Cd28 costimulation is required for induction of autoimmune uveitis, but not for endotoxin-induced uveitis

Purpose. Optimal T cell activation requires both the engagement of the TCR by Antigen/MHC and of CD28 by B7 molecule(s). The purpose of this study was to investigate whether CD28 is essential for induction of immunologically mediated disease in two murine uveitis models: 1 ) Experimental autoimmune uveitis (EAU), a T cell mediated autoimmune disease induced by immunization with the retinal antigen (IRBP); and 2) Endotoxin-induced uveitis (EIU), an ocular inflammatory response elicited by footpad injection of LPS, where T cells have been shown to play a role, but whose mechanism is not fully understood. Methods. CD28-deficient mice (C57B1/6 backround) were tested for susceptibility to EAU by immunization with increasing doses of IRBP (50-300 u,g). EAU development was also assessed in B10. A mice immunized with IRBP and treated with antibodies to B7-1 and B7-2 individually (1050 ug total) or together (2100 ug total). EAU was graded by histopathology 21 days after immunization. Response to IRBP was determined by lymphocyte proliferation. In the EIU model, CD28-deficient and wild type mice received a footpad injection of 300 jig of LPS. Disease was evaluated 24 h later by determining the number of inflammatory cells and level of IL-6 in the anterior chamber of the eye. Results. EAU was suppressed in mice treated with antibodies to either B7-1 or B7-2. Mice given both antibodies were completely protected from disease, and their lymphocytes did not proliferate to IRBP. CD28-deficient mice did not develop EAU even after immunization with 300 ug of IRBP, and had reduced proliferative responses to IRBP. In contrast, the CD28-deficient mice were fully capable of developing LPS uveitis. Conclusions. CD28 costimulation is required for EAU induction and for priming of uveitogenic effector T cells. In contrast, CD28 costimulation is not required for development of endotoxin induced uveitis.