The deleterious and undesirable immune response by auto- and allo-reactive T cells to host antigens is the fundamental and therapeutic problem in autoimmunity and transplantation, respectively. For example, to impart an effective cure for type 1 diabetes (T1D), we would need to: (i) prevent or halt the T cell-mediated destruction of insulin-producing, pancreatic beta cells, or (ii) preserve the host islet cell mass or surgically-supplied replacement islets, from destruction by antigen- specific T cells. To date, these goals remain unfulfilled. While progress has been made with new non-steroidal T cell immunosuppressive drugs, the underlying strategy remains global suppression of all T cell-mediated immunity to inhibit the few detrimental effector T cells responsible for syngeneic or allogeneic islet cell destruction. This broad inhibitory approach, while temporally effective, is the equivalent of declaring immunologic martial law, curtailing the normal and beneficial actions of most adaptive immune cells in order to stop the rare rogue T cell. This approach has three major drawbacks: (i) it lacks specificity;(ii) it increases the risks of opportunistic infections and cancers;and (iii) it causes secondary organ damage and toxicity. Thus, it is clear that we need to do better by finding novel and innovative means of controlling infrequent, yet injurious, autoimmune T cells while maintaining beneficial memory T cells to pathogens and vaccines and na?ve T cells needed to combat newly encountered pathogens. We believe we have a novel approach to the specific targeting of unwanted T cells in vivo. We find that as T cells transition between their three major states - na?ve, activated and memory - they exhibit distinct and dynamic patterns of pro- and anti-apoptotic Bcl-2 family members that have fundamental biologic consequences, for example, setting the initial levels of na?ve T cells, expanding activated effector T cells, restoring post-activation homeostasis, and potentiating long-term survival of memory T cells. Thus, the dynamism between pro-apoptotic (e.g., Bim, Bax, and Bak) and the anti-apoptotic (e.g., Bcl-2 Bcl-xL, and Mcl-1) Bcl-2 family members forms a regulatory circuit that controls the survival of individual populations of T cells. Owing to these unique expression patterns, na?ve, activated, and memory T cells also exhibit differential sensitivity to apoptosis, with activated T cells being most sensitive. Recently, we have used small-molecule antagonists of Bcl-2 family members to target T cells for destruction based on their activation state. These antagonists exert their specificity based on the subtle structural differences among the cell-death, BH3, domains of Bcl-2 family members. Our preliminary data demonstrate that in vivo treatment with one BH3 inhibitor completely protects mice from diabetes following adoptive transfer of diabetogenic CD4+ T cells, while ABT-737 dramatically reduces antigen-specific CD8+ T cell memory cells. Importantly, the selective hypersensitivity of activate T cells to BH3 antagonism suggests an innovative means of attacking the problem of autoreactive or unwanted T cell responses. We believe immunosuppression therapy should be turned on its head. Rather than using broad and blunt immunosuppression of all T cells, unwanted auto- and allo-reactive T cells should be acutely activated, in vivo, and then differentially targeted for apoptosis using specific BH3-domain antagonists. The net effect would be to spare beneficial immunity, while purging undesirable rogue T cells. To this end, we propose the following specific aims:
Aim 1 : To determine the efficacy of specific novel small-molecule BH3 antagonists in establishing functional T cell tolerance to syngeneic islets while preserving na?ve and memory T cell function in CD8+ T cells.
Aim 2 : To determine the efficacy of specific novel small-molecule BH3 antagonists in establishing functional T cell tolerance to syngeneic islets while preserving na?ve and memory T cell function in CD4+ T cells.
This application focuses on a novel technique to selectively destroy T lymphocytes that cause type 1 diabetes (T1D) while largely keeping the existing naove and memory T lymphocyte populations untouched. For years the only way to inhibit unwanted T cell responses to self antigens - like those found in and on the insulin-producing pancreatic beta cells - was to inhibit ALL T cells by the use of broad spectrum immunosuppressive drugs. This has worked to allow for most organ transplantation but has had limited effects with pancreatic islet cell transplants. What is novel in our proposal in the identification of new small molecule inhibitors of cell proteins that regulate T cell survival. Normally, when T lymphocytes encounter their antigen - including self antigens - the T cell proliferates and gain effector functions. But when they do, they also become more sensitive to the natural cell death program called apoptosis, or programmed cell death. This program is regulated by members of the Bcl-2 family of proteins. In activated T cells several of these proteins change in their expression making it easier to kill off these activated cells (which is important and normal once they are no longer needed, such as after the clearance of a virus). What we have found is that by using small molecule inhibitors (drugs) that target this cells we can preferentially destroy activated T cells while sparing resting na?ve cells or long-term memory cells. When given to a host with an ongoing autoimmune disease, such as T1D, we can purge the host of these rogue pancreatic beta cell specific T cells and protect the host from T1D. What we propose here is to understand the mechanism behind these small molecule inhibitors and to determine just how specific these drugs are at targeting activated disease causing T cells while ignoring the beneficial memory and na?ve cells we all need.
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