluble CTLA4 mutant molecule is L104EA29YIg as shown in FIG. 19 (SEQ ID NO:

9) beginning with methionine at position +1 or with alanine at position −

1 and ending with lysine at position +357 as shown in FIG. 19 (SEQ ID NO;

     9).

42. The method of claim 1, 2, 29, 30, 31, 34, 35, 36, 37, 38, 39 or 40, wherein the effective amount of soluble CTLA4 is between about 0.5 through 100 mg/kg weight of the subject, about 0.1 to 100 mg/kg weight of the subject, about 0.5 to 10 mg/kg weight of a subject, about 0.5 to 5 mg/kg weight of a subject, about 5 to 10 mg/kg weight of a subject, about 10 to 15 mg/kg weight of a subject, about 15 to 20 mg/kg weight of a subject, about 20 to 25 mg/kg weight of a subject, about 25 to 30 mg/kg weight of a subject, about 30 to 35 mg/kg weight of a subject, about 35 to 40 mg/kg weight of a subject, about 40 to 45 mg/kg weight of a subject, about 45 to 50 mg/kg weight of a subject, about 50 to 55 mg/kg weight of a subject, about 55 to 60 mg/kg weight of a subject, about 60 to 65 mg/kg weight of a subject, about 65 to 70 mg/kg weight of a subject, about 70 to 75 mg/kg weight of a subject, about 75 to 80 mg/kg weight of a subject, about 80 to 85 mg/kg weight of a subject, about 85 to 90 mg/kg weight of a subject, about 90 to 95 mg/kg weight of a subject, about 95 to 100 mg/kg weight of a subject, about 2 to 10 mg/kg weight of a subject, about 0.1 to 4 mg/kg weight of a subject, about 0.1 to 0.5 mg/kg weight of a subject, about 0.5 to 1.0 mg/kg weight of a subject, about 1.0 to 1.5 mg/kg weight of a subject, about 1.5 to 2.0 mg/kg weight of a subject, about 2.0 to 2.5 mg/kg weight of a subject, about 2.5 to 3.0 mg/kg weight of a subject, about 3.0 to 3.5 mg/kg weight of a subject, about 3.5 to 4.0 mg/kg about 4.0 to 4.5 mg/kg weight of a subject, about 4.5 to 5.0 mg/kg weight of a subject, about 5.0 to 5.5 mg/kg weight of a subject, about 5.5 to 6.0 mg/kg weight of a subject, about 6.0 to 6.5 mg/kg weight of a subject, about 6.5 to 7.0 mg/kg weight of a subject, about 7.0 to 7.5 mg/kg weight of a subject, about 7.5 to 8.0 mg/kg weight of a subject, about 8.0 to 8.5 mg/kg weight of a subject, about 8.5 to 9.0 mg/kg weight of a subject, about 9.0 to 9.5 mg/kg weight of a subject, about 9.5 to 10.0 mg/kg weight of a subject, weight of a subject, about 0.1 to 20 mg/kg weight of a subject, about 0.1 to 2 mg/kg weight of a subject, about 2 to 4 mg/kg weight of a subject, about 4 to 6 mg/kg weight of a subject, about 6 to 8 mg/kg weight of a subject, about 8 to 10 mg/kg weight of a subject, about 10 to 12 mg/kg weight of a subject, about 12 to 14 mg/kg weight of a subject, about 14 to 16 mg/kg weight of a subject, about 16 to 18 mg/kg weight of a subject, about 18 to 20 mg/kg weight of a subject, 0.5 mg/kg weight of the subject, 2 mg/kg weight of a subject, 10 mg/kg weight of a subject, about 0.5 mg/kg weight of the subject, 2 mg/kg weight of the subject, 10 mg/kg weight of the subject, about 0.5 mg/kg to 100 weight of the subject, about 0.5 to 10 mg/kg weight of a subject, about 0.1 to 20 mg/kg weight of a subject, about 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg.

59. The method of claim 1, 2, 5, 6, 29, 30, 31, 34, 35, 36, 37, 38, 39, 40, 50, 51, 52, 53 or 54, wherein administration of the agents is effected locally or systemically.

60. The method of claim 59, wherein administration is selected from the group consisting of, intravenous, intramuscular, intraperitoneal, oral, inhalation, subcutaneous, implantable pump, continuous infusion, gene therapy, liposomes, suppositories, topical contact, vesicles, capsules, biodegradable polymers, hydrogels, controlled release patch and injection methods.

61. The method of claim 1, 2, 5, 6, 29, 30, 31, 34, 35, 36, 37, 38, 39, 40, 50, 51, 52, 53 or 54, wherein the subject is selected from the group consisting of human, monkey, ape, dog, cat, cow, horse, rabbit, mouse, and rat.

62. The method of claim 22 or 29, wherein the CTLA4Ig is encoded by a nucleic acid molecule designated ATCC No. 68629.

63. The method of claim 28, 32, 51, 53 or 54, wherein L104EA29YIg is encoded by a DNA sequence designated ATCC PTA-2104.

2. A method for treating an immune system disease comprising administering to a subject an effective amount of a first agent and a second agent, wherein

a) the first agent is a soluble CTLA4 molecule, and

b) the second agent is selected from a group consisting of immunosuppressive agents, corticosteroids, nonsteroidal antiinflammatory drugs, prednisone, azathioprine, methotrexate, TNFα

blockers or antagonists, infliximab, any biological agent targeting an inflammatory cytokine, hydroxychloroquine, sulphasalazopryine, gold salts, etanercept, anakinra, cyclophosphamide, leflunomide, collagen, dnaJ, a molecule that blocks TNF receptors, pegsunercept, a molecule that blocks cytokine function, AMG719, a molecule that blocks LFA-1 function, efalizumab, acetyl salicylic acid, choline magnesium salicylate, diflunisal, magnesium salicylate, salsalate, sodium salicylate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, nabumetone, phenylbutazone, piroxicam, sulindac, tolmetin, acetaminophen, ibuprofen, Cox-2 inhibitors, meloxicam, codeine phosphate, propoxyphene napsylate, oxycodone hydrochloride, oxycodone bitartrate and tramadol.

43. The method of claim 2, 6, 29, 30, 31, 34, 36, 38 or 40, wherein the immune system disease is a rheumatic disease.

44. The method of claim 43, wherein the rheumatic disease is rheumatoid arthritis.

45. The method of claim 2, 6, 29, 30, 31, 34, 36, 38 or 40,, wherein the immune system disease is selected from autoimmune diseases, psoriasis, immune disorders associated with graft transplantation rejection, T cell lymphoma, T cell acute lymphoblastic leukemia, testicular angiocentric T cell lymphoma, benign lymphocytic angiitis, lupus erythematosus, Hashimoto'"'"'s thyroiditis, primary myxedema, Graves'"'"' disease, pernicious anemia, autoimmune atrophic gastritis, Addison'"'"'s disease, insulin dependent diabetes mellitis, good pasture'"'"'s syndrome, myasthenia gravis, pemiphigus, Crohn'"'"'s disease, sympathetic ophthalmia, autoimmune uveitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren'"'"'s syndrome, rheumatic disease, rheumatoid arthritis, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra-articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, systemic lupus erythematosus, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis and chondrocalcinosis.

46. The method of claim 2, 6, 29, 30, 31, 34, 36, 38 or 40,, wherein the immune system disease is selected from graft related disorders, chronic rejection, tissue or cell allo- or xenografts, skin allo- or xenografts, islet allo- or xenografts, muscle allo- or xenografts, hepatocyte allo- or xenografts and neuron allo- or xenografts.

47. The method of claim 2, 6, 29, 30, 31, 34, 36, 38 or 40,, wherein a symptom associated with the immune system disease is alleviated and wherein the symptom is selected from the group consisting of joint swelling, pain, tenderness, morning stiffness, structural damage, an elevated level of serum C-reactive protein, an elevated level of soluble IL-2r, an elevated level of soluble ICAM-1, an elevated level of soluble E-selectin and an elevated erythrocyte sedimentation rate.

48. The method of claim 2, 6, 29, 30, 31, 34, 36, 38 or 40, wherein treating a subject suffering from an immune system disease induces a pathophysiological change.

49. The method of claim 48, wherein the pathophysiological change associated with the immune system disease is reduced structural damage.

5. A method for blocking B7 interactions with CTLA4 and/or CD28 comprising administering to a subject an effective amount of a soluble CTLA4 molecule, wherein the effective amount of soluble CTLA4 is about 0.1 to 100 mg/kg weight of the subject, about 0.5 to 5 mg/kg weight of a subject, about 5 to 10 mg/kg weight of a subject, about 10 to 15 mg/kg weight of a subject, about 15 to 20 mg/kg weight of a subject, about 20 to 25 mg/kg weight of a subject, about 25 to 30 mg/kg weight of a subject, about 30 to 35 mg/kg weight of a subject, about 35 to 40 mg/kg weight of a subject, about 40 to 45 mg/kg of a subject, about 45 to 50 mg/kg weight of a subject, about 50 to 55 mg/kg weight of a subject, about 55 to 60 mg/kg weight of a subject, about 60 to 65 mg/kg weight of a subject, about 65 to 70 mg/kg weight of a subject, about 70 to 75 mg/kg weight of a subject, about 75 to 80 mg/kg weight of a subject, about 80 to 85 mg/kg weight of a subject, about 85 to 90 mg/kg weight of a subject, about 90 to 95 mg/kg weight of a subject, about 95 to 100 mg/kg weight of a subject, about 2 to 10 mg/kg weight of a subject, about 0.1 to 4 mg/kg weight of a subject, about 0.1 to 0.5 mg/kg weight of a subject, about 0.5 to 1.0 mg/kg weight of a subject, about 1.0 to 1.5 mg/kg weight of a subject, about 1.5 to 2.0 mg/kg weight of a subject, about 2.0 to 2.5 mg/kg weight of a subject, about 2.5 to 3.0 mg/kg weight of a subject, about 3.0 to 3.5 mg/kg weight of a subject, about 3.5 to 4.0 mg/kg weight of a subject, about 4.0 to 4.5 mg/kg weight of a subject, about 4.5 to 5.0 mg/kg weight of a subject, about 5.0 to 5.5 mg/kg weight of a subject, about 5.5 to 6.0 mg/kg weight of a subject, about 6.0 to 6.5 mg/kg weight of a subject, about 6.5 to 7.0 mg/kg weight of a subject, about 7.0 to 7.5 mg/kg weight of a subject, about 7.5 to 8.0 mg/kg weight of a subject, about 8.0 to 8.5 mg/kg weight of a subject, about 8.5 to 9.0 mg/kg weight of a subject, about 9.0 to 9.5 mg/kg weight of a subject, about 9.5 to 10.0 mg/kg weight of a subject, about 0.1 to 2 mg/kg weight of a subject, about 2 to 4 mg/kg weight of a subject, about 4 to 6 mg/kg weight of a subject, about 6 to 8 mg/kg weight of a subject, about 8 to 10 mg/kg weight of a subject, about 10 to 12 mg/kg weight of a subject, about 12 to 14 mg/kg weight of a subject, about 14 to 16 mg/kg weight of a subject, about 16 to 18 mg/kg weight of a subject, about 18 to 20 mg/kg weight of a subject, about 0.5 mg/kg weight of the subject, 2 mg/kg weight of the subject, 10 mg/kg weight of the subject, about 0.5 mg/kg to 100 weight of the subject, about 0.5 to 10 mg/kg weight of a subject, about 0.1 to 20 mg/kg weight of a subject, about 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg).

