Stromal keratitis resulting from infection with Herpes Simplex Virus (HSV) is an important cause of blindness in the USA. The lesions are assumed represent an immunopathological response to viral antigens in the cornea. From studies of a mouse animal model of herpetic stromal keratitis (HSK) the mechanism of immunopathology appears to involve the essential participation of T lymphocytes.. Our previous investigations have demonstrated that in the absence of CD4+ T lymphocytes, HSK is diminished in severity, but that in CD8- mice, HSK is even more severe than it is in immunologically normal mice. in this proposal experiments are designed to further define the role of CD4+ T lymphocytes in HSK as well as the part played by CD8+ T cells at modulating the HSK reaction. Efforts will be made to identify viral proteins and peptides that provide target epitopes for both the CD4+ and CD8+ T cells with the hope that ultimately vaccines Could be designed which would favorably influence the HSK reaction. Experiments are also planned to establish the mechanism(s) by which the CD4+ lymphocytes mediate the immunopathological reaction. The working hypothesis is that the CD4+ T lymphocytes mediate a delayed type hypersensitivity response which involved an essential participation of the cytokines gamma interferon (IFNgamma) and tumor necrosis factor alpha (TNFalpha) and perhaps other cytokines. Thus, modulation of cytokine expression may favorably influence the outcome of HSK. A mouse model depleted of T cells but reconstituted with adoptive transfers of immune T lymphocytes of various types and antigen reactivity will be the principal test system. Efforts will also be made to develop mice in which the cytokine genes IFNgamma and TNFalpha have been made nonfunctional by targeted gene disruption.
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