Doctoral Dissertations

Date of Award

5-1999

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Barry T. Rouse

Committee Members

Albert T. Ichiki, Philip N. Bochsler, Robert N. Moore

Abstract

Experimental infection of mice by scarification of cornea with HSV exhibits ocular disease pattem similar to the histopathological manifestations seen in man. An experiment in athymic mice that did not succumb to herpetic stromal keratitis (HSK) showed that HSK is an immunopathological manifestation of host T cell mediated immune response. It was confirmed later that following infection of corneas in the murine model with RE strain of HSV-1, the immunopathology is manifested by CD4+T lymphocytes that exhibit the Thl cytokine profile. A prominent cell type present in HSK lesions is the neutrophil (PMN), the infiltration of which is a biphasic event following HSV infection of immunocompetent mice, an initial transient infiltration appeared to be triggered by replicating virus and a second more intense invasion along with other inflammatory cells including CD4+ cells. This secondary PMN invasion episode, seemingly orchestrated by CD4+T cells, is called HSK and is not apparently triggered by replicating virus which remains undetectable at this stage. By taking advantage of cell depletion and adoptive transfer studies, the type of cells involved and sequence of cellular events in initiation and effector phase have been addressed. While some of these approaches could explain one facet of HSK immunopathology, identifying the antigen(s) (viral and/or host) to which T cells respond is another interesting field. Some of the recent observations lend credence to the growing notion that HSK represents an autoreactive inflammatory reaction set off by HSV that unmasks sequestered corneal antigens is normally accessible to the immune system. In this study, experiments were designed to address such issues and hence primarily focussed on elucidating the mechanisms which drive the inflammatory responses in HSV-infected murine cornea.

Experiments described in this dissertation are aimed at T cell specificity, role of viral antigens in lesion development and mechanisms that drive the inflammatory response in the infected cornea. The series of experiments described here and their results indicate 'nonspecific activation of CD4+T cells' as a novel mechanism in herpes-induced stromal keratitis.

Following an overview of herpes induced ocular disease in part 1, part 2 in addition to supporting HSK as a T cell-mediated immunoinflammatory disease, the results also show the potential for controlling the disease by coreceptor modulation. In part 3, characterization of a unique mouse model with skewed T cell repertoire (Tg- SCID) has been described which is useful for studying antigen specificity in T cell-mediated immunopathological disorders. Results of experiments described in part 4 propose nonspecific activation of T cells and hence the cytokine milieu by virus replication as a novel mechanism by which CD4+ T cells could orchestrate a virus induced ocular immunopathology. Finally, using adoptive transfer protocols, part 5 examines whether lesion development in Tg-SCID mice is virus replication, persistence and CD4+ T cell dependent. Additionally, in part 5, the differential role of HSV-specific antiserum and CD8+ T cells on virus dissemination was analyzed in the infected cornea.

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