Publication Date

2005-07-13

Document Type

Doctoral Dissertation

Academic Program

MD/PhD

Department

Program in Molecular Medicine

First Thesis Advisor

Dr. Michael Czech

Keywords

Clonal Anergy, DNA-Binding Proteins, Transcription Factors, Zinc Fingers, Antigens, Surface, CD4-Positive T-Lymphocytes, Diabetes Mellitus, Type 1, Islets of Langerhans Transplantation, Immune Tolerance, Immunosuppression

Abstract

The prevalence of diabetes is approaching epidemic proportions worldwide. There is currently no cure for type 1 diabetes, and successful treatment requires constant monitoring of blood sugars and use of exogenous insulin to prevent hyperglycemia. Diabetes will be curable when pancreatic β-islet cells can be transplanted into diabetes patients without requiring long-term immunosuppression. This will require learning more about the induction of functional tolerance, a state that maintains the competence of the immune system to most antigens but protects graft-specific antigens from immune rejection, permitting transplantation. One known mechanism of peripheral tolerance is T cell anergy, a phenotype of hypo-reponsiveness in CD4+ T cells. The focus of this thesis is a description of factors shown to be specific to the induction and maintenance of T cell anergy, whose loss reverses the anergic phenotype, restoring the ability of the cells to proliferate in response to antigen. The first of these is Egr-2, a zinc-finger transcription factor, whose presence is required for the induction of anergy induced in T cell clones by TCR stimulation in the absence of costimulation. Egr-2 is shown to be important to anergy induction but not anergy maintenance. In contrast, a negative costimulation receptor, PD-1, is shown to be necessary for the maintenance of anergy. It is possible that learning more about the genetic factors that orchestrate T cell anergy will prove useful in the development of tolerance-based protocols for organ and tissue transplantation without the use of long-term immunosuppression.

DOI

10.13028/jhfw-c454

Rights and Permissions

Copyright is held by the author, with all rights reserved.

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