Immunomodulating tumor necrosis factor receptor 25 (TNFR25) agonists, antagonists, and immunotoxins
Compositions and methods utilizing immunomodulating agents can either stimulate or indirectly augment the immune system or have an immunosuppressive effect. TNFR25 agonists disclosed herein have an anti-inflammatory and healing effect. They can be used to treat disease caused by asthma and chronic inflammation such as inflammatory bowel diseases including ulcerative colitis and Crohn's Disease. TNFR25 antagonists disclosed herein are capable of inhibiting CD8 T cell-mediated cellular immune responses and can for example, mitigate organ or tissue rejection following a tissue transplantation.
1. A method for enhancing expansion of antigen-specific CD8 T cells in a subject, the method comprising the steps of:
(a) administering to the subject (i) an antigenic composition comprising a cell expressing a cognate antigen of the antigen specific CD8 T cells, wherein the cognate antigen is a non-self antigen; and (ii) an immunostimulatory agent, wherein the immunostimulatory agent enhances the subject's immune response to the antigenic composition; and
wherein administration of (i) and (ii) is effective for inducing expansion of the antigen-specific CD8 T cells in the subject; and
(b) administering to the subject an agonistic anti-TNFR25 antibody which specifically binds TNFR25 in an amount effective enhance the expansion of the antigen-specific CD8 T cells induced in step (a).
2. The method of claim 1 , wherein the cell is allogeneic to the subject.
3. The method of claim 1 , wherein the cell is a cancer cell.
4. The method of claim 1 , wherein the non-self antigen is derived from a pathogen.
5. The method of claim 1 , wherein the non-self antigen is an alloantigen.
6. The method of claim 1 , wherein the non-self antigen is derived from a tumor cell.
7. The method of claim 3 , wherein the non-self antigen is derived from a tumor cell.
8. The method of claim 1 , wherein the immunostimulatory agent is an adjuvant.
9. The method of claim 1 , wherein the antigenic composition in step (a)(i) comprises the immunostimulatory agent in step (a)(ii).
10. The method of claim 9 , wherein the immunostimulatory agent is a heatshock protein engineered to be secreted.
11. The method of claim 1 , wherein the antibody is 4C12.
12. The method of claim 1 , wherein the antibody is a functional equivalent of 4C12.
13. The method of claim 1 , wherein the method further comprises inhibiting the suppressive effects of T regulatory cells.
14. The method of claim 1 , wherein the method further comprises depleting the subject of T regulatory cells.
15. The method of claim 1 , wherein the immunostimulatory agent enhances the subject's immune response to the antigen by increasing T cell activity, or by downregulating suppressor cell activity, or both.