7. The method of claim 5 or 6, wherein cytokine production is regulated.

8. The method of claim 5 or 6, wherein ACR 20, 50 and/or 70 response rates are improved.

6. A method for treating an immune system disease comprising administering to a subject an effective amount of a soluble CTLA4 molecule, wherein the effective amount of soluble CTLA4 is about 0.1 to 100 mg/kg weight of the subject, about 0.5 to 5 mg/kg weight of a subject, about 5 to 10 mg/kg weight of a subject, about 10 to 15 mg/kg weight of a subject, about 15 to 20 mg/kg weight of a subject, about. 20 to 25 mg/kg weight of a subject, about 25 to 30 mg/kg weight of a subject, about 30 to 35 mg/kg weight of a subject, about 35 to 40 mg/kg weight of a subject, about 40 to 45 mg/kg weight of a subject, about 45 to 50 mg/kg weight of a subject, about 50 to 55 mg/kg weight of a subject, about 55 to 60 mg/kg weight of a subject, about 60 to 65 mg/kg weight of a subject, about 65 to 70 mg/kg weight of a subject, about 70 to 75 mg/kg weight of a subject, about 75 to 80 mg/kg weight of a subject, about 80 to 85 mg/kg weight of a subject, about 85 to 90 mg/kg weight of a subject, about 90 to 95 mg/kg weight of a subject, about 95 to 100 mg/kg weight of a subject, about 2 to 10 mg/kg weight of a subject, about 0.1 to 4 mg/kg weight of a subject, about 0.1 to 0.5 mg/kg weight of a subject, about 0.5 to 1.0 mg/kg weight of a subject, about 1.0 to 1.5 mg/kg weight of a subject, about 1.5 to 2.0 mg/kg weight of a subject, about 2.0 to 2.5 mg/kg weight of a subject, about 2.5 to 3.0 mg/kg weight of a subject, about 3.0 to 3.5 mg/kg weight of a subject, about 3.5 to 4.0 mg/kg weight of a subject, about 4.0 to 4.5 mg/kg weight of a subject, about 4.5 to 5.0 mg/kg weight of a subject, about 5.0 to 5.5 mg/kg weight of a subject, about 5.5 to 6.0 mg/kg weight of a subject, about 6.0 to 6.5 mg/kg weight of a subject, about 6.5 to 7.0 mg/kg weight of a subject, about 7.0 to 7.5 mg/kg weight of a subject, about 7.5 to 8.0 mg/kg weight of a subject, about 8.0 to 8.5 mg/kg weight of a subject, about 8.5 to 9.0 mg/kg weight of a subject, about 9.0 to 9.5 mg/kg weight of a subject, about 9.5 to 10.0 mg/kg weight of a subject, about 0.1 to 2 mg/kg weight of a subject, about 2 to 4 mg/kg weight of a subject, about 4 to 6 mg/kg weight of a subject, about 6 to 8 mg/kg weight of a subject, about 8 to 10 mg/kg weight of a subject, about 10 to 12 mg/kg weight of a subject, about 12 to 14 mg/kg weight of a subject, about 14 to 16 mg/kg weight of a subject, about 16 to 18 mg/kg weight of a subject, about 18 to 20 mg/kg weight of a subject, about 0.5 mg/kg weight of the subject, 2 mg/kg weight of the subject, 10 mg/kg weight of the subject, about 0.5 mg/kg to 100 weight of the subject, about 0.5 to 10 mg/kg weight of a subject, about 0.1 to 20 mg/kg weight of a subject, about 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg.

13. The method of 12, wherein the non-CTLA4 molecule comprises an amino acid sequence which alters the solubility or affinity of the soluble CTLA4 molecule.

14. The method of claim 13, wherein the amino acid sequence which alters the solubility or affinity comprises an immunoglobulin moiety.

15. The method of claim 14, wherein the immunoglubulin moiety comprises one or more mutations to reduce effector function.

16. The method of claim 14, wherein the immunoglubulin moiety is an immunoglubulin constant region or portion thereof.

17. The method of claim 15, wherein the immunoglubulin constant region or portion thereof is mutated to reduce effector function.

18. The method of claim 15, wherein the immunoglubulin constant region comprises a hinge, CH2 and CH3 regions of an immunoglobulin molecule.

19. The method of claim 15, wherein the immunoglubulin constant region or portion thereof is a human or monkey immunoglobulin constant region.

29. A method for treating an immune system disease comprising administering to a subject a combination of an effective amount of a soluble CTLA4 and a second agent, wherein

a) the soluble CTLA4 is a CTLA4Ig beginning with methionine at position +1 or with alanine at position −

1 and ending with lysine as position +357 as shown in FIG. 24 (SEQ ID NO;

     19), and

b) the second agent is selected from a group consisting of immunosuppressive agents, corticosteroids, nonsteroidal antiinflammatory drugs, prednisone, azathioprine, methotrexate, TNFα

blockers or antagonists, infliximab, any biological agent targeting an inflammatory cytokine, hydroxychloroquine, sulphasalazopryine, gold salts, etanercept, anakinra, cyclophosphamide, leflunomide, collagen, dnaJ, a molecule that blocks TNF receptors, pegsunercept, a molecule that blocks cytokine function, AMG719, a molecule that blocks LFA-1 function, efalizumab, acetyl salicylic acid, choline magnesium salicylate, diflunisal, magnesium salicylate, salsalate, sodium salicylate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, nabumetone, phenylbutazone, piroxicam, sulindac, tolmetin, acetaminophen, ibuprofen, Cox-2 inhibitors, meloxicam, codeine phosphate, propoxyphene napsylate, oxycodone hydrochloride, oxycodone bitartrate and tramadol.

57. The method of claim 29, 30, 31, 34, 35, 36, 37, 38, 39, 40, 50, 51, 52, 53 or 54, wherein the soluble CTLA4 molecule comprises an amino acid sequence which permits secretion of the soluble CTLA4 molecule.

58. The method of claim 57, wherein the amino acid sequence which permits secretion comprises an oncostatin M signal peptide.

30. A method for treating an immune system disease comprising administering to a subject a combination of an effective amount of a soluble CTLA4 and a second agent, wherein

a) the soluble CTLA4 comprises the extracellular domain of a CTLA4 molecule as shown in FIG. 23 (SEQ ID NO:

17) beginning with methionine at position +1 or with alanine at position −

1 and ending with aspartic acid at position +124, and

b) the second agent is selected from a group consisting of immunosuppressive agents, corticosteroids, nonsteroidal antiinflammatory drugs, prednisone, azathioprine, methotrexate, TNFα

blockers or antagonists, infliximab, any biological agent targeting an inflammatory cytokine, hydroxychloroquine, sulphasalazopryine, gold salts, etanercept, anakinra, cyclophosphamide, leflunomide, collagen, dnaJ, a molecule that blocks TNF receptors, pegsunercept, a molecule that blocks cytokine function, AMG719, a molecule that blocks LFA-1 function, efalizumab, acetyl salicylic acid, choline magnesium salicylate, diflunisal, magnesium salicylate, salsalate, sodium salicylate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, nabumetone, phenylbutazone, piroxicam, sulindac, tolmetin, acetaminophen, ibuprofen, Cox-2 inhibitors, meloxicam, codeine phosphate, propoxyphene napsylate, oxycodone hydrochloride, oxycodone bitartrate and tramadol.

31. A method for treating an immune system disease comprising administering to a subject a combination of an effective amount of a soluble CTLA4 and a second agent, wherein

a) the soluble CTLA4 mutant molecule comprises an extracellular domain of CTLA4,

i) wherein the extracellular domain of CTLA4 begins with methionine at position +1 or with alanine at position −

1 and ends with aspartic acid at position +124 as shown in FIG. 23 or 24 (SEQ ID NO;

17 or

     19), and

ii) wherein at position +104 of the extracellular domain of CTLA4, leucine is substituted with any other amino acid.

b) the second agent is selected from a group consisting of immunosuppressive agents, corticosteroids, nonsteroidal antiinflammatory drugs, prednisone, azathioprine, methotrexate, TNFα

blockers or antagonists, infliximab, any biological agent targeting an inflammatory cytokine, hydroxychloroquine, sulphasalazopryine, gold salts, etanercept, anakinra, cyclophosphamide, leflunomide, collagen, dnaJ, a molecule that blocks TNF receptors, pegsunercept, a molecule that blocks cytokine function, AMG719, a molecule that blocks LFA-1 function, efalizumab, acetyl salicylic acid, choline magnesium salicylate, diflunisal, magnesium salicylate, salsalate, sodium salicylate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, nabumetone, phenylbutazone, piroxicam, sulindac, tolmetin, acetaminophen, ibuprofen, Cox-2 inhibitors, meloxicam, codeine phosphate, propoxyphene napsylate, oxycodone hydrochloride, oxycodone bitartrate and tramadol.

32. The method of claim 31, wherein the soluble CTLA4 mutant molecule comprises an extracellular domain of CTLA4,

a) wherein the extracellular domain of CTLA4 begins with methionine at position +1 or with alanine at position −

1 and ends with aspartic acid at position +124 as shown in FIG. 23 or 24 (SEQ ID NO;

17 or

     19),

b) wherein at position +104 of the extracellular domain of CTLA4, leucine is substituted with glutamic acid, and

c) wherein at position +29 of the extracellular domain of CTLA4, alanine is substituted with tyrosine.

33. The method of claim 31, wherein the soluble CTLA4 mutant molecule is L104EA29YIg as shown in FIG. 19 (SEQ ID NO:

9) beginning with methionine at position +1 or with alanine at position −

1 and ending with lysine at position +357 as shown in FIG. 19 (SEQ ID NO;

     9).

34. A method for treating an immune system disease comprising administering to a subject a combination of an effective amount of a soluble CTLA4 and a second agent, wherein

a) the soluble CTLA4 is L104EA29YIg beginning with methionine at position +1 or with alanine at position −

1 and ending with lysine as position +357 as shown in FIG. 19 (SEQ ID NO;

     9), and

b) the second agent is selected from a group consisting of immunosuppressive agents, corticosteroids, nonsteroidal antiinflammatory drugs, prednisone, azathioprine, methotrexate, TNFα

blockers or antagonists, infliximab, any biological agent targeting an inflammatory cytokine, hydroxychloroquine, sulphasalazopryine, gold salts, etanercept, anakinra, cyclophosphamide, leflunomide, collagen, dnaJ, a molecule that blocks TNF receptors, pegsunercept, a molecule that blocks cytokine function, AMG719, a molecule that blocks LFA-1 function, efalizumab, acetyl salicylic acid, choline magnesium salicylate, diflunisal, magnesium salicylate, salsalate, sodium salicylate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, nabumetone, phenylbutazone, piroxicam, sulindac, tolmetin, acetaminophen, ibuprofen, Cox-2 inhibitors, meloxicam, codeine phosphate, propoxyphene napsylate, oxycodone hydrochloride, oxycodone bitartrate and tramadol.

