Date of Graduation

5-2015

Document Type

Dissertation (PhD)

Program Affiliation

Immunology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Laurence Cooper, MD, PhD,

Committee Member

Dean Lee, MD, PhD

Committee Member

Russell Broaddus, MD, PhD

Committee Member

Joya Chandra, PhD

Committee Member

Dat Tran, MD

Abstract

T cells are blood cells which organize the immune system of the host. These cells are necessary for the host to respond appropriately to threats from foreign organisms and cancerous growth. However, in the case of certain infections and cancer, T cells are unable to respond appropriately to a threat and establish immunity. This leads to disease when the infection or cancer is not sufficiently eliminated. On the other hand, T cells can lack tolerance for healthy tissue and perceive healthy tissue as infected. The ensuing over-reactive immune response also leads to disease. A delicate balance must exist between immunity and tolerance to prevent these diseases. Small molecules have been developed to ameliorate human diseases resulting from the failure of T cell immunity or T cell tolerance, but these small molecules rarely lead to cure. This has driven investigators to develop approaches where T cells are modified to target disease in order to restore the balance between immunity and tolerance. The results have been promising and include long-term cure of disease. Furthermore, genetic modification of T cells has the potential to provide supra-physiological capacities to T cells, including targeting infection or cancer in ways that T cells could never achieve naturally within the host. These gene therapy approaches are hindered by technical challenges such as selecting for genetically-modified T cells and against unwanted T cell phenotypes. Here we describe novel methods utilizing unique transgenes and small molecules aimed at improving the selection of genetically-modified T cells for the treatment of disease in humans.

Keywords

Immunology, Immunotherapy, Gene Therapy, Dihydrofolate Reductase, thymidylate synthase, chimeric antigen receptor, regulatory T cells, drug resistance, methotrexate