PILOT--INDUCTION OF T CELL TOLERANCE TO ANTIVIRAL VECTOR

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Description (adapted from the application): An unsolved problem in adenovirus-based gene therapy is the elicitation of an immune response that rapidly eliminates infected cells and ablates transgene expression. Although deletion of certain antigenic structure from the adenovirus improves the prolongation of transgene expression, the immune response and the subsequent tissue inflammation remain major problems in the application of adenovirus based gene therapy. Thus, it is both reasonable and desirable to design an immunointervention strategy to induce specific immune tolerance to the adenoviral vector. The overall goal of this application is to test an innovative strategy to induce specific tolerance by syngeneic antigen presenting cells (APCs) that express Fas ligand. The central hypothesis is that when the APCs present adenoviral antigens to the responding T cells, high levels of Fas ligand expression by these APCs would induce apoptosis of adenovirus specific T cells. Thus, exposure of host to adenoviral vector infected APCs expressing Fas ligand would lead to depletion of a specific T cell population, and therefore induce immune tolerance to the adenoviral vector. The decreased immune response to the adenoviral vectors would protect the transfected host cells from T cell attack and prolong transgene expression. Moreover, if transgenic products are immunogenic, then T cell tolerance can be induced in a similar manner. To test this hypothesis, we will first determine whether immune tolerance to adenoviral vectors can be specifically induced by adenoviral antigen presenting cells that express Fas ligand; and then determine whether treatment with adenoviral antigen presenting cells that express Fas ligand improves the efficacy of adenoviral gene therapy in an animal model of cystic fibrosis. The present application will introduce a novel and powerful immunointervention strategy into adenoviral vector based gene therapy designed to inhibit the inflammatory response and prolong transgene expression. The accomplishment of this application might improve adenoviral gene therapy in the treatment of cystic fibrosis.