The Role of OX40/OX40L Pathway in Murine Experimental Autoimmune Uveoretinitis (EAU)

Abstract

Abstract: : Purpose: Experimental autoimmune uveoretinitis (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. OX40 ligand (OX40L) expressed on APCs, and its receptor, OX40 on activated T cells, are members of the TNF superfamily, and contribute to the development or pathogenesis of the various animal autoimmune diseases. Although developtment of EAU is dependent upon T cell costimulation through CD28–B7 and CD40L–CD40 pathway, the importance of OX40 in EAU remains unknown. In this study, we have examined the involvement of the OX40/OX40L costimulatory pathway in murine EAU by using anti–OX40L (RM134L) mAb and OX40–deficient mice. Methods: EAU was induced in C57BL/6 mice by immunization with IRBP 1–20 peptide in CFA with M.tuberculosis H37RA and injection of pertussis toxin. Anti–OX40L mAb or control IgG (400µg) were injected i.p. on alternate days from day –1 to 14 (entire phase treatment). –1 to 7 (induction phase treatment), or 8 to 14 (effector phase treatment). EAU was also challenged in OX40L–deficient mice as well. Severity of EAU was evaluated clinically and histopathologically on day 16. Immunological responses were assessed by proliferation responses and cytokine production to IRBP–peptide. Results: EAU was predominantly exacerbated clinically and histopathologically in mice treated with the anti–OX40L mAb in the entire and induction phase, but not in the effector phase. Similar results were observed in OX40L–deficient mice. Treatment with anti–OX40L mAb during the entire and induction phase significantly enhanced their IFN–g production. Conclusions: These results indicate that the blockade of OX40/OX40L pathway deteriorated the disease by enhancing Th1 responses, suggesting that OX40 costimulation plays an inhibitory role in the developtment of murine EAU.

Keywords: uveitis-clinical/animal model • immunomodulation/immunoregulation • autoimmune disease