The research objective is to understand the cellular and molecular mechanisms using experimental murine models that define the pathogenesis of herpetic stromal keratitis, a common cause of human visual impairment. Experiments are planned to define the relationship between three events hypothesized as crucial in HSK pathogenesis. These are replication by herpes simplex virus, primary neutrophil invasion, and orchestration of a chronic inflammatory response by CD4+ T lymphocytes. The neutrophil invasion, occurring in response to appropriate chemokine induction is hypothesized to contribute to viral removal as well as to cause expression of corneal autoantigens. The clinically evident HSK disease is hypothesized to represent principally a CD4+ T cell controlled autoreactive inflammatory event, which persists until stimuli for type 2 T cell cytokine induction, primarily IL-10, predominate after which resolution occurs. Experiments to manipulate the expression of HSK with plasmid DNA encoding cytokines and other immunoregulatory molecules are proposed. This approach may provide an alternative and/or adjunct means of managing the clinical expression of HSK in the natural host.
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