Corneal inflammation is a significant cause of visual morbidity. Inflammation can be induced by a variety of infectious and noninfectious agents.The corneal stromal inflammation associated with HSV-1 infections is the leading infectious cause of blindness in this country. The KOS and RE strains of Herpes simplex virus (HSV-1) have been found to induce markedly different types of inflammation in the corneas of A/J mice.CD8 T lymphocytes play a critical role in the inflammation induced in the cornea by KOS HSV-1, which is characterized primarily by a mononuclear infiltrate. RE HSV-1 infection leads to a predominantly neutrophilic infiltration, in which CD4 T lymphocytes play an essential role. Since leukocyte extravasation and migration into inflammatory sites appear to be controlled by local expression of cytokines and adhesion molecules, the involvement of these molecules will be investigated in the corneal inflammation induced in mouse corneas by the KOS and RE strains of HSV-1. These studies will involve both in vivo and in vitro assays for leukocyte extravasation and migration. The cornea is an ideal tissue in which to conduct these studies becaused it is avascular.Thus, leukocytes that extravasate from the vessels at the peripheral margin of the cornea must migrate through several millimeters of tissue to reach the site of infection in the central cornea. This permits one to separately study the processes of extravasation and migration through the extracellular matrix of the corneal stroma. The involvement of various cytokines in the extravasion and migration of different populations of inflammatory cells into KOS- and RE HSV-1-infected corneas will be tested. This will be done in vivo by treatment of infected mice with monoclonal antibodies capable of neutralizing various cytokines, and then following the progress of the inflammatory response. The same antibodies will be employed that are need to block migration of leukocytes into infected corneal buttons, an assay recently developed in our laboratory. Similar studies will be conducted with antibodies to adhesion molecules and other inhibitors of the interaction of adhesion molecules with their ligands on vascular endothelium and extracellular matrix proteins.These studies may lead to the development of new means of intervening in the blinding inflammatory disease that is associated with HSV-1 corneal infections. These studies may also provide a useful paradigm for studying other inflammatory diesases that occur in the cornea as well as other tissues.
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