Doctoral Dissertations

Date of Award

8-1995

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Barry T, Rouse

Committee Members

David O. Slauson, Malcolm McCracken, J. Erby Wilkinson, Al Ichiki

Abstract

This dissertation firstly compared the histopathological features of HSK in the established BALB/c mouse to a new model, the reconstituted SCID mouse. HSV-1 infected SCID mice reconstituted with immune lymphocytes developed corneal lesions that were histopathologically similar to lesions in immunocompetent BALB/c mice and therefore provide an appropriate animal model in which to study the immunopathology of HSK. In SCID mice reconstituted with naive donor cells, however, corneal lesion development may not be solely a function of immunopathological host response to viral antigen. This conclusion was based on the finding that some of these mice develop clinical HSK without a concurrent HSV-1 immune response. Secondly, the reconstituted SCID mouse model was used to explore the contributions of NK cells and endogenous IFN-γ to the immunopathology of HSK. In vivo administration of anti-asialo GMI to deplete NK cells in reconstituted SCID mice resulted in diminished incidence and severity of HSK when compared to controls (13% vs. 43%). However, evidence to prove that SCID mouse NK cells (and endogenous IFN-γ) regulated the donor T cell cytokine profiles and influenced the maintenance of a pathological, Th1 immune response, were inconclusive. Yet depletion of NK cells did significantly lower the number of PMN present in the corneas of reconstituted SCID mice and overall diminished the inflammatory cell density. Therefore, NK cells may indirectly contribute to HSK in this model through the secretion of cytokines other than IFN-γ and possible candidates include IL-1, TNF-α or GM-CSF. Finally, to further explore the role of IFN-k in the manifestation of HSK, IFN-γ knockout (gko -/-) mice were infected on the corneas with HSV-1, and subsequent virus kinetics, virus specific immune responses and lesion development were characterized. Gko -/- mice were highly susceptible to virus induced encephalitis and virus persisted in the corneas twice as long as in controls. Gko -/- mice developed typical HSK indicating that although IFN-γ plays an important role in viral clearance, it is not essential for HSK. Lesions in gko -/- mice may develop, in part, due to non-specific mechanisms such as prolonged virus replication that results in excessive corneal damage.

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