35. A method for blocking B7 interactions with CTLA4 and/or CD28 comprising administering to a subject an effective amount of a first agent and a second agent, wherein

a) the first agent is a soluble CTLA4 molecule, and

b) the second agent is Methotrexate,

wherein the effective amount of Methotrexate is about 0.1 to 40 mg per week, about 5 to 30 mg per week, about 0.1 to 5 mg/week, about 5 to 10 mg/week, about 10 to 15 mg/week, about 15 to 20 mg/week, about 20 to 25 mg/week, about 25 to 30 mg/week, about 30 to 35 mg/week, about 35 to 40 mg/week or about 10 to 30 mg/week.

55. The method of claim 35, 37, or 39, cytokine production is regulated.

56. The method of claim 35, 37, or 39, wherein improves ACR 20, 50 and/or 70 response rates is improved.

36. A method for treating an immune system disease comprising administering to a subject an effective amount of a first agent and a second agent, wherein

a) the first agent is a soluble CTLA4 molecule, and

b) the second agent is Methotrexate,

wherein the effective amount of Methotrexate is about 0.1 to 40 mg per week, about 5 to 30 mg per week, about 0.1 to 5 mg/week, about 5 to 10 mg/week, about 10 to 15 mg/week, about 15 to 20 mg/week, about 20 to 25 mg/week, about 25 to 30 mg/week, about 30 to 35 mg/week, about 35 to 40 mg/week or about 10 to 30 mg/week.

37. A method for blocking B7 interactions with CTLA4 and/or CD28 comprising administering to a subject an effective amount of a first agent and a second agent, wherein

a) the first agent is a soluble CTLA4 molecule, and

b) the second agent is Etanercept,

wherein the effective amount of Etanercept is about 10 to 100 mg per week, about 50 mg per week, about 0.1 to 50 mg/kg body weight per week

38. A method for treating an immune system disease comprising administering to a subject an effective amount of a first agent and a second agent, wherein

a) the first agent is a soluble CTLA4 molecule, and

b) the second agent is Etanercept,

wherein the effective amount of Etanercept is about 10 to 100 mg per week, about 50 mg per week, about 0.1 to 50 mg/kg body weight per week

39. A method for blocking B7 interactions with CTLA4 and/or CD28 comprising administering to a subject an effective amount of a first agent and a second agent, wherein

a) the first agent is a soluble CTLA4 molecule, and

b) the second agent is a DMARD,

wherein the effective amount of the DMARD is about 1 to about 5000 mg/day, about 1 to 10 mg/day, about 10 to 50 mg/day, about 50 to 100 mg/day, about 100 to 150 mg/day, about 150 to 200 mg/day, about 200 to 250 mg/day, about 250 to 300 mg/day, about 300 to 350 mg/day, about 350 to 400 mg/day, about 400 to 450 mg/day, about 450 to 500 mg/day, about 500 to 550 mg/day, about 550 to 600 mg/day, about 600 to 650 mg/day, about 650 to 700 mg/day, about 700 to 750 mg/day, about 750 to 800 mg/day, about 800 to 850 mg/day, about 850 to 900 mg/day, about 900 to 950 mg/day, about 950 to 1000 mg/day, about 1000 to 1100 mg/day, about 1100 to 1200 mg/day, about 1200 to 1300 mg/day, about 1300 to 1400 mg/day, about 1400 to 1500 mg/day, about 1500 to 1600 mg/day, about 1600 to 1700 mg/day, about 1700 to 1800 mg/day, about 1800 to 1900 mg/day, about 1900 to 2000 mg/day, about 2000 to 2500 mg/day, about 2500 to 3000 mg/day, about 3000 to 3500 mg/day, about 3500 to 4000 mg/day, about 4000 to 4500 mg/day or about 4500 to 5000 mg/day.

40. A method for treating an immune system disease administering to a subject an effective amount of a first agent and a second agent, wherein

a) the first agent is a soluble CTLA4 molecule, and

b) the second agent is a DMARD,

wherein the effective amount of the DMARD is about 1 to about 5000 mg/day, about 1 to 10 mg/day, about 10 to 50 mg/day, about 50 to 100 mg/day, about 100 to 150 mg/day, about 150 to 200 mg/day, about 200 to 250 mg/day, about 250 to 300 mg/day, about 300 to 350 mg/day, about 350 to 400 mg/day, about 400 to 450 mg/day, about 450 to 500 mg/day, about 500 to 550 mg/day, about 550 to 600 mg/day, about 600 to 650 mg/day, about 650 to 700 mg/day, about 700 to 750 mg/day, about 750 to 800 mg/day, about 800 to 850 mg/day, about 850 to 900 mg/day, about 900 to 950 mg/day, about 950 to 1000 mg/day, about 1000 to 1100 mg/day, about 1100 to 1200 mg/day, about 1200 to 1300 mg/day, about 1300 to 1400 mg/day, about 1400 to 1500 mg/day, about 1500 to 1600 mg/day, about 1600 to 1700 mg/day, about 1700 to 1800 mg/day, about 1800 to 1900 mg/day, about 1900 to 2000 mg/day, about 2000 to 2500 mg/day, about 2500 to 3000 mg/day, about 3000 to 3500 mg/day, about 3500 to 4000 mg/day, about 4000 to 4500 mg/day or about 4500 to 5000 mg/day.

41. The method of claim 40, wherein the DMARD is selected from a group consisting of a dihydrofolic acid reductase inhibitor, cyclophosphamide, cyclosporine, cyclosporin A, chloroquine, hydroxychloroquine, sulfasalazine (sulphasalazopyrine), gold salts, D-penicillamine, leflunomide, azathioprine, anakinra, a TNF blocker, a biological agent that targets an inflammatory cytokine, methotrexate or etanercept.

50. A method for treating a disease selected from autoimmune diseases, psoriasis, immune disorders associated with graft transplantation rejection, T cell lymphoma, T cell acute lymphoblastic leukemia, testicular angiocentric T cell lymphoma, benign lymphocytic angiitis, lupus erythematosus, Hashimoto'"'"'s thyroiditis, primary myxedema, Graves'"'"' disease, pernicious anemia, autoimmune atrophic gastritis, Addison'"'"'s disease, insulin dependent diabetes mellitis, good pasture'"'"'s syndrome, myasthenia gravis, pemphigus, Crohn'"'"'s disease, sympathetic ophthalmia, autoimmune uveitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren'"'"'s syndrome, rheumatic disease, rheumatoid arthritis, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra-articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, systemic lupus erythematosus, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis and chondrocalcinosis, by administering to a subject an effective amount of a soluble CTLA4 molecule comprising the sequence shown in FIG. 19 (SEQ ID NO:

9) beginning with methionine at position +1 or with alanine at position −

1 and ending with aspartic acid at position +124, and wherein the effective amount is about 0.1 to 100 mg/kg weight of the subject, about 0.5 to 5 mg/kg weight of a subject, about 5 to 10 mg/kg weight of a subject, about 10 to 15 mg/kg weight of a subject, about 15 to 20 mg/kg weight of a subject, about 20 to 25 mg/kg weight of a subject, about 25 to 30 mg/kg weight of a subject, about 30 to 35 mg/kg weight of a subject, about 35 to 40 mg/kg weight of a subject, about 40 to 45 mg/kg weight of a subject, about 45 to 50 mg/kg weight of a subject, about 50 to 55 mg/kg weight of a subject, about 55 to 60 mg/kg weight of a subject, about 60 to 65 mg/kg weight of a subject, about 65 to 70 mg/kg weight of a subject, about 70 to 75 mg/kg weight of a subject, about 75 to 80 mg/kg weight of a subject, about 80 to 85 mg/kg weight of a subject, about 85 to 90 mg/kg weight of a subject, about 90 to 95 mg/kg weight of a subject, about 95 to 100 mg/kg weight of a subject, about 2 to 10 mg/kg weight of a subject, about 0.1 to 4 mg/kg weight of a subject, about 0.1 to 0.5 mg/kg weight of a subject, about 0.5 to 1.0 mg/kg weight of a subject, about 1.0 to 1.5 mg/kg weight of a subject, about 1.5 to 2.0 mg/kg weight of a subject, about 2.0 to 2.5 mg/kg weight of a subject, about 2.5 to 3.0 mg/kg weight of a subject, about 3.0 to 3.5 mg/kg weight of a subject, about 3.5 to 4.0 mg/kg weight of a subject, about 4.0 to 4.5 mg/kg weight of a subject, about 4.5 to 5.0 mg/kg weight of a subject, about 5.0 to 5.5 mg/kg weight of a subject, about 5.5 to 6.0 mg/kg weight of a subject, about 6.0 to 6.5 mg/kg weight of a subject, about 6.5 to 7.0 mg/kg weight of a subject, about 7.0 to 7.5 mg/kg weight of a subject, about 7.5 to 8.0 mg/kg weight of a subject, about 8.0 to 8.5 mg/kg weight of a subject, about 8.5 to 9.0 mg/kg weight of a subject, about 9.0 to 9.5 mg/kg weight of a subject, about 9.5 to 10.0 mg/kg weight of a subject, about 0.1 to 2 mg/kg weight of a subject, about 2 to 4 mg/kg weight of a subject, about 4 to 6 mg/kg weight of a subject, about 6 to 8 mg/kg weight of a subject, about 8 to 10 mg/kg weight of a subject, about 10 to 12 mg/kg weight of a subject, about 12 to 14 mg/kg weight of a subject, about 14 to 16 mg/kg weight of a subject, about 16 to 18 mg/kg weight of a subject, about 18 to 20 mg/kg weight of a subject about 0.5 mg/kg weight of the subject, 2 mg/kg weight of the subject, 10 mg/kg weight of the subject, about 0.5 mg/kg to 100 weight of the subject, about 0.5 to 10 mg/kg weight of a subject, about 0.1 to 20 mg/kg weight of a subject, about 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg.

