Date of Award

1998

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Gillian Galbraith

Second Advisor

Prabhakar Baliga

Third Advisor

Jean-Michel Goust

Fourth Advisor

Kathryn E. Meier

Fifth Advisor

Michael G. Schmidt

Abstract

Transferrin receptor (TfR) appears on activated T cells following interaction of the antigen-major histocompatibility complex (MHC) with the T cell receptor (TCR) and the resulting expression of IL-2 receptor (IL-2R). Previous work in the laboratory has demonstrated allograft prolongation following administration of anti-TfR monoclonal antibody (mAb). Studies in the area of cancer immunotherapy have shown that TfR blockade and modulation deprives the tumor of iron, which is essential for continued growth and proliferation, while TfR modulation results in poor T cell proliferation, respectively. This dissertation focuses on the hypothesis that modulation of T cell TfR expression is associated with altered T cell responses to alloantigen. The studies presented here explored the immunosuppressive effects of anti-TfR mAb in experimental transplantation. U sing heterotopic, nonvascularized cardiac allograft and cell-mediated immunity models, anti-TfR mAb was demonstrated to be a' potent immunosuppressant in prolonging cardiac allograft survival and altering T cell responses to alloantigen. Enhanced cardiac allograft survival was achieved by simultaneous blockade of TfR and IL-2R. The possible mechanisms responsible for this allograft prolongation and suppressed T cell responses include alterations in T cell surface receptors, shifts in the intragraft cytokine profiles, and modulation in signaling pathways. TfR modulation in association with the immunosuppressive effects of DST was demonstrated by a decrease in TfR expression that paralleled early CTL suppression. In addition, TfR modulation was observed following delivery ofanti-CD3 mAb or anti-TfR mAb in combination with anti-IL-2R mAb. The induction of TfR expression appeared to be independent of CD28 and IL-2R signaling, while CD3 signaling was involved in the promotion of TfR expression. The novel blockade of TfR, alone or in combination with blockade of IL-2R, in transplant and cell-mediated immunity models have provided additional insights into the development of better immunosuppressive regimens for clinical transplantation.

Rights

All rights reserved. Copyright is held by the author.

Download

Share

COinS