Date of Award

5-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Barry T. Rouse

Committee Members

Seung J. Baek, Melissa Kennedy, Stephen J. Kennel

Abstract

Herpetic stromal keratitis (SK) is an immunoinflammatory corneal lesion caused by herpes simplex virus (HSV) infection. This infection, in some cases, can result in a chronic immunoinflammatory lesion that is the most common cause of infectious blindness in the developed world. Studies in animal models have revealed that SK lesions are orchestrated mainly by IFN-gamma producing CD4+ T cells (Th1) and neutrophils that infiltrate the corneal stroma.

The first part of this dissertation (I) reviews literature on HSV induced corneal SK immunopathology and the role of Tregs in viral infections. It also focuses on the understanding of HSV-1 induced immunoinflammatory events in the corneas, particularly T cells. The next three parts (II-IV) concentrate on the inflammatory and regulatory mechanisms that happen following HSV-1 infection in both, the cornea and secondary lymphoid tissues, and the use of therapies to control the inflammatory immune responses and the immunopathological lesions. Results in Part II evaluate the role of regulatory T cells in controlling the progression of the inflammatory lesions during the clinical phase of SK and the mechanisms used by Tregs to control immunopathology. Results of the third section show that modulating the aryl hydrocarbon receptor signaling by the use of TCDD shifts the balance toward regulatory T cells, mainly by inducing apoptosis on T effectors and generating Tregs, which results in diminished severity of SK. The fourth section describes the role of lymphotoxin-alpha (LT-a) after HSV infection, a proinflammatory molecule that can be secreted by or expressed in some subsets of T cells. Depletion of LT-a positive T cells, by the use of a monoclonal antibody seemed to be an effective approach to terminate Th1 responses thereby reducing the severity of lesions.

Collectively, in these studies, experiments were designed to understand the role of regulatory T cells during the disease and to control the progression of ongoing inflammatory reactions by developing different therapeutic strategies for SK, the most common cause of infectious blindness in the Western World.

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