51. A method for treating a disease selected from autoimmune diseases, psoriasis, immune disorders associated with graft transplantation rejection, T cell lymphoma, T cell acute lymphoblastic leukemia, testicular angiocentric T cell lymphoma, benign lymphocytic angiitis, lupus erythematosus, Hashimoto'"'"'s thyroiditis, primary myxedema, Graves'"'"' disease, pernicious anemia, autoimmune atrophic gastritis, Addison'"'"'s disease, insulin dependent diabetes mellitis, good pasture'"'"'s syndrome, myasthenia gravis, pemphigus, Crohn'"'"'s disease, sympathetic ophthalmia, autoimmune uveitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren'"'"'s syndrome, rheumatic disease, rheumatoid arthritis, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra-articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, systemic lupus erythematosus, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis and chondrocalcinosis, by administering to a subject an effective amount of a soluble CTLA4 molecule L104EA29YIg having the sequence shown in FIG. 19 (SEQ ID NO:

9) beginning with methionine at position +1 or with alanine at position −

1 and ending with lysine as position +357, and wherein the effective amount is about 0.1 to 100 mg/kg weight of the subject, about 0.5 to 5 mg/kg weight of a subject, about 5 to 10 mg/kg weight of a subject, about 10 to 15 mg/kg weight of a subject, about 15 to 20 mg/kg weight of a subject, about 20 to 25 mg/kg weight of a subject, about 25 to 30 mg/kg weight of a subject, about 30 to 35 mg/kg weight of a subject, about 35 to 40 mg/kg weight of a subject, about 40 to 45 mg/kg weight of a subject, about 45 to 50 mg/kg weight of a subject, about 50 to 55 mg/kg weight of a subject, about 55 to 60 mg/kg weight of a subject, about 60 to 65 mg/kg weight of a subject, about 65 to 70 mg/kg weight of a subject, about 70 to 75 mg/kg weight of a subject, about 75 to 80 mg/kg weight of a subject, about 80 to 85 mg/kg weight of a subject, about 85 to 90 mg/kg weight of a subject, about 90 to 95 mg/kg weight of a subject, about 95 to 100 mg/kg weight of a subject, about 2 to 10 mg/kg weight of a subject, about 0.1 to 4 mg/kg weight of a subject, about 0.1 to 0.5 mg/kg weight of a subject, about 0.5 to 1.0 mg/kg weight of a subject, about 1.0 to 1.5 mg/kg weight of a subject, about 1.5 to 2.0 mg/kg weight of a subject, about 2.0 to 2.5 mg/kg weight of a subject, about 2.5 to 3.0 mg/kg weight of a subject, about 3.0 to 3.5 mg/kg weight of a subject, about 3.5 to 4.0 mg/kg weight of a subject, about 4.0 to 4.5 mg/kg weight of a subject, about 4.5 to 5.0 mg/kg weight of a subject, about 5.0 to 5.5 mg/kg weight of a subject, about 5.5 to 6.0 mg/kg weight of a subject, about 6.0 to 6.5 mg/kg weight of a subject, about 6.5 to 7.0 mg/kg weight of a subject, about 7.0 to 7.5 mg/kg weight of a subject, about 7.5 to 8.0 mg/kg weight of a subject, about 8.0 to 8.5 mg/kg weight of a subject, about 8.5 to 9.0 mg/kg weight of a subject, about 9.0 to 9.5 mg/kg weight of a subject, about 9.5 to 10.0 mg/kg weight of a subject, about 0.1 to 2 mg/kg weight of a subject, about 2 to 4 mg/kg weight of a subject, about 4 to 6 mg/kg weight of a subject, about 6 to 8 mg/kg weight of a subject, about 8 to 10 mg/kg weight of a subject, about 10 to 12 mg/kg weight of a subject, about 12 to 14 mg/kg weight of a subject, about 14 to 16 mg/kg weight of a subject, about 16 to 18 mg/kg weight of a subject, about 18 to 20 mg/kg weight of a subject, about 0.5 mg/kg weight of the subject, 2 mg/kg weight of the subject, 10 mg/kg weight of the subject, about 0.5 mg/kg to 100 weight of the subject, about 0.5 to 10 mg/kg weight of a subject, about 0.1 to 20 mg/kg weight of a subject, about 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg.

52. A method for treating a disease selected from graft related disorders, chronic rejection, tissue or cell allo- or xenografts, skin allo- or xenografts, islet allo- or xenografts, muscle allo- or xenografts, hepatocyte allo- or xenografts and neuron allo- or xenografts, by administering to a subject an effective amount of a soluble CTLA4 molecule comprising the sequence shown in FIG. 19 (SEQ ID NO:

9) beginning with methionine at position +1 or with alanine at position −

1 and ending with aspartic acid at position +124, and wherein the effective amount is about 0.1 to 100 mg/kg weight of the subject, about 0.5 to 5 mg/kg weight of a subject, about 5 to 10 mg/kg weight of a subject, about 10 to 15 mg/kg weight of a subject, about 15 to 20 mg/kg weight of a subject, about 20 to 25 mg/kg weight of a subject, about 25 to 30 mg/kg weight of a subject, about 30 to 35 mg/kg weight of a subject, about 35 to 40 mg/kg weight of a subject, about 40 to 45 mg/kg weight of a subject, about 45 to 50 mg/kg weight of a subject, about 50 to 55 mg/kg weight of a subject, about 55 to 60 mg/kg weight of a subject, about 60 to 65 mg/kg weight of a subject, about 65 to 70 mg/kg weight of a subject, about 70 to 75 mg/kg weight of a subject, about 75 to 80 mg/kg weight of a subject, about 80 to 85 mg/kg weight of a subject, about 85 to 90 mg/kg weight of a subject, about 90 to 95 mg/kg weight of a subject, about 95 to 100 mg/kg weight of a subject, about 2 to 10 mg/kg weight of a subject, about 0.1 to 4 mg/kg weight of a subject, about 0.1 to 0.5 mg/kg weight of a subject, about 0.5 to 1.0 mg/kg weight of a subject, about 1.0 to 1.5 mg/kg weight of a subject, about 1.5 to 2.0 mg/kg weight of a subject, about 2.0 to 2.5 mg/kg weight of a subject, about 2.5 to 3.0 mg/kg weight of a subject, about 3.0 to 3.5 mg/kg weight of a subject, about 3.5 to 4.0 mg/kg about 4.0 to 4.5 mg/kg weight of a subject, about 4.5 to 5.0 mg/kg weight of a subject, about 5.0 to 5.5 mg/kg weight of a subject, about 5.5 to 6.0 mg/kg weight of a subject, about 6.0 to 6.5 mg/kg weight of a subject, about 6.5 to 7.0 mg/kg weight of a subject, about 7.0 to 7.5 mg/kg weight of a subject, about 7.5 to 8.0 mg/kg weight of a subject, about 8.0 to 8.5 mg/kg weight of a subject, about 8.5 to 9.0 mg/kg weight of a subject, about 9.0 to 9.5 mg/kg weight of a subject, about 9.5 to 10.0 mg/kg weight of a subject, weight of a subject, about 0.1 to 2 mg/kg weight of a subject, about 2 to 4 mg/kg weight of a subject, about 4 to 6 mg/kg weight of a subject, about 6 to 8 mg/kg weight of a subject, about 8 to 10 mg/kg weight of a subject, about 10 to 12 mg/kg weight of a subject, about 12 to 14 mg/kg weight of a subject, about 14 to 16 mg/kg weight of a subject, about 16 to 18 mg/kg weight of a subject, about 18 to 20 mg/kg weight of a subject, about 0.5 mg/kg weight of the subject, 2 mg/kg weight of the subject, 10 mg/kg weight of the subject, about 0.5 mg/kg to 100 weight of the subject, about 0.5 to 10 mg/kg weight of a subject, about 0.1 to 20 mg/kg weight of a subject, about 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg.

53. A method for treating a disease selected from graft related disorders, chronic rejection, tissue or cell allo- or xenografts, skin allo- or xenografts, islet allo- or xenografts, muscle allo- or xenografts, hepatocyte allo- or xenografts and neuron allo- or xenografts, by administering to a subject an effective amount of a soluble CTLA4 molecule L104EA29YIg having the sequence shown in FIG. 19 (SEQ ID NO:

9) beginning with methionine at position +1 or with alanine at position −

1 and ending with lysine as position +357, and wherein the effective amount is about 0.1 to 100 mg/kg weight of the subject, about 0.5 to 5 mg/kg weight of a subject, about 5 to 10 mg/kg weight of a subject, about 10 to 15 mg/kg weight of a subject, about 15 to 20 mg/kg weight of a subject, about 20 to 25 mg/kg weight of a subject, about 25 to 30 mg/kg weight of a subject, about 30 to 35 mg/kg weight of a subject, about 35 to 40 mg/kg weight of a subject, about 40 to 45 mg/kg weight of a subject, about 45 to 50 mg/kg weight of a subject, about 50 to 55 mg/kg weight of a subject, about 55 to 60 mg/kg weight of a subject, about 60 to 65 mg/kg weight of a subject, about 65 to 70 mg/kg weight of a subject, about 70 to 75 mg/kg weight of a subject, about 75 to 80 mg/kg weight of a subject, about 80 to 85 mg/kg weight of a subject, about 85 to 90 mg/kg weight of a subject, about 90 to 95 mg/kg weight of a subject, about 95 to 100 mg/kg weight of a subject, about 2 to 10 mg/kg weight of a subject, about 0.1 to 4 mg/kg weight of a subject, about 0.1 to 0.5 mg/kg weight of a subject, about 0.5 to 1.0 mg/kg weight of a subject, about 1.0 to 1.5 mg/kg weight of a subject, about 1.5 to 2.0 mg/kg weight of a subject, about 2.0 to 2.5 mg/kg weight of a subject, about 2.5 to 3.0 mg/kg weight of a subject, about 3.0 to 3.5 mg/kg weight of a subject, about 3.5 to 4.0 mg/kg weight of a subject, about 4.0 to 4.5 mg/kg weight of a subject, about 4.5 to 5.0 mg/kg weight of a subject, about 5.0 to 5.5 mg/kg weight of a subject, about 5.5 to 6.0 mg/kg weight of a subject, about 6.0 to 6.5 mg/kg weight of a subject, about 6.5 to 7.0 mg/kg weight of a subject, about 7.0 to 7.5 mg/kg weight of a subject, about 7.5 to 8.0 mg/kg weight of a subject, about 8.0 to 8.5 mg/kg weight of a subject, about 8.5 to 9.0 mg/kg weight of a subject, about 9.0 to 9.5 mg/kg weight of a subject, about 9.5 to 10.0 mg/kg weight of a subject, about 0.9 to 2 mg/kg weight of a subject, about 2 to 4 mg/kg weight of a subject, about 4 to 6 mg/kg weight of a subject, about 6 to 8 mg/kg weight of a subject, about 8 to 10 mg/kg weight of a subject, about 10 to 12 mg/kg weight of a subject, about 12 to 14 mg/kg weight of a subject, about 14 to 16 mg/kg weight of a subject, about 16 to 18 mg/kg weight of a subject, about 18 to 20 mg/kg weight of a subject, about 0.5 mg/kg weight of the subject, 2 mg/kg weight of the subject, 10 mg/kg weight of the subject, about 0.5 mg/kg to 100 weight of the subject, about 0.5 to 10 mg/kg weight of a subject, about 0.1 to 20 mg/kg weight of a subject, about 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg.

