PROINFLAMMATORY FUNCTIONS OF IL-2 IN HERPES-SIMPLEX VIRUS CORNEAL INFECTION

Herpes simplex virus type 1 infection of corneas can lead to blinding inflammation in the corneal stroma, which is referred to clinically as herpes stromal keratitis. In our mouse model of this prevalent human disease, a heavy polymorphonuclear neutrophil (PMN) infiltration of th e infected cornea leads to progressive tissue destruction. This inflam matory process can be abrogated by in vivo depletion of CD4 T lymphocy tes and by neutralization of the cytokines IL-2 and IFN-gamma. The goa l of this study was to define the mechanisms by which IL-2 mediates th e corneal inflammation, Systemic neutralization of IL-2 after the onse t of corneal disease resulted in a rapid regression of inflammation an d complete resolution in 50% of the treated mice. The disease remissio n was associated with loss of IFN-gamma expression in the cornea, as d etermined by immunohistochemistry, and a significant reduction of IFN- gamma mRNA, as measured by a semiquantitative reverse transcription-PC R analysis. Within 48 h after anti-IL-2 mAb administration, the PMN ch emotactic gradient in the infected corneas was abolished, and those PM N that were already present in the central cornea exhibited clear sign s of apoptotic cell death. Our results demonstrate that IL-2 mediates corneal inflammation by 1) regulating local IFN-gamma production in an autocrine or a paracrine fashion, 2) establishing a PMN chemotactic g radient, and 3) maintaining PMN viability in the cornea, These results suggest that IL-2 might be targeted for therapeutic intervention in t his blinding disease.