CONTROL OF HERPETIC STROMAL KERATITIS USING CTLA4IG FUSION PROTEIN

Herpetic stromal keratitis (HSK) is an immunoinflammatory lesion in th e cornea of the eye set off by infection with herpes simplex virus (HS V). 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 intraperitoneall y on a single occasion with CTLA4Ig or L6 control (IgG Fc) given on da y 2, day 5, or day 8 postinfection. Lesions in CTLA4Ig-treated mice sh owed 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 res ponses. Judged by the profile of T cell and IgG subset responses, inhi bition by CTLA4Ig appeared more directly on the HSV-specific Th1 respo nse, correlating with the known role of such cells in HSE. Delay of tr eatment until the time of disease onset (day 8) had marginal or neglig ible effects. The results indicate that blockade of coreceptor interac tion between T cells and antigen-presenting cells during the induction phase of immune response significantly impairs onset and severity of herpetic stromal keratitis. (C) 1998 Academic Press.