Methods and Compositions for the Generation and Maintenance of Regulatory T Cells

• US 20170165325A1
• Filed: 02/24/2017
• Published: 06/15/2017
• Est. Priority Date: 03/06/2009
• Status: Abandoned Application

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: Brigham and Women's Hospital Incorporated, President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Francisco, Loise M., Sharpe, Arlene, Kuchroo, Vijay
• Application Number:
  US15/441,671
• Publication Number:
  US 20170165325A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2035/122 for inducing tolerance or supression of immune responses
• CPC Class Codes: A61K 2239/31 characterized by the route of administration
• CPC Class Codes: A61K 2239/38 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 35/17 Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes when activated by a specific antigen A61K39/00
• 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 39/4611 T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/4621 immunosuppressive or immunotolerising
• CPC Class Codes: A61K 39/46433 Antigens related to auto-immune diseases; Preparations to induce self-tolerance
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 16/2827 against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 2317/75 Agonist effect on antigen
• CPC Class Codes: C12N 2501/15 Transforming growth factor beta (TGF-β)
• CPC Class Codes: C12N 2501/48 Regulators of apoptosis
• CPC Class Codes: C12N 2501/51 B7 molecules, e.g. CD80, CD86, CD28 (ligand), CD152 (ligand)
• CPC Class Codes: C12N 2501/515 CD3, T-cell receptor complex
• CPC Class Codes: C12N 5/0636 T lymphocytes
• CPC Class Codes: C12N 5/0637 Immunosuppressive T lymphocytes, e.g. regulatory T cells or Treg

Abstract

Methods and compositions for generating and maintaining induced regulatory T cells (iTregs) are provided. Methods and compositions for treating an autoimmune disorder, organ transplant rejection, graft versus host disease or allergic or hypersensitivity and inflammation are also provided.

Claims

1-11. -11. (canceled)

12. A method of culturing a regulatory T cell (Treg) comprising the steps of:

a) providing a Treg; and

b) incubating the Treg in the presence of PD-L, such that activities of the Treg are retained or enhanced.

13. The method of claim 12, wherein the activities of the Treg is expressing Foxp3 or suppressing Teff activation.

14. The method of claim 12, wherein the Treg is obtained by contacting a naï

ve T cell with PD-L to induce the naï

ve T cell to differentiate into a Treg.

15. The method of claim 12, wherein the PD-L is one or both of PD-L1 and PD-L2.

16. A method of treating an autoimmune disorder in an individual in need thereof comprising contacting naï

ve T cells within the individual with exogenous PD-L to differentiate the naï

ve T cells into iTreg, such that one or more symptoms of said autoimmune disorder are reduced in said individual.

17. The method of claim 16, wherein Foxp3 expression is increased in said individual.

18. The method of claim 16, wherein Teff activation is suppressed in said individual.

19. The method of claim 16, wherein the Akt signaling pathway is suppressed in said individual.

20. The method of claim 16, wherein the PD-L is one or both of PD-L1 and PD-L2.

21. A method of treating an autoimmune disorder in an individual in need thereof comprising administering exogenous iTreg to the individual, such that one or more symptoms of said autoimmune disorder are reduced in said individual.

22. The method of claim 21, wherein Foxp3 expression is increased in said individual.

23. The method of claim 21, wherein Teff activation is suppressed in said individual.

24. A method of treating an autoimmune disorder in an individual in need thereof comprising contacting the individual with a compound that stimulates one or more PD-L-mediated activities in said individual.

25. The method of claim 24, wherein the compound is a PD-L agonist.

26. The method of claim 24, wherein the PD-L is one or both of PD-L1 and PD-L2.

42. The method of claim 25, wherein the PD-L agonist is a mAb against PD-1.

43. The method of claim 42, wherein the mAb against PD-1 delivers a signal into naï

ve T cells after activation or into regulatory T cells that express PD-1.

27. A method of ameliorating, preventing and/or treating diseases, symptoms and/or disorders associated with an autoimmune disorder, organ transplant rejection, graft versus host disease or allergic or hypersensitivity response in an individual in need thereof comprising administering exogenous PD-L to the individual to differentiate naï

ve T cells into iTreg, such that one or more diseases, symptoms and/or disorders associated with the autoimmune disorder, organ transplant rejection, graft versus host disease or allergic or hypersensitivity response is reduced or prevented in the individual.

28. The method of claim 27, wherein Foxp3 expression is increased in said individual.

29. The method of claim 27, wherein Teff activation is suppressed in said individual.

30. The method of claim 27, wherein the Akt signaling pathway is suppressed in said individual.

31. The method of claim 27, wherein the PD-L is one or both of PD-L1 and PD-L2.

32. A method of ameliorating, preventing and/or treating diseases, symptoms and/or disorders associated with an autoimmune disorder, organ transplant rejection, graft versus host disease or allergic or hypersensitivity response in an individual in need thereof comprising administering exogenous iTreg to the individual such that one or more diseases, symptoms and/or disorders associated with the autoimmune disorder, organ transplant rejection, graft versus host disease or allergic or hypersensitivity response is reduced or prevented in the individual.

33. The method of claim 32, wherein Foxp3 expression is increased in said individual.

34. The method of claim 32, wherein Teff activation is suppressed in said individual.

35. The method of claim 32, wherein the Akt signaling pathway is suppressed in said individual.

36. A method of ameliorating, preventing and/or treating immune responses in tissue, comprising contacting the tissue with exogenous PD-L or exogenous iTreg at the site of tissue inflammation such that the inflammation is reduced.

37. The method of claim 36, wherein the tissue is eye tissue.

38. The method of claim 36, wherein the PD-L is one or both of PD-L1 and PD-L2.

39. A method of generating an iTreg comprising the steps of:

a) providing an naï

ve T cell; and

b) differentiating the naï

ve T cell into an iTreg by contacting the naï

ve T cell with an agonistic anti-PD-L monoclonal antibody (mAb).

40. The method of claim 39, wherein the iTreg expresses Foxp3.

41. The method of claim 39, wherein the mAb is an anti-PD-L1 antibody or an anti-PD-L2 antibody.