54. A method for treating rheumatic disease comprising administering to a subject an effective amount of a soluble CTLA4 molecule L104EA29YIg having the sequence shown in FIG. 19 (SEQ ID NO:

9) beginning with methionine at position +1 or with alanine at position −

1 and ending with lysine as position +357, and wherein the effective amount is about 0.1 to 100 mg/kg weight of the subject, about 0.5 to 5 mg/kg weight of a subject, about 5 to 10 mg/kg weight of a subject, about 10 to 15 mg/kg weight of a subject, about 15 to 20 mg/kg weight of a subject, about 20 to 25 mg/kg weight of a subject, about 25 to 30 mg/kg weight of a subject, about 30 to 35 mg/kg weight of a subject, about 35 to 40 mg/kg weight of a subject, about 40 to 45 mg/kg weight of a subject, about 45 to 50 mg/kg weight of a subject, about 50 to 55 mg/kg weight of a subject, about 55 to 60 mg/kg weight of a subject, about 60 to 65 mg/kg weight of a subject, about 65 to 70 mg/kg weight of a subject, about 70 to 75 mg/kg weight of a subject, about 75 to 80 mg/kg weight of a subject, about 80 to 85 mg/kg weight of a subject, about 85 to 90 mg/kg weight of a subject, about 90 to 95 mg/kg weight of a subject, about 95 to 100 mg/kg weight of a subject, about 2 to 10 mg/kg weight of a subject, about 0.1 to 4 mg/kg weight of a subject, about 0.1 to 0.5 mg/kg weight of a subject, about 0.5 to 1.0 mg/kg weight of a subject, about 1.0 to 1.5 mg/kg weight of a subject, about 1.5 to 2.0 mg/kg weight of a subject, about 2.0 to 2.5 mg/kg weight of a subject, about 2.5 to 3.0 mg/kg weight of a subject, about 3.0 to 3.5 mg/kg weight of a subject, about 3.5 to 4.0 mg/kg weight of a subject, about 4.0 to 4.5 mg/kg weight of a subject, about 4.5 to 5.0 mg/kg weight of a subject, about 5.0 to 5.5 mg/kg weight of a subject, about 5.5 to 6.0 mg/kg weight of a subject, about 6.0 to 6.5 mg/kg weight of a subject, about 6.5 to 7.0 mg/kg weight of a subject, about 7.0 to 7.5 mg/kg weight of a subject, about 7.5 to 8.0 mg/kg weight of a subject, about 8.0 to 8.5 mg/kg weight of a subject, about 8.5 to 9.0 mg/kg weight of a subject, about 9.0 to 9.5 mg/kg weight of a subject, about 9.5 to 10.0 mg/kg weight of a subject, about 0.1 to 2 mg/kg weight of a subject, about 2 to 4 mg/kg weight of a subject, about 4 to 6 mg/kg weight of a subject, about 6 to 8 mg/kg weight of a subject, about 8 to 10 mg/kg weight of a subject, about 10 to 12 mg/kg weight of a subject, about 12 to 14 mg/kg weight of a subject, about 14 to 16 mg/kg weight of a subject, about 16 to 18 mg/kg weight of a subject, about 18 to 20 mg/kg weight of a subject, about 0.5 mg/kg weight of the subject, 2 mg/kg weight of the subject, 10 mg/kg weight of the subject, about 0.5 mg/kg to 100 weight of the subject, about 0.5 to 10 mg/kg weight of a subject, about 0.1 to 20 mg/kg weight of a subject, about 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg.

64. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a first agent and a second agent, wherein

a) the first agent is soluble CTLA4, and

b) the second agent is selected from a group consisting of immunosuppressive agents, corticosteroids, nonsteroidal antiinflammatory drugs, prednisone, azathioprine, methotrexate, TNFα

blockers or antagonists, infliximab, any biological agent targeting an inflammatory cytokine, hydroxychloroquine, sulphasalazopryine, gold salts, etanercept, anakinra, cyclophosphamide, leflunomide, collagen, dnaJ, a molecule that blocks TNF receptors, pegsunercept, a molecule that blocks cytokine function, AMG719, a molecule that blocks LFA-1 function, efalizumab, acetyl salicylic acid, choline magnesium salicylate, diflunisal, magnesium salicylate, salsalate, sodium salicylate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, nabumetone, phenylbutazone, piroxicam, sulindac, tolmetin, acetaminophen, ibuprofen, Cox-2 inhibitors, meloxicam, codeine phosphate, propoxyphene napsylate, oxycodone hydrochloride, oxycodone bitartrate and tramadol.

65. The pharmaceutical composition of claim 64, wherein the soluble CTLA4 comprises the extracellular domain of a CTLA4 molecule, or portion thereof, which binds a B7 antigen expressed on activated B cells.

66. The pharmaceutical composition of claim 64, wherein the soluble CTLA4 is a CTLA4 fusion molecule.

67. The pharmaceutical composition of claim 66, wherein the CTLA4 fusion molecule comprises an extracellular domain of a CTLA4 molecule which binds a B7 antigen expressed on activated B cells joined to a non-CTLA4 molecule.

68. The pharmaceutical composition of claim 64, wherein the soluble CTLA4 is a soluble CTLA4 mutant molecule.

69. The pharmaceutical composition of claim 68, wherein the soluble CTLA4 mutant molecule comprises an extracellular domain of CTLA4,

a) wherein the extracellular domain of CTLA4 begins with methionine at position +1 or with alanine at position −

1 and ends with aspartic acid at position +124 as shown in FIG. 23 or 24 (SEQ ID NO;

17 or

     19), and

b) wherein at position +104 of the extracellular domain of CTLA4, leucine is substituted with any other amino acid.

70. The pharmaceutical composition of claim 68, wherein the soluble CTLA4 mutant molecule comprises an extracellular domain of CTLA4,

a) wherein the extracellular domain of CTLA4 begins with methionine at position +1 or with alanine at position −

1 and ends with aspartic acid at position +124 as shown in FIG. 23 or 24 (SEQ ID NO;

17 or

     19),

b) wherein at position +104 of the extracellular domain of CTLA4, leucine is substituted with glutamic acid, and

c) wherein at position +29 of the extracellular domain of CTLA4, alanine is substituted with tyrosine.

71. The pharmaceutical composition of claim 68, wherein the soluble CTLA4 mutant molecule is L104EA29YIg as shown in FIG. 19 (SEQ ID NO:

9), beginning with methionine at position +1 or with alanine at position −

1 and ending with lysine at position +357.

72. The pharmaceutical composition of claim 64, wherein the pharmaceutically acceptable carrier is selected ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, phosphate buffered saline solution, water, emulsions, salts or electrolytes, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sterile solutions, tablets, excipients, sucrose, glucose, maltose, flavor and color additives, lipid compositions and polymeric compositions.

94. Use of a kit comprising the pharmaceutical composition of claim 68, a container and a label.

73. Combination of a pharmaceutical composition comprising a soluble CTLA4 with a pharmaceutical composition comprising an agent selected from a group consisting of immunosuppressive agents, corticosteroids, nonsteroidal antiinflammatory drugs, prednisone, azathioprine, methotrexate, TNFα

blockers or antagonists, infliximab, any biological agent targeting an inflammatory cytokine, hydroxychloroquine, sulphasalazopryine, gold salts, etanercept, anakinra, cyclophosphamide, leflunomide, collagen, dnaJ, a molecule that blocks TNF receptors, pegsunercept, a molecule that blocks cytokine function, AMG719, a molecule that blocks LFA-1 function, efalizumab, acetyl salicylic acid, choline magnesium salicylate, diflunisal, magnesium salicylate, salsalate, sodium salicylate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, nabumetone, phenylbutazone, piroxicam, sulindac, tolmetin, acetaminophen, ibuprofen, Cox-2 inhibitors, meloxicam, codeine phosphate, propoxyphene napsylate, oxycodone hydrochloride, oxycodone bitartrate and tramadol, for use in therapy.

74. A kit comprising an effective amount of a first agent and a second agent, wherein

a) the first agent is soluble CTLA4, and

b) the second agent is selected from a group consisting of immunosuppressive agents, corticosteroids, nonsteroidal antiinflammatory drugs, prednisone, azathioprine, methotrexate, TNFα

blockers or antagonists, infliximab, any biological agent targeting an inflammatory cytokine, hydroxychloroquine, sulphasalazopryine, gold salts, etanercept, anakinra, cyclophosphamide, leflunomide, corticosteroids, nonsteroidal antiinflammatory drugs, prednisone, azathioprine, methotrexate, TNFα

blockers or antagonists, infliximab, any biological agent targeting an inflammatory cytokine, hydroxychloroquine, sulphasalazopryine, gold salts, etanercept, anakinra, cyclophosphamide, leflunomide, collagen, dnaJ, a molecule that blocks TNF receptors, pegsunercept, a molecule that blocks cytokine function, AMG719, a molecule that blocks LFA-1 function, efalizumab, acetyl salicylic acid, choline magnesium salicylate, diflunisal, magnesium salicylate, salsalate, sodium salicylate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, nabumetone, phenylbutazone, piroxicam, sulindac, tolmetin, acetaminophen, ibuprofen, Cox-2 inhibitors, meloxicam, codeine phosphate, propoxyphene napsylate, oxycodone hydrochloride, oxycodone bitartrate and tramadol.

75. The kit of claim 74, further comprising a label indicating that the first and second agents are useful to treat an immune system disease.

