The role of the ICOS/B7RP–1 costimulatory pathway in experimental autoimmune uveitis (EAU) in mice

Abstract

Abstract: : Purpose: Experimental autoimmune uveitis (EAU) has been used as a model for human uveitis in relation to the autoimmune mechanism and proved to be a T–cell mediated autoimmune disease. Recently, inducible costimulator (ICOS), a homology of CD28, was cloned and shown to provide costimulatory signal to T cells. Expression of ICOS is restricted to activated T cells. On the other hand, its ligand B7RP–1(B7h) is expressed on B cells, macrophages, and dendritic cells. In some circumstances, B7RP–1/ICOS pathway may play an important role in T cell differentiation and autoimmune diseases. In this study, we used blocking mAb (HK5.3) to B7RP–1 to investigate whether B7RP–1/ICOS pathway plays a role in the regulation of EAU. Methods:To induce EAU, C57BL/6 mice were immunized by human IRBP peptide1–20 (hIRBP–p) emulsificated with CFA suplumented of M. tuberculosis H37RA and simultaneously injected I.p. with pertussis toxin. Anti–B7RP–1 mAbs or isotype control–IgG (400µg) were injected intraperitoneally every other day from –1 to 20 (entire phase treatment), –1 to 7 (afferent phase treatment), or 8 to 20 (efferent phase treatment). Ocular inflammation was evaluated clinically by microscope at day 14 and 21, and histopathologically at day 21 after immunization. Immunologic responses were assessed by delayed–type hypersensitibity (DTH) and cytokine production (IFN–g and IL–4) to hIRBP–p. Results:A significant inhibition (p<0.05) of the clinical scores, histopathological scores, and DTH responses were observed when anti–B7RP–1 mAbs was administered during the entire and afferent phase but not efferent phase. Moreover, ICOS–deficient mice were apparently resistant to EAU. Mice treated with anti B7RP–1 mAbs during the afferent phase failed to produce IFN–g by stimulation with hIRBP–p. Conclusions:These results indicate that the ICOS/B7RP–1 pathway plays pivotal roles in occurrence of EAU by immunization with hIRBP–p. It is conceivable that the suppressive mechanism accounts for down–regulation of Th1 cellular immune responses.

Keywords: uveitis–clinical/animal model • antigen presentation/processing • immunomodulation/immunoregulation