Requirement of B7-mediated costimulation in the induction of experimental autoimmune anterior uveitis

PURPOSE. To study the role of costimulatory signaling through the CD28-B7 i nteraction in experimental autoimmune anterior uveitis (EAAU). METHODS. Naive Lewis rats were immunized with insoluble melanin-associated antigen (MAA) derived from bovine iris and ciliary, body. CTLA4-Fc, a recom binant protein comprised of the extracellular domain of human CTLA4 bound t o mouse IgG2a Fc, was used to block the CD28-B7 interaction. A mutant versi on (CTLA4-Fc-mutant) was used as a control. The effect of CTLA4-Fc on the i n vivo induction of disease with MAA was studied. Subsequently, the mechani sm by which CTLA4-Fc blocked the interaction of CD28 and B7 was investigate d in vivo, using the adoptive transfer of T cells derived from CTLA4Fc-trea ted rats, and in vitro, using the proliferative response and cytokine produ ction of MAA-T cells in the presence of CTLA4-Fc. RESULTS. CTLA4-Fc markedly reduced the incidence and severity of EAAU in Le wis rats after sensitization with MAA. The adoptive transfer of sensitized T cells from CTLA4-Fc-treated donors did not induce EAAU in naive recipient s. CTLA4-Fc inhibited the expansion of antigen-specific MAA-T cells and the production of TNF-alpha. CONCLUSIONS. The costimulatory signal delivered through CD28-B7 is required for the induction and pathogenesis of EAAU. In the absence of this signal, antigen-specific expansion of MAA reactive T cells as well as production o f TNF-alpha is inhibited. Abrogation of this costimulatory signal may be an important therapeutic option for EAAU.