T-helper cell type 17 lineage-specific adjuvants, compositions and methods
The present invention relates to compositions and methods for the modulation of T N 17 responses. The invention provides compositions for the induction of T N 17 responses containing a TLR agonist and an apoptotic cell-associated agent or containing a microbe-infected apoptotic cell. The compositions of the present invention may also contain dendritic cells capable inducing T N 17 responses. In other embodiments, the invention provides compositions for the inhibition of T N 17 responses containing one or more blocking agents. Methods and compositions for the modulation of T N 17 responses and for the treatment of T N 17-associated diseases and for cancer are also provided.
1. An isolated T H 17-inducing dendritic cell (DC), which comprises a DC loaded with an apoptotic cell, wherein the apoptotic cell comprises a TLR ligand or an inactivated microbe, and wherein the microbe expresses an exogenous immune antigen.
2. A method for inducing a T H 17 response in a mammal, which comprises administering to a mammal in need of such induction the microbe-infected apoptotic cell that expresses an exogenous immune antigen, wherein the cell is administered to the mammal in an effective amount for inducing the T H 17 response.
3. The method of claim 2 , wherein the microbe is selected from the group consisting of attenuated live Mycobacterium bovis, Salmonella typhi , and Vibrio cholerae.
4. A method for inducing a T H 17 response in a mammal, which comprises administering to a mammal in need of such induction an effective amount for inducing the T H 17 response of an isolated T H 17-inducing DC that secretes interleukin-6 (IL-6) and transforming growth factor beta (TGF-β), wherein the combined amount of IL-6 and TGF-β is effective for inducing a T H 17 response.
5. A vaccine composition comprising a) a T H 17-inducing dendritic cell (DC) that secretes interleukin-6 (IL-6) and transforming growth factor beta isoform 1 (TGF-β), b) an immune antigen, and c) a pharmaceutically acceptable carrier or diluent, wherein a combined amount of IL-6 and TGF-β secreted by said DC and said immune antigen is effective for eliciting a T H 17 response to said immune antigen.
6. The vaccine composition of claim 5 , wherein the T H 17-inducing DC is pre-treated in vitro with the immune antigen or with a peptide fragment derived from the immune antigen.
7. The vaccine composition of claim 5 , wherein the vaccine composition further comprises a microbe-infected apoptotic cell, and a combined amount of the microbe-infected apoptotic cell, a), and b) is effective for eliciting an immune response.
8. The vaccine composition of claim 7 , wherein said microbe-infected apoptotic cell expresses said immune antigen, and wherein said immune antigen is an exogenous immune antigen.
9. A method for treating or preventing cancer in a mammal, which comprises administering to a mammal in need of such treatment the vaccine composition according to any one of claim 8 , 5 , 6 or 7 in an effective amount for treating or preventing cancer, wherein the antigen is a tumor-specific antigen.
10. The method of claim 9 , wherein the mammal is a human.
11. The method of claim 9 , wherein the cancer is an epithelial or mixed epithelial carcinoma.
12. The method of claim 11 , wherein the epithelial or mixed epithelial carcinoma is a member selected from the group consisting of ovarian cancer, breast cancer, pancreatic cancer, lung carcinoma, laryngeal carcinoma, adenoid cystic carcinoma, epithelial carcinomas of the upper aero digestive tract, hepato cellular carcinoma, colorectal carcinoma, lymphoepithelial carcinoma, squamous cell carcinoma, renal cell carcinoma, mixed epithelial and stromal tumors of the kidney, and renal angiomyoadenomatous tumors.
13. A method for inducing in a patient a T H 17-driven immune response to an antigen, which comprises administering to a patient in need of such treatment the vaccine composition according to any one of claim 8 , 5 , 6 or 7 in an effective amount for inducing a T H 17-driven immune response.
14. A method for modulating an immune response of a mammal, which comprises administering to a mammal in need of such treatment the vaccine composition according to any one of claim 8 , 5 , 6 or 7 in an effective amount for modulating the immune response of the mammal.
15. The method of claim 14 , wherein the mammal is a human.
16. The vaccine composition according to claim 5 , wherein the vaccine composition is delivered by an oral or mucosal route.
17. A method for treating or preventing cancer in a mammal, which comprises administering to a mammal in need of such treatment a vaccine composition comprising a) a microbe-infected apoptotic cell, b) a tumor specific antigen, and c) a pharmaceutically acceptable carrier or diluent, wherein the combined amount of a) and b) is effective for eliciting an immune response directed toward the tumor specific antigen and the vaccine composition is administered in an effective amount for treating or preventing cancer.
18. The method of claim 17 , wherein the cancer is an epithelial or mixed epithelial carcinoma.
19. A method for inducing in a patient a T H 17-driven immune response to an antigen, which comprises administering to a patient in need of such treatment a vaccine composition comprising a) a microbe-infected apoptotic cell, b) a tumor specific antigen, and c) a pharmaceutically acceptable carrier or diluent, wherein the combined amount of a) and b) is effective for eliciting an immune response directed toward the tumor specific antigen and the vaccine composition is administered in an effective amount for inducing a T H 17-driven immune response.
20. The method of claim 19 , wherein the patient is a human.
21. A method for modulating an immune response of a mammal, which comprises administering to a mammal in need of such treatment a vaccine composition comprising a) a microbe-infected apoptotic cell, b) a tumor specific antigen, and c) a pharmaceutically acceptable carrier or diluent, wherein the combined amount of a) and b) is effective for eliciting an immune response directed toward the tumor specific antigen and the vaccine composition is administered in an effective amount for modulating the immune response of the mammal.
22. The method of claim 18 , wherein the epithelial or mixed epithelial carcinoma is a member selected from the group consisting of ovarian cancer, breast cancer, pancreatic cancer, lung carcinoma, laryngeal carcinoma, adenoid cystic carcinoma, epithelial carcinomas of the upper aerodigestive tract, hepato cellular carcinoma, colorectal carcinoma, lymphoepithelial carcinoma, squamous cell carcinoma, renal cell carcinoma, mixed epithelial and stromal tumors of the kidney, and renal angiomyoadenomatous tumors.
23. The method of any one of claim 2 , 4 , 17 , or 21 , wherein the mammal is a human.
24. The method according to any one of claim 2 , 4 , or 21 , wherein the T H 17 response or immune response is a mucosal immune response.
25. A composition comprising a T H 17-inducing dendritic cell (DC) and interleukin-6, wherein the DC is loaded with an apoptotic cell, and wherein the apoptotic cell expresses an exogenous immune antigen.
26. A method for inducing a T H 17 response in a mammal, which comprises administering to a mammal in need of such induction the T H 17-inducing DC of claim 1 or 25 , in an effective amount for inducing the T H 17 response.