76. The kit of claim 75, wherein the label indicates an effective amount for the first agent being about 0.1 to 100 mg/kg weight of the subject, about 0.5 to 5 mg/kg weight of a subject, about 5 to 10 mg/kg weight of a subject, about 10 to 15 mg/kg weight of a subject, about 15 to 20 mg/kg weight of a subject, about 20 to 25 mg/kg weight of a subject, about 25 to 30 mg/kg weight of a subject, about 30 to 35 mg/kg weight of a subject, about 35 to 40 mg/kg weight of a subject, about 40 to 45 mg/kg weight of a subject, about 45 to 50 mg/kg weight of a subject, about 50 to 55 mg/kg weight of a subject, about 55 to 60 mg/kg weight of a subject, about 60 to 65 mg/kg weight of a subject, about 65 to 70 mg/kg weight of a subject, about 70 to 75 mg/kg weight of a subject, about 75 to 80 mg/kg weight of a subject, about 80 to 85 mg/kg weight of a subject, about 85 to 90 mg/kg weight of a subject, about 90 to 95 mg/kg weight of a subject, about 95 to 100 mg/kg weight of a subject, about 2 to 10 mg/kg weight of a subject, about 0.1 to 4 mg/kg weight of a subject, about 0.1 to 0.5 mg/kg weight of a subject, about 0.5 to 1.0 mg/kg weight of a subject, about 1.0 to 1.5 mg/kg weight of a subject, about 1.5 to 2.0 mg/kg weight of a subject, about 2.0 to 2.5 mg/kg weight of a subject, about 2.5 to 3.0 mg/kg weight of a subject, about 3.0 to 3.5 mg/kg weight of a subject, about 3.5 to 4.0 mg/kg weight of a subject, about 4.0 to 4.5 mg/kg weight of a subject, about 4.5 to 5.0 mg/kg weight of a subject, about 5.0 to 5.5 mg/kg weight of a subject, about 5.5 to 6.0 mg/kg weight of a subject, about 6.0 to 6.5 mg/kg weight of a subject, about 6.5 to 7.0 mg/kg weight of a subject, about 7.0 to 7.5 mg/kg weight of a subject, about 7.5 to 8.0 mg/kg weight of a subject, about 8.0 to 8.5 mg/kg weight of a subject, about 8.5 to 9.0 mg/kg weight of a subject, about 9.0 to 9.5 mg/kg weight of a subject, about 9.5 to 10.0 mg/kg weight of a subject, about 0.1 to 2 mg/kg weight of a subject, about 2 to 4 mg/kg weight of a subject, about 4 to 6 mg/kg weight of a subject, about 6 to 8 mg/kg weight of a subject, about 8 to 10 mg/kg weight of a subject, about 10 to 12 mg/kg weight of a subject, about 12 to 14 mg/kg weight of a subject, about 14 to 16 mg/kg weight of a subject, about 16 to 18 mg/kg weight of a subject, about 18 to 20 mg/kg weight of a subject, about 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg.

77. The kit of claim 75, wherein the label indicates an effective amount for the second agent being about 0.1 to 40 mg per week, about 5 to 30 mg per week, about 0.1 to 5 mg/week, about 5 to 10 mg/week, about 10 to 15 mg/week, about 15 to 20 mg/week, about 20 to 25 mg/week, about 25 to 30 mg/week, about 30 to 35 mg/week, about 35 to 40 mg/week, about 10 to 30 mg/week, about 10 to 100 mg/week, about 50 mg/week, about 0.1 to 50 mg/kg body weight per week, about 1 to about 5000 mg/day, about 1 to 10 mg/day, about 10 to 50 mg/day, about 50 to 100 mg/day, about 100 to 150 mg/day, about 150 to 200 mg/day, about 200 to 250 mg/day, about 250 to 300 mg/day, about 300 to 350 mg/day, about 350 to 400 mg/day, about 400 to 450 mg/day, about 450 to 500 mg/day, about 500 to 550 mg/day, about 550 to 600 mg/day, about 600 to 650 mg/day, about 650 to 700 mg/day, about 700 to 750 mg/day, about 750 to 800 mg/day, about 800 to 850 mg/day, about 850 to 900 mg/day, about 900 to 950 mg/day, about 950 to 1000 mg/day, about 1000 to 1100 mg/day, about 1100 to 1200 mg/day, about 1200 to 1300 mg/day, about 1300 to 1400 mg/day, about 1400 to 1500 mg/day, about 1500 to 1600 mg/day, about 1600 to 1700 mg/day, about 1700 to 1800 mg/day, about 1800 to 1900 mg/day, about 1900 to 2000 mg/day, about 2000 to 2500 mg/day, about 2500 to 3000 mg/day, about 3000 to 3500 mg/day, about 3500 to 4000 mg/day, about 4000 to 4500 mg/day or about 4500 to 5000 mg/day.

78. The kit of claim 75, wherein the label indicates an effective amount for the first and second agent

a. the effective amount of the first agent being about 0.1 to 100 mg/kg weight of the subject, about 0.5 to 5 mg/kg weight of a subject, about 5 to 10 mg/kg weight of a subject, about 10 to 15 mg/kg weight of a subject, about 15 to 20 mg/kg weight of a subject, about 20 to 25 mg/kg weight of a subject, about 25 to 30 mg/kg weight of a subject, about 30 to 35 mg/kg weight of a subject, about 35 to 40 mg/kg weight of a subject, about 40 to 45 mg/kg weight of a subject, about 45 to 50 mg/kg weight of a subject, about 50 to 55 mg/kg weight of a subject, about 55 to 60 mg/kg weight of a subject, about 60 to 65 mg/kg weight of a subject, about 65 to 70 mg/kg weight of a subject, about 70 to 75 mg/kg weight of a subject, about 75 to 80 mg/kg weight of a subject, about 80 to 85 mg/kg weight of a subject, about 85 to 90 mg/kg weight of a subject, about 90 to 95 mg/kg weight of a subject, about 95 to 100 mg/kg weight of a subject, about 2 to 10 mg/kg weight of a subject, about 0.1 to 4 mg/kg weight of a subject, about 0.1 to 0.5 mg/kg weight of a subject, about 0.5 to 1.0 mg/kg weight of a subject, about 1.0 to 1.5 mg/kg weight of a subject, about 1.5 to 2.0 mg/kg weight of a subject, about 2.0 to 2.5 mg/kg weight of a subject, about 2.5 to 3.0 mg/kg weight of a subject, about 3.0 to 3.5 mg/kg weight of a subject, about 3.5 to 4.0 mg/kg weight of a subject, about 4.0 to 4.5 mg/kg weight of a subject, about 4.5 to 5.0 mg/kg weight of a subject, about 5.0 to 5.5 mg/kg weight of a subject, about 5.5 to 6.0 mg/kg weight of a subject, about 6.0 to 6.5 mg/kg weight of a subject, about 6.5 to 7.0 mg/kg weight of a subject, about 7.0 to 7.5 mg/kg weight of a subject, about 7.5 to 8.0 mg/kg weight of a subject, about 8.0 to 8.5 mg/kg weight of a subject, about 8.5 to 9.0 mg/kg weight of a subject, about 9.0 to 9.5 mg/kg weight of a subject, about 9.5 to 10.0 mg/kg weight of a subject, about 0.1 to 2 mg/kg weight of a subject, about 2 to 4 mg/kg weight of a subject, about 4 to 6 mg/kg weight of a subject, about 6 to 8 mg/kg weight of a subject, about 8 to 10 mg/kg weight of a subject, about 10 to 12 mg/kg weight of a subject, about 12 to 14 mg/kg weight of a subject, about 14 to 16 mg/kg weight of a subject, about 16 to 18 mg/kg weight of a subject, about 18 to 20 mg/kg weight of a subject, about 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg, and

b. the effective amount of the second agent is about 0.1 to 40 mg per week, about 5 to 30 mg per week, about 0.1 to 5 mg/week, about 5 to 10 mg/week, about 10 to 15 mg/week, about 15 to 20 mg/week, about 20 to 25 mg/week, about 25 to 30 mg/week, about 30 to 35 mg/week, about 35 to 40 mg/week, about 10 to 30 mg/week, about 10 to 100 mg/week, about 50 mg/week, about 0.1 to 50 mg/kg body weight per week, about 1 to about 5000 mg/day, about 1 to 10 mg/day, about 10 to 50 mg/day, about 50 to 100 mg/day, about 100 to 150 mg/day, about 150 to 200 mg/day, about 200 to 250 mg/day, about 250 to 300 mg/day, about 300 to 350 mg/day, about 350 to 400 mg/day, about 400 to 450 mg/day, about 450 to 500 mg/day, about 500 to 550 mg/day, about 550 to 600 mg/day, about 600 to 650 mg/day, about 650 to 700 mg/day, about 700 to 750 mg/day, about 750 to 800 mg/day, about 800 to 850 mg/day, about 850 to 900 mg/day, about 900 to 950 mg/day, about 950 to 1000 mg/day, about 1000 to 1100 mg/day, about 1100 to 1200 mg/day, about 1200 to 1300 mg/day, about 1300 to 1400 mg/day, about 1400 to 1500 mg/day, about 1500 to 1600 mg/day, about 1600 to 1700 mg/day, about 1700 to 1800 mg/day, about 1800 to 1900 mg/day, about 1900 to 2000 mg/day, about 2000 to 2500 mg/day, about 2500 to 3000 mg/day, about 3000 to 3500 mg/day, about 3500 to 4000 mg/day, about 4000 to 4500 mg/day or about 4500 to 5000 mg/day.

79. The kit of claim 75, wherein the immune system disease is selected from autoimmune diseases, psoriasis, immune disorders associated with graft transplantation rejection, T cell lymphoma, T cell acute lymphoblastic leukemia, testicular angiocentric T cell lymphoma, benign lymphocytic angiitis, lupus erythematosus, Hashimoto'"'"'s thyroiditis, primary myxedema, Graves'"'"' disease, pernicious anemia, autoimmune atrophic gastritis, Addison'"'"'s disease, insulin dependent diabetes mellitis, good pasture'"'"'s syndrome, myasthenia gravis, pemphigus, Crohn'"'"'s disease, sympathetic ophthalmia, autoimmune uveitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren'"'"'s syndrome, rheumatic disease, rheumatoid arthritis, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra-articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, systemic lupus erythematosus, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis and chondrocalcinosis.

80. The kit of claim 74, further comprising a container.

81. The kit of claim 74, wherein the soluble CTLA4 comprises the extracellular domain of a CTLA4 molecule, or portion thereof, which binds a B7 antigen expressed on activated B cells.

82. The kit of claim 74, wherein the soluble CTLA4 comprises the extracellular domain of a CTLA4 molecule as shown in FIG. 23 (SEQ ID NO:

17) beginning with methionine at position +1 or with alanine at position −

1 and ending with aspartic acid at position +124.

83. The kit of claim 74, wherein the soluble CTLA4 is a CTLA4 fusion molecule.

84. The kit of claim 83, wherein the CTLA4 fusion molecule comprises an extracellular domain of a CTLA4 molecule which binds a B7 antigen expressed on activated B cells joined to a non-CTLA4 molecule.

85. The kit of claim 84, wherein the non-CTLA4 molecule comprises an amino acid sequence which alters the solubility or affinity which comprises an immunoglobulin moiety.

86. The kit of claim 85, wherein the immunoglubulin moiety is an immunoglubulin constant region or portion thereof.

87. The kit of claim 86, wherein the immunoglubulin constant region or portion thereof is mutated to reduce effector function.

88. The kit of claim 83, wherein the CTLA4 fusion molecule is CTLA4Ig.

89. The kit of claim 88, wherein the CTLA4Ig is shown in FIG. 24 (SEQ ID NO:

19) beginning with methionine at position +1 or with alanine at position −

1 and ending with lysine at position +357.

90. The kit of claim 74, wherein the soluble CTLA4 is a soluble CTLA4 mutant molecule.

91. The kit of claim 90, wherein the soluble CTLA4 mutant molecule comprises an extracellular domain of CTLA4,

a) wherein the extracellular domain of CTLA4 begins with methionine at position +1 or with alanine at position −

1 and ends with aspartic acid at position +124 as shown in FIG. 23 or 24 (SEQ ID NO;

17 or

     19), and

b) wherein at position +104 of the extracellular domain of CTLA4, leucine is substituted with any other amino acid.

