Control of herpetic stromal keratitis using CTLA4Ig fusion protein

Herpetic stromal keratitis (HSK) is an immunoinflammatory lesion in the cornea of the eye set off by infection with herpes simplex virus (HSV). The disease appears to be orchestrated by CD4+ T cells of the Th1 phenotype but the identity of target antigens involved in HSK remains unknown. In this proposal, we investigated if the inhibition of T cell activation with the fusion protein CTLA4Ig would abrogate the disease process when administered systemically. BALB/c mice infected with HSV-1 (RE strain) by corneal scarification were injected intraperitoneally on a single occasion with CTLA4Ig or L6 control (IgG Fc) given on day 2, day 5, or day 8 postinfection. Lesions in CTLA4Ig-treated mice showed markedly reduced severity judged by both slit lamp biomicroscopy and histopathology if treated on day 2 or day 5. Treated animals also expressed minimal HSV-specific splenic T cell and humoral antibody responses. Judged by the profile of T cell and IgG subset responses, inhibition by CTLA4Ig appeared more directly on the HSV-specific Th1 response, correlating with the known role of such cells in HSK. Delay of treatment until the time of disease onset (day 8) had marginal or negligible effects. The results indicate that blockade of coreceptor interaction between T cells and antigen-presenting cells during the induction phase of immune response significantly impairs onset and severity of herpetic stromal keratitis.