GSBS Dissertations and Theses
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.
Repository Citation
Bishop KD. (2005). Egr-2 and PD-1 Are Required for Induction and Maintenance of T Cell Anergy: A Dissertation. GSBS Dissertations and Theses. https://doi.org/10.13028/jhfw-c454. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/354
DOI
10.13028/jhfw-c454
DOI Link
Rights and Permissions
Copyright is held by the author, with all rights reserved.
Included in
Amino Acids, Peptides, and Proteins Commons, Biological Factors Commons, Cells Commons, Endocrine System Diseases Commons, Genetic Phenomena Commons, Hemic and Immune Systems Commons, Immune System Diseases Commons, Nutritional and Metabolic Diseases Commons, Surgical Procedures, Operative Commons, Therapeutics Commons