92. The kit of claim 90, wherein the soluble CTLA4 mutant molecule comprises an extracellular domain of CTLA4,

a) wherein the extracellular domain of CTLA4 begins with methionine at position +1 or with alanine at position −

1 and ends with aspartic acid at position +124 as shown in FIG. 23 or 24 (SEQ ID NO;

17 or

     19),

b) wherein at position +104 of the extracellular domain of CTLA4, leucine is substituted with glutamic acid, and

c) wherein at position +29 of the extracellular domain of CTLA4, alanine is substituted with tyrosine.

93. The kit of claim 90, wherein the soluble CTLA4 mutant molecule is L104EA29YIg as shown in FIG. 19 (SEQ. ID NO:

9) beginning with methionine at position +1 or with alanine at position −

1 and ending with lysine at position +357 as shown in FIG. 19 (SEQ ID NO;

     9).

95. A kit comprising an effective amount of a first agent and a label, wherein

a) the first agent is soluble CTLA4, and

b) the label indicates that the first agent can be used with a second agent selected from a group consisting of immunosuppressive agents, corticosteroids, nonsteroidal antiinflammatory drugs, prednisone, azathioprine, methotrexate, TNFα

blockers or antagonists, infliximab, any biological agent targeting an inflammatory cytokine, hydroxychloroquine, sulphasalazopryine, gold salts, etanercept, anakinra, cyclophosphamide, leflunomide, collagen, dnaJ, a molecule that blocks TNF receptors, pegsunercept, a molecule that blocks cytokine function, AMG719, a molecule that blocks LFA-1 function, efalizumab, acetyl salicylic acid, choline magnesium salicylate, diflunisal, magnesium salicylate, salsalate, sodium salicylate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, nabumetone, phenylbutazone, piroxicam, sulindac, tolmetin, acetaminophen, ibuprofen, Cox-2 inhibitors, meloxicam, codeine phosphate, propoxyphene napsylate, oxycodone hydrochloride, oxycodone bitartrate and tramadol.

96. The kit of claim 95, wherein the label further indicates an effective amount for the first agent being about 0.1 to 100 mg/kg weight of the subject, about 0.5 to 5 mg/kg weight of a subject, about 5 to 10 mg/kg weight of a subject, about 10 to 15 mg/kg weight of a subject, about 15 to 20 mg/kg weight of a subject, about 20 to 25 mg/kg weight of a subject, about 25 to 30 mg/kg weight of a subject, about 30 to 35 mg/kg weight of a subject, about 35 to 40 mg/kg weight of a subject, about 40 to 45 mg/kg weight of a subject, about 45 to 50 mg/kg weight of a subject, about 50 to 55 mg/kg weight of a subject, about 55 to 60 mg/kg weight of a subject, about 60 to 65 mg/kg weight of a subject, about 65 to 70 mg/kg weight of a subject, about 70 to 75 mg/kg weight of a subject, about 75 to 80 mg/kg weight of a subject, about 80 to 85 mg/kg weight of a subject, about 85 to 90 mg/kg weight of a subject, about 90 to 95 mg/kg weight of a subject, about 95 to 100 mg/kg weight of a subject, about 2 to 10 mg/kg weight of a subject, about 0.1 to 4 mg/kg weight of a subject, about 0.1 to 0.5 mg/kg weight of a subject, about 0.5 to 1.0 mg/kg weight of a subject, about 1.0 to 1.5 mg/kg weight of a subject, about 1.5 to 2.0 mg/kg weight of a subject, about 2.0 to 2.5 mg/kg weight of a subject, about 2.5 to 3.0 mg/kg weight of a subject, about 3.0 to 3.5 mg/kg weight of a subject, about 3.5 to 4.0 mg/kg weight of a subject, about 4.0 to 4.5 mg/kg weight of a subject, about 4.5 to 5.0 mg/kg weight of a subject, about 5.0 to 5.5 mg/kg weight of a subject, about 5.5 to 6.0 mg/kg weight of a subject, about 6.0 to 6.5 mg/kg weight of a subject, about 6.5 to 7.0 mg/kg weight of a subject, about 7.0 to 7.5 mg/kg weight of a subject, about 7.5 to 8.0 mg/kg weight of a subject, about 8.0 to 8.5 mg/kg weight of a subject, about 8.5 to 9.0 mg/kg weight of a subject, about 9.0 to 9.5 mg/kg weight of a subject, about 9.5 to 10.0 mg/kg weight of a subject, about 0.1 to 2 mg/kg weight of a subject, about 2 to 4 mg/kg weight of a subject, about 4 to 6 mg/kg weight of a subject, about 6 to 8 mg/kg weight of a subject, about 8 to 10 mg/kg weight of a subject, about 10 to 12 mg/kg weight of a subject, about 12 to 14 mg/kg weight of a subject, about 14 to 16 mg/kg weight of a subject, about 16 to 18 mg/kg weight of a subject, about 18 to 20 mg/kg weight of a subject, about 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg.

97. The kit of claim 95, wherein the label indicates an effective amount for the second agent being about 0.1 to 40 mg per week, about 5 to 30 mg per week, about 0.1 to 5 mg/week, about 5 to 10 mg/week, about 10 to 15 mg/week, about 15 to 20 mg/week, about 20 to 25 mg/week, about 25 to 30 mg/week, about 30 to 35 mg/week, about 35 to 40 mg/week, about 10 to 30 mg/week, about 10 to 100 mg/week, about 50 mg/week, about 0.1 to 50 mg/kg body weight per week, about 1 to about 5000 mg/day, about 1 to 10 mg/day, about 10 to 50 mg/day, about 50 to 100 mg/day, about 100 to 150 mg/day, about 150 to 200 mg/day, about 200 to 250 mg/day, about 250 to 300 mg/day, about 300 to 350 mg/day, about 350 to 400 mg/day, about 400 to 450 mg/day, about 450 to 500 mg/day, about 500 to 550 mg/day, about 550 to 600 mg/day, about 600 to 650 mg/day, about 650 to 700 mg/day, about 700 to 750 mg/day, about 750 to 800 mg/day, about 800 to 850 mg/day, about 850 to 900 mg/day, about 900 to 950 mg/day, about 950 to 1000 mg/day, about 1000 to 1100 mg/day, about 1100 to 1200 mg/day, about 1200 to 1300 mg/day, about 1300 to 1400 mg/day, about 1400 to 1500 mg/day, about 1500 to 1600 mg/day, about 1600 to 1700 mg/day, about 1700 to 1800 mg/day, about 1800 to 1900 mg/day, about 1900 to 2000 mg/day, about 2000 to 2500 mg/day, about 2500 to 3000 mg/day, about 3000 to 3500 mg/day, about 3500 to 4000 mg/day, about 4000 to 4500 mg/day or about 4500 to 5000 mg/day.

98. The kit of claim 95, wherein the label indicates an effective amount for the first and second agent,

a. wherein the effective amount of the first agent being about 0.1 to 100 mg/kg weight of the subject, about 0.5 to 5 mg/kg weight of a subject, about 5 to 10 mg/kg weight of a subject, about 10 to 15 mg/kg weight of a subject, about 15 to 20 mg/kg weight of a subject, about 20 to 25 mg/kg weight of a subject, about 25 to 30 mg/kg weight of a subject, about 30 to 35 mg/kg weight of a subject, about 35 to 40 mg/kg weight of a subject, about 40 to 45 mg/kg weight of a subject, about 45 to 50 mg/kg weight of a subject, about 50 to 55 mg/kg weight of a subject, about 55 to 60 mg/kg weight of a subject, about 60 to 65 mg/kg weight of a subject, about 65 to 70 mg/kg weight of a subject, about 70 to 75 mg/kg weight of a subject, about 75 to 80 mg/kg weight of a subject, about 80 to 85 mg/kg weight of a subject, about 85 to 90 mg/kg weight of a subject, about 90 to 95 mg/kg weight of a subject, about 95 to 100 mg/kg weight of a subject, about 2 to 10 mg/kg weight of a subject, about 0.1 to 4 mg/kg weight of a subject, about 0.1 to 0.5 mg/kg weight of a subject, about 0.5 to 1.0 mg/kg weight of a subject, about 1.0 to 1.5 mg/kg weight of a subject, about 1.5 to 2.0 mg/kg weight of a subject, about 2.0 to 2.5 mg/kg weight of a subject, about 2.5 to 3.0 mg/kg weight of a subject, about 3.0 to 3.5 mg/kg weight of a subject, about 3.5 to 4.0 mg/kg weight of a subject, about 4.0 to 4.5 mg/kg weight of a subject, about 4.5 to 5.0 mg/kg weight of a subject, about 5.0 to 5.5 mg/kg weight of a subject, about 5.5 to 6.0 mg/kg weight of a subject, about 6.0 to 6.5 mg/kg weight of a subject, about 6.5 to 7.0 mg/kg weight of a subject, about 7.0 to 7.5 mg/kg weight of a subject, about 7.5 to 8.0 mg/kg weight of a subject, about 8.0 to 8.5 mg/kg weight of a subject, about 8.5 to 9.0 mg/kg weight of a subject, about 9.0 to 9.5 mg/kg weight of a subject, about 9.5 to 10.0 mg/kg weight of a subject, about 0.1 to 2 mg/kg weight of a subject, about 2 to 4 mg/kg weight of a subject, about 4 to 6 mg/kg weight of a subject, about 6 to 8 mg/kg weight of a subject, about 8 to 10 mg/kg weight of a subject, about 10 to 12 mg/kg weight of a subject, about 12 to 14 mg/kg weight of a subject, about 14 to 16 mg/kg weight of a subject, about 16 to 18 mg/kg weight of a subject, about 18 to 20 mg/kg weight of a subject, about 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg, and

b. wherein the effective amount of the second agent is about 0.1 to 40 mg per week, about 5 to 30 mg per week, about 0.1 to 5 mg/week, about 5 to 10 mg/week, about 10 to 15 mg/week, about 15 to 20 mg/week, about 20 to 25 mg/week, about 25 to 30 mg/week, about 30 to 35 mg/week, about 35 to 40 mg/week, about 10 to 30 mg/week, about 10 to 100 mg/week, about 50 mg/week, about 0.1 to 50 mg/kg body weight per week, about 1 to about 5000 mg/day, about 1 to 10 mg/day, about 10 to 50 mg/day, about 50 to 100 mg/day, about 100 to 150 mg/day, about 150 to 200 mg/day, about 200 to 250 mg/day, about 250 to 300 mg/day, about 300 to 350 mg/day, about 350 to 400 mg/day, about 400 to 450 mg/day, about 450 to 500 mg/day, about 500 to 550 mg/day, about 550 to 600 mg/day, about 600 to 650 mg/day, about 650 to 700 mg/day, about 700 to 750 mg/day, about 750 to 800 mg/day, about 800 to 850 mg/day, about 850 to 900 mg/day, about 900 to 950 mg/day, about 950 to 1000 mg/day, about 1000 to 1100 mg/day, about 1100 to 1200 mg/day, about 1200 to 1300 mg/day, about 1300 to 1400 mg/day, about 1400 to 1500 mg/day, about 1500 to 1600 mg/day, about 1600 to 1700 mg/day, about 1700 to 1800 mg/day, about 1800 to 1900 mg/day, about 1900 to 2000 mg/day, about 2000 to 2500 mg/day, about 2500 to 3000 mg/day, about 3000 to 3500 mg/day, about 3500 to 4000 mg/day, about 4000 to 4500 mg/day or about 4500 to 5000 mg/day.

