Compositions and methods of treating T cell mediated disorder

Patent metadata

Field	Value
Publication number	US-9290736-B2
Application number	US-201013505976-A
Country	US
Kind code	B2
Filing date	Nov 4, 2010
Priority date	Nov 4, 2009
Publication date	Mar 22, 2016
Grant date	Mar 22, 2016

Abstract

A method of generating a CD4 + FoxP3 + Treg cell, the method includes administering at least one complement antagonist to a naive CD4 + T cell at an amount effective to substantially inhibits C3a receptor (C3aR) and/or C5a receptor (C5aR) signal transduction in the CD4 + T cell, induce TGF-β1 expression of the CD4 + T cell, and induce differentiation of the of the naive CD4 + T cell into a CD4 + FoxP3 + Treg cell.

First claim

Having described the invention, we claim:

1. A method of generating a CD4 + FoxP3 + Treg cell, the method comprising:
isolating a naive CD4 + T cell;
culturing the naive CD4 + T cell in the presence of dendritic cells or antigen presenting cells, anti-CD3, and IL 2; and
administering a C3a antagonist or C3aR antagonist and a C5a antagonist or C5aR antagonist to the naive CD4 + T cell at an amount effective to substantially inhibit interaction of C3a and C5a with the C3aR and C5aR of the CD4 + T cell, induce TGF-β1 expression of the CD4 + T cell, and induce differentiation of the of the naive CD4 + T cell into a CD4 + FoxP3 + Treg cell.

2. The method of claim 1 , the C3a antagonist or C3aR antagonist and the C5a antagonist or C5aR antagonist being selected from the group consisting of a small molecule, a polypeptide, and a polynucleotide.

3. The method of claim 2 , the polypeptide comprising an antibody directed against at least one of C3a, C5a, C3aR, or C5aR.

4. The method of claim 2 , the polynucleotide comprising a small interfering RNA directed against a polynucleotide encoding at least one of C3, C5, C3aR, or C5aR.

5. The method of claim 1 , the step of administering the complement antagonist includes administering to the naive CD4 + T cell a C3aR antagonist and a C5aR antagonist.

6. The method of claim 5 , wherein the C3aR antagonist and the C5aR antagonist are antibodies.

7. The method of claim 1 , the step of administering the at least one complement antagonist includes administering to the naïve CD4 + T cell a C3a antagonist and a C5a antagonist.

8. The method of claim 7 , wherein the C3a antagonist and C5a antagonist are antibodies.

9. The method of claim 1 , the naive CD4 + T cell comprising a human CD45 hi CD44 low CD4 + T cell.

10. The method of claim 1 , wherein the complement antagonist substantially induces naive CD4+ cell expression of CD25, CTLA-4, FoxP3, DAF and C5L2, downregulates dendritic cell B7/CD40 and CD4+ effector cell CD28/CD40 ligand costimulatory molecule expression, and inhibits dendritic cell C5a/C3a production and CD4 + cell C5aR/C3aR signal transduction.

11. The method of claim 1 , wherein the antigen presenting cells are dendritic cells.

12. A method of treating a T cell mediated autoimmune disorder or disease in a subject comprising:
culturing a naive CD4 + T cell in the presence of or antigen presenting cells, anti-CD3, and IL-2; and
administering a C3a antagonist or a C3aR antagonist and a C5a antagonist or a C5aR antagonist to the naive CD4 + T cell at an amount effective to substantially inhibit interaction of C3a and C5a with the C3aR and C5aR of the CD4 + T cell, induce TGF-β1 expression of the CD4 + T cell, and induce differentiation of the of the naive CD4 + T cell into a CD4 + FoxP3 + Treg cell; and
administering a therapeutically effective amount of the CD4 + FoxP3 + Treg cells to the subject.

13. The method of claim 12 , the step of administering the complement antagonist includes administering to the naive CD4 + T cell a C3aR antagonist and a C5aR antagonist.

14. The method of claim 12 , the step of administering the at least one complement antagonist includes administering to the CD4 + T cell a C3a antagonist and a C5a antagonist.

15. The method of claim 12 , the CD4 + FoxP3 + Treg cells being administered systemically to the subject being treated.

16. The method of claim 12 , wherein the antigen presenting cells are dendritic cells.

Assignees

• Medof M Edward
• Lin Feng
• Strainic Michael G
• Univ Case Western Reserve

Inventors

• Medof M Edward
• Lin Feng
• Strainic Michael G

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K38/00

  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 title

• C12N2501/998

  Proteins not provided for elsewhere · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61K2035/124

  the cells being hematopoietic, bone marrow derived or blood cells · CPC title