Manipulation of cytokine levels using cd83 gene products

• US 20060083740A1
• Filed: 11/21/2002
• Published: 04/20/2006
• Est. Priority Date: 11/21/2001
• Status: Active Grant

• Current Assignee: Celltech Group Limited (UCB SA)
• Original Assignee: Celltech Group Limited (UCB SA)
• Inventors: Garcia-Martinez, Leon Fernando, Ramsdell, Fred, Proll, Sean C., Appleby, Mark W., Staehling-Hampton, Karen
• Granted Patent: US 7,618,629 B2
• Time in Patent Office: Days
• US Class Current: 424/145.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 33/02 : Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/10 : Anthelmintics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07K 14/70503 : Immunoglobulin superfamily
• CPC Class Codes: C07K 16/2803 : against the immunoglobulin superfamily
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides methods for modulating cytokine levels, GM-CSF levels and the immune system using CD83 nucleic acids, CD83 polypeptides, anti-CD83 antibodies and factors that influence CD83 activity or expression. The invention also provides mice having a mutant CD83 gene and mice having a transgenic CD83 gene, which are useful for defining the role of CD83 in the immune system and for identifying compounds that can modulate CD83 and the immune system.

Claims

1. A method of modulating cytokine production in a mammal by modulating the activity or expression of a CD83 polypeptide.

2. A method of modulating cytokine production in a mammal by administering to the mammal an antibody that can modulate the activity or expression of a CD83 polypeptide.

3. A method of modulating cytokine production by a T cell by modulating the activity or expression of a CD83 polypeptide in the T cell.

4. A method of modulating cytokine production by a T cell by contacting the T cell with an antibody that can modulate the activity or expression of a CD83 polypeptide.

5. A method of modulating a CD4+ T cell by modulating the activity or expression of a CD83 polypeptide in the T cell.

6. A method of modulating a CD4+ T cell by contacting the T cell with an antibody that can modulate the activity or expression of a CD83 polypeptide.

7. A method of modulating granulocyte macrophage colony stimulating factor production in a mammal by modulating the activity or expression of CD83 polypeptides.

8. A method of modulating granulocyte macrophage colony stimulating factor production in a mammal by administering to the mammal an antibody that can modulate the activity or expression of CD83 polypeptides.

9. A method of modulating granulocyte macrophage colony stimulating factor production by a T cell by modulating the activity or expression of a CD83 polypeptide in the T cell.

10. A method of modulating granulocyte macrophage colony stimulating factor production by a T cell by contacting the T cell with an antibody that can modulate the activity or expression of a CD83 polypeptide.

11. A method of tumor necrosis factor production in a mammal by modulating the activity or expression of CD83 polypeptides.

12. A method of modulating tumor necrosis factor production in a mammal by administering to the mammal an antibody that can modulate the activity or to expression of CD83 polypeptides.

13. A method of inhibiting proliferation of a human peripheral blood mononuclear cell by modulating the activity or expression of CD83 polypeptides.

14. A method of inhibiting proliferation of a human peripheral blood mononuclear cell in a mammal by administering to the mammal an antibody that can modulate the activity or expression of CD83 polypeptides.

15. An antibody that can bind to a CD83 polypeptide comprising SEQ ID NO:

4, SEQ ID NO;

8 or SEQ ID NO;

9, wherein activated CD4⁺ T-cells produce lower levels of interleukin-4 when said T-cells are contacted with the antibody.

16. An antibody that can bind to a CD83 polypeptide comprising SEQ ID NO:

4, SEQ ID NO;

8 or SEQ ID NO;

9, wherein CD4⁺ T-cells proliferation is decreased when said T-cells are contacted with the antibody.

17. An antibody comprising SEQ ID NO:

11, SEQ ID NO;

13, SEQ ID NO;

15, SEQ ID NO;

17, SEQ ID NO;

19, SEQ ID NO;

21, SEQ ID NO;

23, SEQ ID NO;

24, SEQ ID NO;

25, SEQ ID NO;

26, SEQ ID NO;

27, SEQ ID NO;

28, SEQ ID NO;

29, SEQ ID NO;

30, SEQ ID NO;

31, SEQ ID NO;

32, SEQ ID NO;

33, SEQ ID NO;

34, SEQ ID NO;

35, SEQ ID NO;

36, SEQ ID NO;

37, SEQ ID NO;

38, SEQ ID NO;

39, SEQ ID NO;

40, SEQ ID NO;

41, SEQ ID NO;

42, SEQ ID NO;

43, SEQ ID NO;

44, SEQ ID NO;

45, SEQ ID NO;

46, SEQ ID NO;

47, SEQ ID NO;

48, SEQ ID NO;

52, SEQ ID NO;

53, SEQ ID NO;

54, SEQ ID NO;

55, SEQ ID NO;

56, SEQ ID NO;

57, SEQ ID NO;

58, SEQ ID NO;

60, SEQ ID NO;

62 or SEQ ID NO;

64.