99. The kit of claim 95, further comprising a label indicating that the first and second agents are useful to treat an immune system disease.

100. The kit of claim 99, wherein the immune system disease is selected from autoimmune diseases, psoriasis, immune disorders associated with graft transplantation rejection, T cell lymphoma, T cell acute lymphoblastic leukemia, testicular angiocentric T cell lymphoma, benign lymphocytic angiitis, lupus erythematosus, Hashimoto'"'"'s thyroiditis, primary myxedema, Graves'"'"' disease, pernicious anemia, autoimmune atrophic gastritis, Addison'"'"'s disease, insulin dependent diabetes mellitis, good pasture'"'"'s syndrome, myasthenia gravis, pemphigus, Crohn'"'"'s disease, sympathetic ophthalmia, autoimmune uveitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren'"'"'s syndrome, rheumatic disease, rheumatoid arthritis, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra-articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, systemic lupus erythematosus, progressive systemic sclerodermia, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis and chondrocalcinosis.

101. A kit comprising an effective amount of a first agent and a label, wherein

a) the first agent is soluble CTLA4, and

b) the label indicates that the first agent can be used with a second agent selected from a group consisting of immunosuppressive agents, corticosteroids, nonsteroidal antiinflammatory drugs, prednisone, azathioprine, methotrexate, TNFα

blockers or antagonists, infliximab, any biological agent targeting an inflammatory cytokine, hydroxychloroquine, sulphasalazopryine, gold salts, etanercept, anakinra, cyclophosphamide, leflunomide, collagen, dnaJ, a molecule that blocks TNF receptors, pegsunercept, a molecule that blocks cytokine function, AMG719, a molecule that blocks LFA-1 function, efalizumab, acetyl salicylic acid, choline magnesium salicylate, diflunisal, magnesium salicylate, salsalate, sodium salicylate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, nabumetone, phenylbutazone, piroxicam, sulindac, tolmetin, acetaminophen, ibuprofen, Cox-2 inhibitors, meloxicam, codeine phosphate, propoxyphene napsylate, oxycodone hydrochloride, oxycodone bitartrate and tramadol,

wherein the label further indicates an effective amount for the first agent being about 0.1 to 100 mg/kg weight of the subject, about 0.5 to 5 mg/kg weight of a subject, about 5 to 10 mg/kg weight of a subject, about 10 to 15 mg/kg weight of a subject, about 15 to 20 mg/kg weight of a subject, about 20 to 25 mg/kg weight of a subject, about 25 to 30 mg/kg weight of a subject, about 30 to 35 mg/kg weight of a subject, about 35 to 40 mg/kg weight of a subject, about 40 to 45 mg/kg weight of a subject, about 45 to 50 mg/kg weight of a subject, about 50 to 55 mg/kg weight of a subject, about 55 to 60 mg/kg weight of a subject, about 60 to 65 mg/kg weight of a subject, about 65 to 70 mg/kg weight of a subject, about 70 to 75 mg/kg weight of a subject, about 75 to 80 mg/kg weight of a subject, about 80 to 85 mg/kg weight of a subject, about 85 to 90 mg/kg weight of a subject, about 90 to 95 mg/kg weight of a subject, about 95 to 100 mg/kg weight of a subject, about 2 to 10 mg/kg weight of a subject, about 0.1 to 4 mg/kg weight of a subject, about 0.1 to 0.5 mg/kg weight of a subject, about 0.5 to 1.0 mg/kg weight of a subject, about 1.0 to 1.5 mg/kg weight of a subject, about 1.5 to 2.0 mg/kg weight of a subject, about 2.0 to 2.5 mg/kg weight of a subject, about 2.5 to 3.0 mg/kg weight of a subject, about 3.0 to 3.5 mg/kg weight of a subject, about 3.5 to 4.0 mg/kg weight of a subject, about 4.0 to 4.5 mg/kg weight of a subject, about 4.5 to 5.0 mg/kg weight of a subject, about 5.0 to 5.5 mg/kg weight of a subject, about 5.5 to 6.0 mg/kg weight of a subject, about 6.0 to 6.5 mg/kg weight of a subject, about 6.5 to 7.0 mg/kg weight of a subject, about 7.0 to 7.5 mg/kg weight of a subject, about 7.5 to 8.0 mg/kg weight of a subject, about 8.0 to 8.5 mg/kg weight of a subject, about 8.5 to 9.0 mg/kg weight of a subject, about 9.0 to 9.5 mg/kg weight of a subject, about 9.5 to 10.0 mg/kg weight of a subject, about 0.1 to 2 mg/kg weight of a subject, about 2 to 4 mg/kg weight of a subject, about 4 to 6 mg/kg weight of a subject, about 6 to 8 mg/kg weight of a subject, about 8 to 10 mg/kg weight of a subject, about 10 to 12 mg/kg weight of a subject, about 12 to 14 mg/kg weight of a subject, about 14 to 16 mg/kg weight of a subject, about 16 to 18 mg/kg weight of a subject, about 18 to 20 mg/kg weight of a subject, about 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg, and

wherein the label indicates an effective amount for the second agent being about 0.1 to 40 mg per week, about 5 to 30 mg per week, about 0.1 to 5 mg/week, about 5 to 10 mg/week, about 10 to 15 mg/week, about 15 to 20 mg/week, about 20 to 25 mg/week, about 25 to 30 mg/week, about 30 to 35 mg/week, about 35 to 40 mg/week, about 10 to 30 mg/week, about 10 to 100 mg/week, about 50 mg/week, about 0.1 to 50 mg/kg body weight per week, about 1 to about 5000 mg/day, about 1 to 10 mg/day, about 10 to 50 mg/day, about 50 to 100 mg/day, about 100 to 150 mg/day, about 150 to 200 mg/day, about 200 to 250 mg/day, about 250 to 300 mg/day, about 300 to 350 mg/day, about 350 to 400 mg/day, about 400 to 450 mg/day, about 450 to 500 mg/day, about 500 to 550 mg/day, about 550 to 600 mg/day, about 600 to 650 mg/day, about 650 to 700 mg/day, about 700 to 750 mg/day, about 750 to 800 mg/day, about 800 to 850 mg/day, about 850 to 900 mg/day, about 900 to 950 mg/day, about 950 to 1000 mg/day, about 1000 to 1100 mg/day, about 1100 to 1200 mg/day, about 1200 to 1300 mg/day, about 1300 to 1400 mg/day, about 1400 to 1500 mg/day, about 1500 to 1600 mg/day, about 1600 to 1700 mg/day, about 1700 to 1800 mg/day, about 1800 to 1900 mg/day, about 1900 to 2000 mg/day, about 2000 to 2500 mg/day, about 2500 to 3000 mg/day, about 3000 to 3500 mg/day, about 3500 to 4000 mg/day, about 4000 to 4500 mg/day or about 4500 to 5000 mg/day.

102. The kit of claim 101, wherein the label further indicates that the first and second agents are useful to treat an immune system disease selected from autoimmune diseases, psoriasis, immune disorders associated with graft transplantation rejection, T cell lymphoma, T cell acute lymphoblastic leukemia, testicular angiocentric T cell lymphoma, benign lymphocytic angiitis, lupus erythematosus, Hashimoto'"'"'s thyroiditis, primary myxedema, Graves'"'"' disease, pernicious anemia, autoimmune atrophic gastritis, Addison'"'"'s disease, insulin dependent diabetes mellitis, good pasture'"'"'s syndrome, myasthenia gravis, pemphigus, Crohn'"'"'s disease, sympathetic ophthalmia, autoimmune uveitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren'"'"'s syndrome, rheumatic disease, rheumatoid arthritis, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra-articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, systemic lupus erythematosus, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis and chondrocalcinosis.

103. The kit of claim 101, further comprising a container.

104. The kit of claim 101, wherein the soluble CTLA4 comprises the extracellular domain of a CTLA4 molecule, or portion thereof, which binds a B7 antigen expressed on activated B cells.

105. The kit of claim 101, wherein the soluble CTLA4 is a CTLA4 fusion molecule.

106. The kit of claim 105, wherein the CTLA4 fusion molecule comprises an extracellular domain of a CTLA4 molecule which binds a B7 antigen expressed on activated B cells joined to a non-CTLA4 molecule.

107. The kit of claim 106, wherein the non-CTLA4 molecule comprises an amino acid sequence which alters the solubility or affinity comprises an immunoglobulin moiety.

108. The kit of claim 107, wherein the immunoglubulin moiety is an immunoglubulin constant region or portion thereof.

109. The kit of claim 108, wherein the immunoglubulin constant region or portion thereof is mutated to reduce effector function.

110. The kit of claim 105, wherein the CTLA4 fusion molecule is CTLA4Ig.

111. The kit of claim 110, wherein the CTLA4Ig is shown in FIG. 24 (SEQ ID NO:

19) beginning with methionine at position +1 or with alanine at position −

1 and ending with lysine at position +357.

112. The kit of claim 101, wherein the soluble CTLA4 is a soluble CTLA4 mutant molecule.

113. The kit of claim 112, wherein the soluble CTLA4 mutant molecule comprises an extracellular domain of CTLA4,

a) wherein the extracellular domain of CTLA4 begins with methionine at position +1 or with alanine at position −

1 and ends with aspartic acid at position +124 as shown in FIG. 23 or 24 (SEQ ID NO;

17 or

     19), and

b) wherein at position +104 of the extracellular domain of CTLA4, leucine is substituted with any other amino acid.

114. The kit of claim 112, wherein the soluble CTLA4 mutant molecule comprises an extracellular domain of CTLA4,

a) wherein the extracellular domain of CTLA4 begins with methionine at position +1 or with alanine at position −

1 and ends with aspartic acid at position +124 as shown in FIG. 23 or 24 (SEQ ID NO;

17 or

     19),

b) wherein at position +104 of the extracellular domain of CTLA4, leucine is substituted with glutamic acid, and

c) wherein at position +29 of the extracellular domain of CTLA4, alanine is substituted with tyrosine.

115. The kit of claim 101, wherein the soluble CTLA4 mutant molecule is L104EA29YIg as shown in FIG. 19 (SEQ ID NO:

9) beginning with methionine at position +1 or with alanine at position −

1 and ending with lysine at position +357 as shown in FIG. 19 (SEQ ID NO;

     9).