Herpes simplex keratitis is the leading cause of infectious blindness in the United States. Visual loss most commonly results from recurrent stromal disease, as opposed to primary herpes keratitis. Most experimental models have focused on primary rather than recurrent keratitis. The PI has created an animal model of recurrent herpetic keratitis in humans. The focal stromal opacification, regional neovascularization and endotheliitis produced in the recurrent keratitis model, is in distinct contrast to the keratinization, limbus to limbus opacification and exudative blepharoconjunctivitis that is seen in primary herpes simplex keratitis in NIH mice. While current data indicates that primary and recurrent herpes keratitis may share some common immune mechanisms, it is the PI's hypothesis that the considerable differences in the clinical pathology, viral antigen distribution within the cornea, and responses to vaccine therapy suggests that the immune responses in these two diseases will not be identical. The PI has proposed studies designed to test the hypothesis that recurrent HSK in NIH inbred mice is mediated by CD4+ T cells of the Th1 phenotype. In order to test this hypothesis he will: (1) define the cellular and costimulatory requirements for recurrent disease by selective depletion experiments; (2) characterize and compare the cytokine profile in corneal tissue during primary versus recurrent keratitis, using ELISA and RT-PCR analysis and then determine the relevance of these cytokines to recurrent disease by specifically targeting cytokines with monoclonal antibodies; (3) determine whether protective vaccination with a vhs-mutant strain of HSV-1 involves the selective stimulation of a Th2-mediated immune response. The information derived from these studies will lead to a better understanding of the biology of recurrent herpes simplex keratitis in mice and thereby this disease in humans. Furthermore, these studies could possibly suggest more specific and effective immunotherapies designed to ameliorate herpes simplex keratitis disease.
