Suppression of established experimental autoimmune uveitis by anti-LFA-1α Ab

PURPOSE. To identify costimulatory molecules that are important in the effector phase of experimental autoimmune uveitis (EAU). METHODS. EAU was induced in C57BL/6 (136) mice by transfer of activated T cells specific for the interphotoreceptor-binding protein (IRBP) 1-20 peptide. The animals were then treated with and without anti-leukocyte function associated antigen (LFA)-1 alpha mAb, at day 0 or 10 (disease onset) after T-cell transfer. Clinical signs of inflammation, ocular histology, and infiltrated inflammatory cells in the eye were compared. The primary and secondary proliferative responses of uveitogenic CD4 and CD8T cells were tested after treatment with costimulatory blockers in vivo and in vitro. Moreover, the abilities of uveitogenic T cell trafficking and their interaction with retinal astrocytes were examined. RESULTS. Anti-LFA-1 alpha Abs caused significant suppression of disease when administered either at the time of effector uveitogenic T cell transfer or at disease onset. Studies of the mechanisms by which anti-LFA-1 alpha Ab inhibits the effector phase of uveitis demonstrated that it blocks multiple pathogenic events of uveitis mediated by IRBP-specific uveitogenic T cells, including the activation of T cells outside and inside the eye and the trafficking of activated autoreactive T cells into the inflammatory site. In addition, Ab treatment selectively suppressed the activation and expansion of pathogenic, but not regulatory, T cells in vivo. CONCLUSIONS. Anti-LFA-1 alpha Abs are potent inhibitors of established autoimmune uveitis and that such treatment may be applicable not only for the prevention, but also the treatment, of T-cell-mediated autoimmune diseases.