Dissertation

Dysregulated T-B Lymphocyte Collaboration in Autoimmunity Poses a Barrier to Transplant Tolerance

Stocks, Blair Taylor

2016

Overview

Organ replacement via surgical transplantation represents a potentially life-saving intervention for numerous autoimmune conditions; however, the heightened immunogenicity characteristic of these autoimmune patients remains a significant barrier to long-term graft acceptance. Every year a significant number of autoimmune transplant recipients must undergo re-transplantation directly attributable to both recurrent autoimmunity and heightened allograft immunogenicity. No better is this clinical scenario modeled than the autoimmune non-obese diabetic (NOD) mouse, a model in which no therapy has ever induced permanent transplant tolerance to islet allografts or any other allograft type in the intact NOD immune system, thereby indicating the severity of this immunologic barrier. Overall, determining the immunological barriers to successful organ tolerance in the autoimmune environment would prove invaluable. Not only would developing a mechanistic understanding of how the autoimmune environment fails to tolerate foreign allografts provide new targets for restoring graft tolerance in autoimmunity, but moreover, this knowledge would enhance the scientific community’s understanding of specific cellular and molecular pathways that govern immunological tolerance. Autoimmune pathogenesis and failures to maintain graft tolerance are in part driven by insufficiently regulated, antigen-specific T and B effector cells of the adaptive immune system. Although numerous studies have so far defined specific roles for inadequate immune regulation in driving autoimmunity and perpetuating loss of graft tolerance independently, it remains to be determined whether the failures in immune regulation that perpetuate loss of self-tolerance in autoimmunity directly contribute to an inability to later “learn” how to tolerate foreign graft tissue as self. Moreover, whether known dysregulations in T-B cell collaboration that drive different forms of autoimmunity directly contribute to an enhanced, inadequately regulated antigraft response remains to be explored. In my dissertation, I explore the specific hypothesis that dysregulated T-B cell collaboration in autoimmunity poses a stringent barrier to transplant tolerance. Using murine models of Type 1 Diabetes (T1D) and Systemic Lupus Erythematosus (SLE), I define specific cellular and molecular T-B cell aberrancies in these autoimmune environments that lead to a generalized resistance to transplant tolerance. In setting the stage for my findings, I have provided background information pertinent to the immunologic mechanisms that drive the transplant response. After conducting a brief historical review of clinical transplantation in the United States, I highlight the pioneering work of basic transplant immunologists and their roles in defining the mechanisms of transplant rejection and tolerance. As T and B cells possess the unique ability to recognize graft tissue in an antigen specific manner, I mechanistically address how these cells actively reject or learn to tolerate foreign graft tissue. Finally, I review the key studies in which a generalized resistance to transplant tolerance in autoimmunity was first described while highlighting the outstanding knowledge gaps generated by these bodies of work. Overall, my findings reveal that enhancing graft-protective T Regulatory Cell function is a necessary component of restoring transplantation tolerance in the autoimmune setting. Moreover, interrupting specific pathways that enhance antigraft effector cell function may further provide a targeted means to enhance transplant tolerance in autoimmunity.

• Publisher: ProQuest Dissertations & Theses
• Subject: Immunology
• ISBN: 9780438823228, 0438823222