Kenneth S. Tung, MD
Mechanisms of maintenance of self-tolerance and pathogenesis of autoimmune disease
The Tung laboratory utilizes in vivo models, immunological technique, immunopathology, protein chemistry and molecular biology to understand how T cell-driven autoimmune response and autoimmune disease are normally controlled by regulatory T cells (Treg), and how defective Treg function lead to spontaneous autoimmune disease development and organ destruction. Another mechanism under intensive investigation is the immune privileged effect of the local testicular environment that confers systemic tolerance and avoids autoimmunity against male germ cell antigens. Although the primary purpose of the work pertains to tolerance for self Ag, the same principles can be extrapolated to response against tumor specific antigens. In essence, their study investigates the fundamental mechanism responsible for cancer resistance to natural and vaccine-induced tumor immunity. Specifically, Treg and local immune privilege of tumor are currently under intense investigation in many laboratories. The local environment of many tumors is known to be infiltrated with and protected by Treg, IDO-producing macrophages, and regulatory cells that protect cancer cells from attack by tumor specific immunity. Experimentally, depletion of Treg also resulted in prompt tumor rejection in animals with concomitant tumor immunity.
In a pilot project supported by funding from the UVA CCSG, a study was initiated to investigate autoimmune disease of the prostate that results from dysregulation of immune system in neonatally thymectomized mice. Using autoantibodies produced by the diseased mice, 2 new murine prostate specific antigens were discovered: 1) a prostate specific transglutaminase and 2) a novel 110 kD unknown protein, both have human homolog. By manipulating the gain and loss of prostate antigen expression, significant results were obtained that indicate the critical dependency of Treg function on self antigen expression. Treg obtained from prostate antigen- positive donors suppress the prostate disease better than Treg from antigen-negative donors. However, the Treg function of prostate antigen-negative mice was fully upregulated after exposure to prostate antigen within 10 days but not 3 days. A new study investigated whether the autoimmune response to prostate antigens associated with autoimmune prostatitis affect development and progression of murine prostate cancer implanted in the same mice. Preliminary data indicated that the prostate tumor was heavily infiltrated by lymphocytes. Whether this can lead to tumor rejection will be determined in future studies.