Hydroxamate-based therapy to target T cell homing in IDDM

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DESCRIPTION (provided by applicant): Our goal is to block the progression of insulin-dependent diabetes mellitus (type I diabetes; IDDM) by using small molecule hydroxamate inhibitors (MMPIs). Hyaluronan-binding CD44 is an adhesion and signaling receptor. The reciprocal relationship between cell surface-associated CD44 and membrane-type 1 matrix metalloproteinase (MT1-MMP) is essential for both efficient adhesion and for transendothelial migration of T killer cells into the islets of Langerhans. After penetration into the islets, cytotoxic T cells cause the destruction of insulin-producing p cells. We have demonstrated that MT1-MMP proteolysis is a key factor in the dynamic regulation of T cell CD44 and the subsequent islet-specific homing of diabetogenic IS-CD8* T killer cells. Inhibitor-induced changes in the reciprocal relationship between MT1-MMP and CD44 interfere with adhesion, transmigration and homing of T killer cells to the pancreas, and cause a significant delay in the onset of diabetes in NOD mice. This rodent model develops a disease closely resembling human IDDM. We will extend our findings and develop a cost-efficient and reliable in vivo strategy to inhibit MT1-MMP proteolysis of T cell CD44 by using existing and available, non-toxic hydroxamate MMPIs. These MMPIs have been tested in cancer patients, proved to be non-toxic and are readily available from major pharmaceutical companies. We hypothesize that the inhibition of MT1-MMP proteolysis of T cell CD44 by low dosages of MMPIs is a novel, highly promising approach and improved therapy of IDDM. Our approach is soundly based on our extensive and in-depth knowledge of MMPs and, especially, on our understanding of the functional role of the MT1-MMP/CD44 interactions in cancer and diabetes. As a "proof-of-principal" we will test the available hydroxamates GM6001 and AG3340. As a control, we will use the non-hydroxamate SB3CT thiol inhibitor that is potent against MMP-2 and MMP-9 but it is not effective against MT1-MMP. Our specific aims are: (1) To determine the physiological impact of the MT1-MMP proteolysis of T cell CD44 on the adhesion and migration of IS-CD8* T killer cells, (2) To validate the pharmacological value of the small molecule antagonists of MT1-MMP (the hydroxamates GM6001 and AG3340, and the thiol compound SB3CT) in a rodent model of adoptive transfer of diabetes, and (3) To validate the pharmacological value of the small molecule antagonists of MT1-MMP (the hydroxamates GM6001 and AG3340, and the thiol compound SB3CT) in pre-diabetic and freshly diseased NOD mice. We strongly believe that the results of our experimental program will lead to the development of new and effective anti-diabetic therapies for IDDM patients.