18. A nucleic acid encoding an antibody comprising SEQ ID NO:

11, SEQ ID NO;

13, SEQ ID NO;

15, SEQ ID NO;

17, SEQ ID NO;

19, SEQ ID NO;

21, SEQ ID NO;

23, SEQ ID NO;

24, SEQ ID NO;

25, SEQ ID NO;

26, SEQ ID NO;

27, SEQ ID NO;

28, SEQ ID NO;

29, SEQ ID NO;

30, SEQ ID NO;

31, SEQ ID NO;

32, SEQ ID NO;

33, SEQ ID NO;

34, SEQ ID NO;

35, SEQ ID NO;

36, SEQ ID NO;

37, SEQ ID NO;

38, SEQ ID NO;

39, SEQ ID NO;

40, SEQ ID NO;

41, SEQ ID NO;

42, SEQ ID NO;

43, SEQ ID NO;

44, SEQ ID NO;

45, SEQ ID NO;

46, SEQ ID NO;

47, SEQ ID NO;

48, SEQ ID NO;

52, SEQ ID NO;

53, SEQ ID NO;

54, SEQ ID NO;

55, SEQ ID NO;

56, SEQ ID NO;

57, SEQ ID NO;

58, SEQ ID NO;

60, SEQ ID NO;

62 or SEQ ID NO;

64.

19. The nucleic acid of claim 18, wherein the nucleic acid comprises nucleotide sequence SEQ ID NO:

12, SEQ ID NO;

14, SEQ ID NO;

16, SEQ ID NO;

18, SEQ ID NO;

20, SEQ ID NO;

22, SEQ ID NO;

59, SEQ ID NO;

61, SEQ ID NO;

63 or SEQ ID NO;

65.

20. A method for decreasing the activity of a CD83 gene product, comprising contacting the CD83 gene product with an antibody that comprises SEQ ID NO:

11, SEQ ID NO;

13, SEQ ID NO;

15, SEQ ID NO;

17, SEQ ID NO;

19, SEQ ID NO;

21, SEQ ID NO;

23, SEQ ID NO;

24, SEQ ID NO;

25, SEQ ID NO;

26, SEQ ID NO;

27, SEQ ID NO;

28, SEQ ID NO;

29, SEQ ID NO;

30, SEQ ID NO;

31, SEQ ID NO;

32, SEQ ID NO;

33, SEQ ID NO;

34, SEQ ID NO;

35, SEQ ID NO;

36, SEQ ID NO;

37, SEQ ID NO;

38, SEQ ID NO;

39, SEQ ID NO;

40, SEQ ID NO;

41, SEQ ID NO;

42, SEQ ID NO;

43, SEQ ID NO;

44, SEQ ID NO;

45, SEQ ID NO;

46, SEQ ID NO;

47, SEQ ID NO;

48, SEQ ID NO;

52, SEQ ID NO;

53, SEQ ID NO;

54, SEQ ID NO;

55, SEQ ID NO;

56, SEQ ID NO;

57, SEQ ID NO;

58, SEQ ID NO;

60, SEQ ID NO;

62 or SEQ ID NO;

64.

21. A method for decreasing the activity of a CD83 gene product in a mammal, comprising administering to the mammal an antibody that comprises SEQ ID NO:

11, SEQ ID NO;

13, SEQ ID NO;

15, SEQ ID NO;

17, SEQ ID NO;

19, SEQ ID NO;

21, SEQ ID NO;

23, SEQ ID NO;

24, SEQ ID NO;

25, SEQ ID NO;

26, SEQ ID NO;

27, SEQ ID NO;

28, SEQ ID NO;

29, SEQ ID NO;

30, SEQ ID NO;

31, SEQ ID NO;

32, SEQ ID NO;

33, SEQ ID NO;

34, SEQ ID NO;

35, SEQ ID NO;

36, SEQ ID NO;

37, SEQ ID NO;

38, SEQ ID NO;

39, SEQ ID NO;

40, SEQ ID NO;

41, SEQ ID NO;

42, SEQ ID NO;

43, SEQ ID NO;

44, SEQ ID NO;

45, SEQ ID NO;

46, SEQ ID NO;

47, SEQ ID NO;

48, SEQ ID NO;

52, SEQ ID NO;

53, SEQ ID NO;

54, SEQ ID NO;

55, SEQ ID NO;

56, SEQ ID NO;

57, SEQ ID NO;

58, SEQ ID NO;

60, SEQ ID NO;

62 or SEQ ID NO;

64.

