Date of Award

12-2008

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Barry T Rouse

Committee Members

Mark Y. Sangster, Robert N. Moore, Stephen J. Kennel

Abstract

Herpetic stromal keratitis (HSK) is an immunoinflammatory corneal lesion caused by herpes simplex virus (HSV) infection. One of the dire consequences of which is blindness resulting from tissue destructive immunopathological reaction in corneal stroma. The lesion is considered to be orchestrated mainly by CD4+ T cells of Th1 phenotype. Studies on two animal models viz. immunocompetent and immunodeficient, shed light on the issues on specificity of the cells which at least in immunocomprised TCR transgenic animals were shown to be activated in a bystander manner. However, initial infiltration by innate immune cells in response to replicating virus set the stage for the chronic inflammation in the corneal stroma. Paradoxically, these cells are also critical in the control of virus in the cornea.

The first part (Part I) of this dissertation focuses on the understanding of HSV-1 induced immunoinflammatory processes in the cornea and trigeminal ganglia including the secondary lymphoid tissues and the involvement of regulatory mechanisms. The next three parts (Part II-IV) focus on the control of the inflammatory lesion and anti-inflammatory mechanisms that are activated following virus infection in the lymphoid organs and cornea. Results in Part II evaluate the immunotherapeutic potential of regulatory T cells in controlling the progression of the inflammatory lesions after ocular HSV infection. Results of the third section show that sequestration of T effector cells in the lymphoid organs and limited access to site of inflammation using a drug FTY720 after HSV infection resulted in diminished severity of SK and expansion of antigen-specific regulatory T cells that could contribute to the diminution of lesion severity. The fourth section describes the role of a previously unexplored inhibitory interaction between a Th1 specific cell surface marker, TIM-3 and its ligand galectin-9 in the causation of the viral induced corneal immunopathology. The administration of galectin-9 seemed to be an effective approach to terminate Th1 responses and promote regulatory cells activity thereby controlling the severity of lesions.

In this study, experiments were designed to control the progression of the ongoing inflammatory reaction in the cornea in order to evaluate some of the therapeutic strategies for HSK.

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