Claims
- 1. A method for stimulating proliferation by a T cell which expresses a cytokine receptor γ chain and which has received a primary activation signal under conditions which normally result in unresponsiveness in a T cell, comprising contacting the T cell with an agent which binds to the cytokine receptor γ chain and stimulates an intracellular signal in the T cell resulting in T cell proliferation, with the proviso that the agent does not consist of natural interleukin-2.
- 2. The method of claim 1, wherein the agent is interleukin-4 or interleukin-7.
- 3. The method of claim 1, wherein the agent is an anti-γ chain antibody.
- 4. The method of claim 1, wherein the T cell is contacted in vivo with the agent.
- 5. The method of claim 1, further comprising contacting the T cell with both an agent which stimulates a primary activation signal in the T cell and an agent which binds to the γ chain and stimulates an intracellular signal in the T cell.
- 6. The method of claim 5, further comprising contacting the T cell with an agent which stimulates a costimulatory signal in the T cell.
- 7. The method of claim 5, wherein the agent which stimulates a primary activation signal in the T cell is an antigen.
- 8. The method of claim 7, wherein the antigen is a pathogen selected from the group consisting of a virus, a bacteria, and a parasite.
- 9. The method of claim 7, wherein the antigen is a tumor antigen.
- 10. The method of claim 7, wherein the T cell is contacted with the antigen in vivo.
- 11. A method for stimulating proliferation by a T cell which expresses a cytokine receptor γ chain and which has received a primary activation signal under conditions which normally result in unresponsiveness in a T cell, comprising contacting the T cell with an agent which acts intracellularly to stimulate phosphorylation of a JAK kinase having a molecular weight of about 116 kD as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis, resulting in proliferation of the T cell.
- 12. The method of claim 11, wherein the T cell is contacted in vivo with the agent.
- 13. The method of claim 11, further comprising contacting the T cell with both an agent which stimulates a primary activation signal in the T cell and an agent which acts intracellularly to stimulate phosphorylation of a JAK kinase having a molecular weight of about 116 kD as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis.
- 14. The method of claim 13, further comprising contacting the T cell with an agent which stimulates a costimulatory signal in the T cell.
- 15. The method of claim 14, wherein the agent which stimulates a primary activation signal in the T cell is an antigen.
- 16. The method of claim 15, wherein the antigen is a pathogen selected from the group consisting of a virus, a bacteria, and a parasite.
- 17. The method of claim 15, wherein the antigen is a tumor antigen.
- 18. The method of claim 15, wherein the T cell is contacted with the antigen in vivo.
- 19. A method for inducing unresponsiveness to an antigen in a T cell which expresses a cytokine receptor γ chain comprising contacting the T cell in the presence of an antigen with an agent which inhibits delivery of a signal through the cytokine receptor γ chain resulting in T cell unresponsiveness to the antigen.
- 20. The method of claim 19, wherein the agent acts extracellularly to inhibit delivery of a signal through the cytokine receptor γ chain.
- 21. The method of claim 20, wherein the agent binds to the cytokine receptor γc chain without stimulating an intracellular signal in the T cell through the cytokine receptor γ chain.
- 22. The method of claim 21, wherein the agent is an anti-γc chain antibody.
- 23. The method of claim 20, wherein the agent binds a natural ligand of the cytokine receptor γ chain to inhibit binding of the ligand to the cytokine receptor γ chain.
- 24. The method of claim 23, wherein the agent is selected from the group consisting of an anti-interleukin-2 antibody, an anti-interleukin-4 antibody and an anti-interleukin-7 antibody.
- 25. The method of claim 19, wherein the agent acts intracellularly to inhibit delivery of a signal through the cytokine receptor γ chain.
- 26. The method of claim 25, wherein the agent inhibits association of the cytokine receptor γ chain with a JAK kinase having a molecular weight of about 116 kD as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis.
- 27. The method of claim 25, wherein the agent inhibits tyrosine phosphorylation of a JAK kinase having a molecular weight of about 116 kD as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis.
- 28. The method of claim 25, wherein the agent inhibits tyrosine phosphorylation of the cytokine receptor γ chain.
- 29. The method of claim 25, wherein the agent inhibits tyrosine phosphorylation of both the cytokine receptor γ chain and a JAK kinase having a molecular weight of about 116 kD as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis.
- 30. The method of claim 19, wherein the T cell is contacted in vivo with the agent.
- 31. The method of claim 19, further comprising contacting the T cell with the antigen.
- 32. The method of claim 31, wherein the antigen is an alloantigen.
- 33. The method of claim 31, wherein the antigen is an autoantigen.
- 34. The method of claim 31, wherein the T cell is contacted with the antigen and the agent in vitro and the method further comprises administering the T cell to a subject.
- 35. The method of claim 34, wherein the antigen is on a surface of an allogeneic or xenogeneic cell and the subject is a recipient of an allogenic or xenogeneic cell.
- 36. The method of claim 34, wherein the subject is suffering from an autoimmune disease or disorder associated with an inappropriate or abnormal immune response.
- 37. A method for inhibiting graft-versus-host disease in a bone marrow transplant recipient, comprising contacting a donor T cell which expresses a cytokine receptor γ chain with a cell which expresses a recipient antigen and an agent which inhibits delivery of a signal through the cytokine receptor γ chain on the T cell, resulting in donor T cell unresponsiveness to the cell which expresses the recipient antigen.
- 38. The method of claim 37, wherein the agent is an anti-γ chain antibody.
- 39. The method of claim 37, wherein the agent binds a natural ligand of the cytokine receptor γ chain to inhibit binding of the ligand to the cytokine receptor γ chain.
- 40. The method of claim 39, wherein the agent is selected from the group consisting of an anti-interleukin-2 antibody, an anti-interleukin-4 antibody and an anti-interleukin-7 antibody.
- 41. The method of claim 39, wherein the agent inhibits association of the cytokine receptor γ chain with a JAK kinase having a molecular weight of about 116 kD as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis.
- 42. The method of claim 39, wherein the agent inhibits tyrosine phosphorylation of a JAK kinase having a molecular weight of about 116 kD as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis.
- 43. The method of claim 39, wherein the agent inhibits tyrosine phosphorylation of the cytokine receptor γ chain.
- 44. The method of claim 39, wherein the agent inhibits tyrosine phosphorylation of both the cytokine receptor γ chain and a JAK kinase having a molecular weight of about 116 kD as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis.
- 45. A method for identifying an agent which inhibits deli very of a signal through a cytokine receptor y chain on a T cell, comprising
a) contacting a T cell which expresses a cytokine receptor y chain with
(1) a first agent which stimulates a primary activation signal in the Tcell, (2) a second agent which stimulates an intracellular signal through the cytokine receptor γ chain, and (3) a third agent to be tested for the ability to inhibit delivery of the signal through the cytokine receptor γ chain; and b) determining the presence of T cell proliferation, wherein inhibition of T cell proliferation indicates that the third agent inhibits delivery of a signal to T cell through the cytokine receptor γ chain.
- 46. The method of claim 45, wherein the second agent is a cytokine.
- 47. The method of claim 46, wherein the cytokine is selected from the group consisting of interleukin-2, interleukin-4 and interleukin-7.
GOVERNMENT FUNDING
[0001] Work described herein was supported under one or more grants awarded by the National Institutes of Health. The U.S. government therefore may have certain rights in this invention.
Continuations (1)
|
Number |
Date |
Country |
Parent |
08270152 |
Jul 1994 |
US |
Child |
10458069 |
Jun 2003 |
US |