22. A method for decreasing the translation of a CD83 gene product in a mammalian cell, comprising contacting the mammalian cell with a nucleic acid complementary to a CD83 nucleic acid comprising SEQ ID NO:

1, SEQ ID NO;

3, SEQ ID NO;

5, or SEQ ID NO;

10.

23. A method for decreasing the translation of a CD83 gene product in a mammal, comprising administering to the mammal a nucleic acid complementary to a CD83 nucleic acid comprising SEQ ID NO:

1, SEQ ID NO;

3, SEQ ID NO;

5, or SEQ ID NO;

10.

24. A method for decreasing proliferation of CD4⁺ T-cells in a mammal comprising administering to the mammal an antibody that can bind to a CD83 gene product, wherein the CD83 gene product comprises SEQ ID NO:

2 or SEQ ID NO;

9.

25. The method of claim 24, wherein the antibody comprises SEQ ID NO:

11, SEQ ID NO;

13, SEQ ID NO;

15, SEQ ID NO;

17, SEQ ID NO;

19, SEQ ID 30 NO;

21, SEQ ID NO;

23, SEQ ID NO;

24, SEQ ID NO;

25, SEQ ID NO;

26, SEQ ID NO;

27, SEQ ID NO;

28, SEQ ID NO;

29, SEQ ID NO;

30, SEQ ID NO;

31, SEQ ID NO;

32, SEQ ID NO;

33, SEQ ID NO;

34, SEQ ID NO;

35, SEQ ID NO;

36, SEQ ID NO;

37, SEQ ID NO;

38, SEQ ID NO;

39, SEQ ID NO;

40, SEQ ID NO;

41, SEQ ID NO;

42, SEQ ID NO;

43, SEQ ID NO;

44, SEQ ID NO;

45, SEQ ID NO;

46, SEQ ID NO;

47, SEQ ID NO;

48, SEQ ID NO;

52, SEQ ID NO;

53, SEQ ID NO;

54, SEQ ID NO;

55, SEQ ID NO;

56, SEQ ID NO;

57, SEQ ID NO;

58, SEQ ID NO;

60, SEQ ID NO;

62 or SEQ ID NO;

64.

26. A method for decreasing interleukin-2 levels and increasing interleukin-4 levels in a mammal comprising administering to the mammal an antibody that can bind to a CD83 gene product, wherein the CD83 gene product comprises SEQ ID NO:

2 or SEQ ID NO;

9.

27. The method of claim 26, wherein the antibody SEQ ID NO:

11, SEQ ID NO;

13, SEQ ID NO;

15, SEQ ID NO;

17, SEQ ID NO;

19, SEQ ID NO;

21, SEQ ID NO;

23, SEQ ID NO;

24, SEQ ID NO;

25, SEQ ID NO;

26, SEQ ID NO;

27, SEQ ID NO;

28, SEQ ID NO;

29, SEQ ID NO;

30, SEQ ID NO;

31, SEQ ID NO;

32, SEQ ID NO;

33, SEQ ID NO;

34, SEQ ID NO;

35, SEQ ID NO;

36, SEQ ID NO;

37, SEQ ID NO;

38, SEQ ID NO;

39, SEQ ID NO;

40, SEQ ID NO;

41, SEQ ID NO;

42, SEQ ID NO;

43, SEQ ID NO;

44, SEQ ID NO;

45, SEQ ID NO;

46, SEQ ID NO;

47, SEQ ID NO;

48, SEQ ID NO;

52, SEQ ID NO;

53, SEQ ID NO;

54, SEQ ID NO;

55, SEQ ID NO;

56, SEQ ID NO;

57, SEQ ID NO;

58, SEQ ID NO;

60, SEQ ID NO;

62 or SEQ ID NO;

64.

29. The method of claim 26 or 28, wherein the interleukin-2 levels are decreased and the interleukin-4 levels are increased to treat an autoimmune disease.

30. The method of claim 29, wherein the autoimmune disease is diabetes mellitus, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis, multiple sclerosis, myasthenia gravis, systemic lupus erythematosis, autoimmune thyroiditis, dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren'"'"'s Syndrome, keratoconjunctivitis sicca secondary to Sjogren'"'"'s Syndrome, alopecia greata, allergic responses due to arthropod bite reactions, Crohn'"'"'s disease, aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, drug eruptions, leprosy reversal reactions, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral progressive sensorineural hearing loss, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, polychondritis, Wegener'"'"'s granulomatosis, chronic active hepatitis, Stevens-Johnson syndrome, idiopathic sprue, lichen planus, Crohn'"'"'s disease, Graves ophthalmopathy, sarcoidosis, primary biliary cirrhosis, uveitis posterior, or interstitial lung fibrosis.

