Methods and compositions for expanding and stabilizing natural regulatory T cells

Patent metadata

Field	Value
Publication number	US-8951796-B2
Application number	US-201113642811-A
Country	US
Kind code	B2
Filing date	Apr 21, 2011
Priority date	Apr 22, 2010
Publication date	Feb 10, 2015
Grant date	Feb 10, 2015

Abstract

The present invention is directed to methods and compositions for expanding and stabilizing the phenotype of natural regulatory T cells. In particular, the present invention provides methods and compositions for treating natural regulatory T cells that renders the cells resistant to factors present in the inflammatory milieu and stabilizes the suppressive properties of the cells.

First claim

What is claimed:

1. A method of expanding natural regulatory T cells (nTregs), said method comprising treating a cell culture comprising nTregs with a regulatory composition, wherein said regulatory composition comprises a vitamin A derivative.

2. The method of claim 1 , wherein said vitamin A derivative is retinoic acid.

3. The method of claim 2 , wherein said retinoic acid is all-trans retinoic acid (atRA).

4. The method of claim 1 , wherein said vitamin A derivative is a synthetic retinoid.

5. The method of claim 4 , wherein said synthetic retinoid is Am80.

6. The method of claim 1 , wherein said regulatory composition further comprises a cytokine.

7. The method of claim 6 , wherein said cytokine is TGF-β.

8. The method of claim 1 , wherein said regulatory composition further comprises IL-2.

9. The method of claim 1 , wherein said regulatory composition further comprises a T cell activator.

10. The method of claim 9 , wherein said T cell activator is a member selected from anti-CD3, anti-CD28, or a combination of anti-CD3 and anti-CD28.

11. The method of claim 1 , wherein said regulatory composition further comprises an agent that prevents methylation of a gene encoding a transcription factor.

12. The method of claim 11 , wherein said agent is a methyltransferase inhibitor.

13. The method of claim 12 , wherein said methyltransferase inhibitor is azacytidine.

14. The method of claim 1 , wherein said regulatory composition further comprises an agent that is a histone deacetylase inhibitor.

15. The method of claim 14 , wherein said histone deacetylase inhibitor is a member selected from trichostatin A, ppAR gamma agonists, and valproic acid.

16. The method of claim 1 , wherein said cell culture is submitted to flow cytometry to enrich for FOXP3+ cells prior to and/or subsequent to said treating with said regulatory composition.

17. A method of stabilizing phenotype of nTregs, said method comprising treating said nTregs with a regulatory composition, wherein said regulatory composition comprises atRA.

18. The method of claim 17 , wherein said stabilizing comprises rendering said nTregs resistant to Th17 conversion.

19. The method of claim 17 , wherein said stabilizing comprises retention of nTreg phenotype in an inflammatory milieu.

20. The method of claim 19 , wherein said nTreg phenotype comprises a method selected from expression of FOXP3, suppressive activity, and combinations thereof.

21. A method of decreasing expression of transcription factors associated with inflammatory responses in nTregs, said method comprising treating said nTregs with a regulatory composition comprising atRA.

22. The method of claim 21 , wherein said regulatory composition further comprises TGF-β.

23. The method of claim 22 , wherein said regulatory composition further comprises IL-2.

24. The method of claim 23 , wherein said regulatory composition further comprises a T cell activator.

25. The method of claim 24 wherein said T cell activator is anti-CD3, anti-CD28, or a combination of anti-CD3 and anti-CD28.

26. A method of treating an aberrant immune response or an autoimmune disease in a patient, said method comprising administering treated nTregs to said patient, wherein said treated nTregs are generated by treating a cell culture comprising nTregs with a regulatory composition comprising atRA.

27. The method of claim 26 , wherein said regulatory composition further comprises TGF-β.

28. The method of claim 27 , wherein said regulatory composition further comprises IL-2.

29. The method of claim 25 , wherein said regulatory composition further comprises a T cell activator.

30. The method of claim 29 wherein said T cell activator is anti-CD3, anti-CD28, or a combination of anti-CD3 and anti-CD28.

Assignees

• Zheng Song Guo
• Horwitz David A
• Wong Juhua
• Univ Southern California

Inventors

• Zheng Song Guo
• Horwitz David A
• Wong Juhua

Classifications

• C12N2501/51

  B7 molecules, e.g. CD80, CD86, CD28 (ligand), CD152 (ligand) · CPC title

• C12N2501/065

  Modulators of histone acetylation · CPC title

• C12N2501/515

  CD3, T-cell receptor complex · CPC title

• A61P37/02

  Immunomodulators · CPC title

• C12N2501/23

  Interleukins [IL] · CPC title