Interstitial keratitis due to Onchocerca volvulus infection is a major cause of visual impairment in Africa and Latin America. The long-term goal of this research is to understand the immunopathogenesis of this corneal pathology so as to advance development of a safe and effective vaccine. Because studies of human corneas are limited by ethical and practical constraints, a murine model of O. volvulus antigen-induced interstitial keratitis was used to investigate this problem. BALB/c mice immunized and challenged intrastromally with O. volvulus antigens(s) develop corneal neovascularization and infiltrate of acute inflammatory cells, whereas similar studies with PPD show less severe corneal pathology. Corneal pathology induced by O. volvulus is dependent on intact CD4 or CD8 cells since immunodeficient nude mice fail to develop interstitial keratitis. Antigen-driven lymphoid cells of O. volvulus- sensitized mice are strictly of the Th2-type (IL-4 and IL-5>IFN-g), whereas PPD induces a strict Th1 response (exclusive IFN-g).
Specific aims of the proposed research are to: 1. Examine the local cytokine responses (IFN-g,IL-4, IL-5, IL-10) and phenotypes of lymphocytes infiltrating corneas in mice with interstitial keratitis. 2. Determine the pathogenic role of Th2 and Th1 cytokines in development of O. volvulus antigen-induced interstitial keratitis. 3. Assess the capacity of human CD4 cells to mediate O. volvulus interstitial keratitis in mice with sever combined immunodeficiency. The studies will advance knowledge of the role of allergic responses and Th2 cytokines in the pathogenesis of ocular manifestations of onchocerciasis. This knowledge will be important in the design of a vaccine to prevent infections and ocular pathology in human onchocerciasis.
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