

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IMM-K (02))
Program Officer
Spain, Lisa M
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Cincinnati Children's Hospital Medical Center
United States
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