Tolerance to self and foreign antigens is an active process that is mediated by multiple mechanisms. Central tolerance is promoted by negative selection or central deletion of a large number of lymphocytes capable of reacting to self molecules. However, some self-reactive lymphocytes escape this process and remain present in the adult and must be regulated by active tolerance mechanisms that involve T regulatory cells, anergy, or apoptosis. Here, we will study a model for peripheral tolerance that can be induced through the eye called Anterior Chamber Associated Immune Deviation (ACAID). The eye is an immune privileged site that has evolved to exhibit immunosuppressive mechanisms that prevent immune inflammatory reactions in the eye in order to preserve vision. In order to better understand how we might adapt ACAID mechanism to immunotherapy of autoimmune disease in the eye, our first aim will investigate the mechanisms of ACAID induction in sensitized vs na?ve mice. During these studies we will also induce antigen specific ACAID in mice that receive cornea transplants or in which experimental autoimmune uveitis is induced by transferring in vitro generated ACAID- like tolerogenic APC, and explore the role of the NKT cell in this therapy. The results of these studies will raise the possibility of a cell based therapy to treat immune inflammatory diseases in the eye.
The study of innate immune cells in immune deviation initiated through immune privilege sites is a novel and useful area for research. It is known that the innate immune NKT cell is involved in self-tolerance since in its absence, a variety of autoimmune diseases arise. Furthermore, the study of eye induced tolerance in sensitized mice and the dependence on NKT cells is novel and not well studied. The study of the generation of peripheral tolerance to antigens to which the host is already sensitized is directly related to the development of the novel therapies for treatment of immune inflammatory disease.
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