Doctoral Dissertations

Date of Award

12-2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Barry T. Rouse

Committee Members

Melissa A. Kennedy, Sarah L. Lebeis, Jon L. Wall

Abstract

Herpes simplex virus 1 (HSV-1) induced stromal keratitis (SK) is a potentially blinding disease which can result in chronic immunoinflammatory stromal keratitis (SK) lesions. These lesions occur as a result of immunopathology and basically involve IFN-gamma producing CD4+ T cells (Th1) and neutrophils. Regulatory T cells are known to play a crucial part in regulating these effector T cell responses and hence hold a significant value in constraining SK lesions. In humans, SK is usually a result of reactivation of HSV-1 from the trigeminal ganglion and the patients infected with this virus usually undergoes anti- viral and anti- inflammatory treatments which are not entirely satisfactory. Hence, new approaches to control SK are needed.

The first part of this dissertation work, sheds light on the pathogenesis and control of SK lesions with emphasis on new methods to control SK. This is followed by chapter 2 in which the role of Interferons in viral immunity is studied with the focus on Interferon lambda (IL-28A). Here, we have shown that administration of IL-28A in mice after HSV-1 infection leads to reduced SK lesions and also that the viral load after the infection is reduced in the mice treated with IL-28A. The third chapter of this thesis describes the role of Retinoic acid in the treatment of SK lesions. We found out that retinoic acid has a prominent role in reducing SK lesions as it is known to stabilize Treg population and also dramatically reduce the T effector population (Th1 cell population). In-vitro and in-vivo experiments have been done to understand the mechanism and role of Retinoic acid.

The fourth chapter includes another approach to control SK lesions by the use of the superagonist monoclonal antibody CD28SA. Treatment with this antibody showed remarkable results with raised Treg to Th1 ratio and increased the function of Treg resulting in the control of SK lesions.

The research work shown here depicts fruitful ways of controlling SK pathogenesis which involves innate as well as adaptive immune response targets. The role of interferons, metabolites of vitamins and superagonist antibodies were studied for the first time in SK pathogenesis.

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