Date of Award

12-2007

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pathology

Research Advisor

Terrence L. Geiger, MD, Ph.D.

Committee

Elisabeth Fitzpatrick, PhD Michael C. Levin, MD Robert B. Lorsbach, MD, PhD Edward F. Rosloniec, PhD

Abstract

The role of autoreactive, antigen-specific T-cells in the development of autoimmunity has long been documented. T-cells expressing chimeric receptors are specifically redirected against such cells and have been proven to suppress autoimmune encephalomyelitis, the murine model of multiple sclerosis. We here demonstrate the ability of humanized chimeric receptors to suppress experimental autoimmune encephalomyelitis (EAE) in a humanized mouse model by redirecting T lymphocytes against autoreactive T-cells. The receptors were synthesized by linking the 84-102 epitope of human myelin basic protein (MBP) to the extracellular and transmembrane domains of the beta chain of human major histocompatibility complex (MHC) class II molecule and the cytoplasmic zeta chain of T cell receptor and pairing it to the alpha chain linked to zeta. CD8+ receptor-modified T-cells (RMTC) were able to recognize the cognate TCR receptor of antigen-specific cells and induce cytokine secretion, proliferation, and cytolysis upon engagement. Most importantly, the RMTC were able to specifically kill antigen-specific cells both in vitro and in vivo and prevent EAE disease. We hypothesize that the humanized chimeric receptors could be used as a therapeutic approach for multiple sclerosis in the future.

DOI

10.21007/etd.cghs.2007.0215

Share

COinS