Immunosuppressive drugs result in global attenuation of the immune response with potential fatal side effects, thus, limiting their utility in treating autoimmune diseases. A more effective approach would involve antigen specific inactivation of autoreactive T cells. The role of the costimulatory molecule CTLA-4 in tolerance induction has been well documented. In spite of the significant tolerogenic response that was observed in our earlier, there are two potential limitations to the targeted delivery of CTLA-4 signaling. The first is a limited accessibility to certain large target tissues second is the need necessary to link anti-CTLA-4 antibody to different tissue specific antibodies for different targets. Further, this strategy may not be effective in treating systemic autoimmune conditions. To overcome these potential limitations, we have recently designed a novel strategy by using matured dendritic cells (DCs) as APCs and manipulating the interaction at the immunological synapse through a DC bound cross-linking anti-CTLA-4 antibody to induce regulatory T cells and tolerance to a specific antigen presented by DCs. The major advantages of this system are 1) one BiAb can be used to induce tolerance to any number of antigens; 2) it can be used to tolerize T cells against autoantigens of systemic as well as organ specific autoimmune diseases and also can induce tolerance to allergens, allo- and xeno-antigens, etc; 3) in vivo injected DCs could migrate into lymphoid structures and target organs throughout the body and inactivate antigen specific T cells; 4) use of the exceptional antigen presenting capability of DCs that could induce a much stronger regulatory T cell expansion and tolerance. ? ? Here, we propose to determine the therapeutic potential of an anti-CTLA-4 antibody coated dendritic cells and in inducing regulatory T cells.
In aim -l, we will test the efficacy of BiAb in inducing regulatory T cells in vivo and in vitro.
In aim -2, we will test the ability of these regulatory T cells in down modulating EAT and CIA. ? ?
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