Role of Immune co-signals in the pathogenesis and development of new treatment of refractory uveoretinitis

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Endogenous uveitis such as Behcet's disease (BD) is a potentially blinding disease in humans and is responsible for 10-15% of the acquired blindness in Japan. Although endogenous uveitis covers a spectrum of clinical entities, all forms are believed to share immunohistological similarities characterized by the infiltration of mainly CD4 T cells. It is well known that CD4 T cell activation requires the integration of at least two distinct signals. Signal one results from antigen-specific T cell receptor engagement by MHC class 2-bound peptide presented by antigen presenting cells (APC). Signal two results from engagement of costimulatory molecules expressed by APC and T cell. The CD28 homolog inducible costimulator (ICOS) has recently been identified as a novel member of the CD28 costimulator family, and is expressed by activated T cells in both humans and mice. The ICOS ligand, B7-related protein (B7RP-1), also known as B7 homologous protein (B7h), is constitutively expressed by APC. As the result of microarray analysis, ICOS in PBMCs showed the greatest difference in expression in BD patients with uveitis compared to healthy controls. ICOS expression on CD4 T cells in BD patients with uveitis was significantly higher than that in healthy individuals both before and after Con A stimulation. Among BD patients, ICOS expression on CD4 T cells was significantly higher in those with active uveitis than in those with remitted uveitis. Blockade of ICOS/B7-related protein-1 interaction by anti-ICOS mAb significantly decreased IFN-γ and IL-17 production by PBMCs when stimulated with Con A or IRBP in BD with active uveitis. In conclusion, our data provide additional evidence for the potential utility of ICOS expression on CD4 T cells as a marker to determine disease activity and that ICOS represents a promising therapeutic target for ocular BD by inhibiting Th1 and Th17 cytokines.