AN IMMUNOLOGISTS VIEW OF HERPES-SIMPLEX KERATITIS - THYGESON-LECTURE 1996, PRESENTED AT THE OCULAR-MICROBIOLOGY-AND-IMMUNOLOGY-GROUP-MEETING, OCTOBER 26, 1996

Purpose, To review recent progress in understanding the mechanisms of herpes simplex virus 1 (HSV-l)-induced immunopathology in the cornea, as revealed by studies in a mouse model. Methods. The corneas of A/J m ice were infected with 5x10(4) plaque-forming units (PFU) of the RE st rain of HSV-1, and the development of inflammation was assessed by sli t-lamp, histologic, or immunohistochemical examination. The immunopath ologic mechanisms were then defined by observing the effect of in vivo depletion of corneal Langerhans' cells, or T-lymphocyte subpopulation s, or in vivo neutralization of cytokines on adhesion molecule express ion or leukocytic infiltration of the infected cornea. Results, After corneal infection, 60-70% of mice develop corneal opacity due to leuko cytic infiltration, neovascularization, and edema. Polymorphonuclear n eutrophils (PMN) represent 90% of the infiltrating cells, with numerou s CD4(+), but few CD8(+), T cells present. Depleting CD4(+) T cells or Langerhans' cells prevents inflammation from developing. Neutralizing interleukin-2 (IL-2) or interferon gamma (IFN-gamma) can prevent infl ammation or cause a remission of existing disease. IFN-gamma neutraliz ation causes a rapid block of PMN extravastion from the blood in assoc iation with reduced platelet endothelial adhesion molecule 1 (PECAM-1) expression on the corneal vascular endothelium. IL-2 neutralization r esults in decreased IFN-gamma production, reduced chemotaxis, and loss of PMN viability in the infected cornea. Conclusion. Herpes stromal k eratitis is a CD4(+) T cell-dependent inflammatory process in which PM N infiltration and destruction of the cornea are regulated, at least i n part, by the T-helper type 1 (Thl) cytokines IL-2 and LFN-gamma.