31. The method of claim 26 or 28, wherein the interleukin-2 levels are decreased and the interleukin-4 levels are increased to stimulate production of Th2-associated cytokines in transplant recipients.

32. The method of claim 31, wherein the Th2-associated cytokines prolong survival of transplanted tissue.

33. The method of claim 32, wherein the transplanted tissue is skin, cardiac or bone marrow.

34. The method of claim 26 or 28, wherein the mammal is a human.

28. A method for decreasing interleukin-2 levels and increasing interleukin-4 levels in a mammal comprising administering to the mammal a nucleic acid complementary to a CD83 nucleic acid comprising SEQ ID NO:

1, SEQ ID NO;

3, SEQ ID NO;

5, or SEQ ID NO;

10.

35. A method for increasing interleukin-10 levels in a mammal comprising administering to the mammal an antibody that can bind to a CD83 gene product, wherein the CD83 gene product comprises SEQ ID NO:

2 or SEQ ID NO;

9.

36. The method of claim 35, wherein the antibody comprises SEQ ID NO:

11, SEQ ID NO;

13, SEQ ID NO;

15, SEQ ID NO;

17, SEQ ID NO;

19, SEQ ID NO;

21, SEQ ID NO;

23, SEQ ID NO;

24, SEQ ID NO;

25, SEQ ID NO;

26, SEQ ID NO;

27, SEQ ID NO;

28, SEQ ID NO;

29, SEQ ID NO;

30, SEQ ID NO;

31, SEQ ID NO;

32, SEQ ID NO;

33, SEQ ID NO;

34, SEQ ID NO;

35, SEQ ID NO;

36, SEQ ID NO;

37, SEQ ID NO;

38, SEQ ID NO;

39, SEQ ID NO;

40, SEQ ID NO;

41, SEQ ID NO;

42, SEQ ID NO;

43, SEQ ID NO;

44, SEQ ID NO;

45, SEQ ID NO;

46, SEQ ID NO;

47, SEQ ID NO;

48, SEQ ID NO;

52, SEQ ID NO;

53, SEQ ID NO;

54, SEQ ID NO;

55, SEQ ID NO;

56, SEQ ID NO;

57, SEQ ID NO;

58, SEQ ID NO;

60, SEQ ID NO;

62 or SEQ ID NO;

64.

38. The method of claim 35 or 37, wherein the interleukin-10 levels are increased to treat neoplastic disease.

39. The method of claim 35 or 37, wherein the interleukin-10 levels are increased to treat a tumor.

37. A method for increasing interleukin-10 levels in a mammal comprising administering to the mammal a nucleic acid complementary to a CD83 nucleic acid comprising SEQ ID NO:

1, SEQ ID NO;

3, SEQ ID NO;

5, or SEQ ID NO;

10.

40. A method for increasing interleukin-2 levels in a mammal comprising administering to the mammal a functional CD83 polypeptide that comprises SEQ ID NO:

9.

41. A method for increasing interleukin-2 levels in a mammal comprising:

(a) transforming a T cell from the mammal with a nucleic acid encoding a functional CD83 polypeptide operably linked to a promoter functional in a mammalian cell, to generate a transformed T cell;

(b) administering the transformed T cell to the mammal to provide increased levels of interleukin-2.

42. The method of claim 41, wherein the CD83 polypeptide comprises SEQ ID NO:

9.

43. The method of claim 41, wherein the nucleic acid comprises SEQ ID NO:

1, SEQ ID NO;

3, SEQ ID NO;

5, or SEQ ID NO;

10.

44. The method of claim 41, wherein the mammal is a human.

45. The method of claim 41, wherein the interleukin-2 levels are increased to treat an allergy or an infectious disease.

46. The method of claim 45, wherein the infectious disease is related to HIV infection, tuberculosis, leishmaniasis, schistosomiasis, filarial nematode infection, or intestinal nematode infection.

47. The method of claim 45, wherein the infectious disease is related to infection by Aeromonas spp., Bacillus spp., Bacteroides spp., Campylobacter spp., Clostridium spp., Enterobacter spp., Enterococcus spp., Escherichia spp., Gastrospirillum sp., Helicobacter spp., Klebsiella spp., Salmonella spp., Shigella spp., Staphylococcus spp., Pseudomonas spp., Vibrio spp., or Yersinia spp.

