T-helper cell type 17 lineage-specific adjuvants, compositions and methods
The present invention relates to compositions and methods for the modulation of T H 17 responses. The invention provides compositions for the induction of T H 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 of inducing T H 17 responses. In other embodiments, the invention provides compositions for the inhibition of T H 17 responses containing one or more blocking agents. Methods and compositions for the modulation of T H 17 responses and for the treatment of T H 17-associated diseases and for cancer are also provided.
1. A method for generating a T H 17-inducing dendritic cell (DC) that secretes interleukin-6 (IL-6) and transforming growth factor beta (TGF-β), wherein the combined amount of IL-6 and TGF-β secreted by the T H 17-inducing DC is effective for inducing a T H 17 response when the T H 17-inducing DC is administered to a subject, the method comprising administering to a DC in vitro a Toll-like receptor (TLR) agonist and an apoptotic cell-associated agent in a combined amount effective for generating the T H 17-inducing DC.
2. The method of claim 1 , wherein the TLR agonist and the apoptotic cell-associated agent are either in direct physical association or are combined in a manner that allows internalization as a single entity by the DC in vitro.
3. The method according to claim 1 , wherein the apoptotic cell-associated agent comprises any one of the agents selected from the group consisting of an apoptotic cell, an apoptotic cell mimic, phosphatidylserine, a microbe-infected apoptotic cell, a phosphatidylserine mimic, a mimic of cell surface calreticulin translocation, and a polypeptide that is a marker of apoptosis.
4. The method according to claim 1 , wherein the TLR agonist comprises any one of the agents selected from the group consisting of a TLR ligand, a TLR ligand mimic, a synthetic or chemical TLR ligand, a cell or particle comprising a pathogen-associated molecular pattern, a microbial pathogen, a bacterium, a virus, and a viral particle.
5. A method for generating a T H 17-inducing dendritic cell (DC) that secretes interleukin-6 (IL-6) and transforming growth factor beta (TGF-β), wherein the combined amount of IL-6 and TGF-β secreted by the T H 17-inducing DC is effective for inducing a T H 17 response when the T H 17-inducing DC is administered to a subject, the method comprising administering to a DC in vitro (i) and (ii), as a single entity or in a combined form, wherein (i) is at least one member selected from the group consisting of a Toll-like receptor (TLR) ligand, a TLR ligand mimic, a synthetic or chemical TLR ligand, a cell or particle comprising a pathogen-associated molecular pattern, a microbial pathogen, a TLR agonist, a bacterium, and a virus or viral-like particle, and wherein (ii) is at least one member selected from the group consisting of an apoptotic cell, a microbe-infected apoptotic cell, an apoptotic cell mimic, phosphatidylserine, a phosphatidylserine mimic, an apoptotic cell-associated agent, a mimic of cell surface calreticulin translocation, and a polypeptide that is a marker of apoptosis; wherein the combined amount of (i) and (ii) is effective for generating the T H 17-inducing DC.
6. An immunogenic composition comprising
a) a T H 17-inducing DC that secretes IL-6 and TGF-β,
b) an immune antigen, and
c) a pharmaceutically acceptable carrier or diluent,
wherein a combined amount of the IL-6 and the TGF-β secreted by the T H 17-inducing DC and the immune antigen is effective for eliciting a T H 17 response to the immune antigen in a subject which is administered the immunogenic composition.
7. The immunogenic composition of claim 6 , wherein the T H 17-inducing DC is generated by a method comprising pre-treating a DC in vitro with a TLR agonist and an apoptotic cell-associated agent in a combined amount effective for generating the T H 17-inducing DC.
8. The immunogenic composition of claim 7 , wherein the TLR agonist and the apoptotic cell-associated agent are combined in a manner that allows internalization as a single entity by the DC in vitro.
9. The immunogenic composition of claim 6 , 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.
10. A method for inducing in a patient an antigen-specific T H 17-driven immune response, which comprises administering to a patient in need thereof the immunogenic composition according to claim 6 in an effective amount for inducing the antigen-specific T H 17-driven immune response.
11. The method according to claim 10 , wherein the antigen-specific T H 17-driven immune response comprises a mucosal immune response.
12. The method according to claim 10 , wherein the patient is a human.
13. A method for treating cancer in a mammal, which comprises administering to a mammal in need thereof the immunogenic composition according to claim 6 in an effective amount for treating cancer, wherein the immune antigen in the immunogenic composition is a tumor-specific antigen.
14. The method of claim 13 , wherein the cancer is an epithelial or mixed epithelial carcinoma.
15. The method of claim 14 , 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, hepatocellular carcinoma, colorectal carcinoma, lymphoepithelial carcinoma, squamous cell carcinoma, renal cell carcinoma, mixed epithelial and stromal tumors of the kidney, and renal angiomyoadenomatous tumors.
16. The method according to claim 13 , wherein the immunogenic composition is administered to the mammal by an oral or mucosal route.