48. The method of claim 45, wherein the infectious disease is related to staph infection, typhus, food poisoning, bascillary dysentery, pneumonia, cholera, an ulcer, diarrhea, hemorrhagic colitis, hemolytic uremic syndrome, or thrombotic thrombocytopenic purpura.

49. The method of claim 45, wherein the infectious disease is related to infection by Staphylococcus aureus, Salmonella typhi, Escherichia coli, Escherichia coli O157:

H7, Shigella dysenteria, Psuedomonas aerugenosa, Pseudomonas cepacia, Vivrio cholerae, Helicobacter pylori, a multiply-resistant strain of Staphylococcus aureus, a vancomycin-resistant strain of Enterococcus faecium, or a vancomycin-resistant strain of Enterococcus faecalis.

50. The method of claim 45, wherein the infectious disease is related to infection by a virus.

51. The method of claim 50, wherein the virus is a hepatitis A virus, hepatitis B virus, hepatitis C virus, human immunodeficiency virus, poxvirus, herpes virus, adenovirus, papovavirus, parvovirus, reovirus, orbivirus, picomavirus, rotavirus, alphavirus, rubivirus, influenza virus type A, influenza virus type B, flavivirus, coronavirus, paramyxovirus, morbillivirus, pneumovirus, rhabdovirus, lyssavirus, orthimyxovirus, bunyavirus, phlebovirus, nairovirus, hepadnavirus, arenavirus, retrovirus, enterovirus, rhinovirus or filovirus.

52. A method for increasing granulocyte macrophage colony stimulating factor levels in a mammal comprising administering to the mammal an antibody that can bind to a CD83 gene product, wherein the CD83 gene product comprises SEQ ID NO:

2 or SEQ ID NO;

9.

53. The method of claim 52, wherein the antibody comprises SEQ ID NO:

11, SEQ ID NO;

13, SEQ ID NO;

15, SEQ ID NO;

17, SEQ ID NO;

19, SEQ ID NO;

21, SEQ ID NO;

23, SEQ ID NO;

24, SEQ ID NO;

25, SEQ ID NO;

26, SEQ ID NO;

27, SEQ ID NO;

28, SEQ ID NO;

29, SEQ ID NO;

30, SEQ ID NO;

31, SEQ ID NO;

32, SEQ ID NO;

33, SEQ ID NO;

34, SEQ ID NO;

35, SEQ ID NO;

36, SEQ ID NO;

37, SEQ ID NO;

38, SEQ ID NO;

39, SEQ ID NO;

40, SEQ ID NO;

41, SEQ ID NO;

42, SEQ ID NO;

43, SEQ ID NO;

44, SEQ ID NO;

45, SEQ ID NO;

46, SEQ ID NO;

47, SEQ ID NO;

48, SEQ ID NO;

52, SEQ ID NO;

53, SEQ ID NO;

54, SEQ ID NO;

55, SEQ ID NO;

56, SEQ ID NO;

57, SEQ ID NO;

58, SEQ ID NO;

60, SEQ ID NO;

62 or SEQ ID NO;

64.

54. A method for increasing granulocyte macrophage colony stimulating factor levels in a mammal comprising administering to the mammal a nucleic acid complementary to a CD83 nucleic acid comprising SEQ ID NO:

1, SEQ ID NO;

3, SEQ ID NO;

5, or SEQ ID NO;

10.

55. A method for increasing tumor necrosis factor levels at a selected site in a mammal comprising administering to the site a functional CD83 polypeptide.

57. The method of claim 55 or 56, wherein the mammal is human and the CD83 polypeptide comprises SEQ ID NO:

9.

56. A method for increasing tumor necrosis factor levels in a selected mammalian cell comprising transforming the cell with a nucleic acid encoding a functional CD83 polypeptide.

58. A method of identifying a compound that can modulate CD4+T cell activation comprising administering a test compound to a mutant mouse and observing whether CD4+ T cells become activated, wherein the somatic and germ cells of the mutant mouse comprise a mutant CD83 gene encoding a polypeptide comprising SEQ ID NO:

4 or SEQ ID NO;

8.

59. A mutant CD83 gene encoding a polypeptide comprising SEQ ID NO:

4 or SEQ ID NO;

8.

60. The mutant CD83 gene of claim 63 comprising nucleotide sequence SEQ ID NO:

3.

61. A mutant mouse whose somatic and germ cells comprise a mutant CD83 gene encoding a polypeptide comprising SEQ ID NO:

4 or SEQ ID NO;

8, wherein expression of said mutant CD83 gene reduces CD4+T cell activation.

62. The mutant mouse of claim 61, wherein the mutant CD83 gene comprises SEQ ID NO:

3.