Specific inhibition of autoimmune T cell transmigration contributes to beta cell functionality and insulin synthesis in non-obese diabetic (NOD) mice
ABSTRACT Human diabetes mellitus (IDDM; type I diabetes) is a T cell-mediated disease that is closely modeled in non-obese diabetic (NOD) mice. The pathogenesis of IDDM involves the transmigration of autoimmune T cells into the pancreatic islets and the subsequent destruction of insulin-producing beta cells. Therapeutic interventions leading to beta cell regeneration and the reversal of established IDDM are exceedingly limited. We report here that specific inhibition of T cell intra-islet transmigration by using a small molecule proteinase inhibitor restores beta cell functionality, increases insulin-producing beta cell mass, and alleviates the severity of IDDM in acutely diabetic NOD mice. As a result, acutely diabetic NOD mice do not require insulin injections for survival for a significant time period, thus providing a promising clue to effect IDDM reversal in humans. The extensive morphometric analyses and the measurements of both the C-peptide blood levels and the proinsulin mRNA levels in the islets support our conclusions. Diabetes transfer experiments suggest that the inhibitor specifically represses the T cell transmigration and homing processes as opposed to causing immunosuppression. Overall, our data provide a rationale for the pharmacological control of the T cell transmigration step in human IDDM.
SourceAvailable from: Alex Y Strongin[Show abstract] [Hide abstract]
ABSTRACT: The pathogenesis of type 1 diabetes begins with the activation of autoimmune T killer cells and is followed by their homing into the pancreatic islets. After penetrating the pancreatic islets, T cells directly contact and destroy insulin-producing beta cells. This review provides an overview of the dynamic interactions which link T cell membrane type-1 matrix metalloproteinase (MT1-MMP) and the signaling adhesion CD44 receptor with T cell transendothelial migration and the subsequent homing of the transmigrated cells to the pancreatic islets. MT1-MMP regulates the functionality of CD44 in diabetogenic T cells. By regulating the functionality of T cell CD44, MT1-MMP mediates the transition of T cell adhesion to endothelial cells to the transendothelial migration of T cells, thus, controlling the rate at which T cells home into the pancreatic islets. As a result, the T cell MT1-MMP-CD44 axis controls the severity of the disease. Inhibition of MT1-MMP proteolysis of CD44 using highly specific and potent synthetic inhibitors, which have been clinically tested in cancer patients, reduces the rate of transendothelial migration and the homing of T cells. Result is a decrease in the net diabetogenic efficiency of T cells and a restoration of beta cell mass and insulin production in NOD mice. The latter is a reliable and widely used model of type I diabetes in humans. Overall, existing experimental evidence suggests that there is a sound mechanistic rationale for clinical trials of the inhibitors of T cell MT1-MMP in human type 1 diabetes patients.Vitamins & Hormones 02/2009; 80:541-62. DOI:10.1016/S0083-6729(08)00618-3 · 1.78 Impact Factor
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ABSTRACT: Pathogenesis of type 1 diabetes involves the activation of autoimmune T cells, consequent homing of activated lymphocytes to the pancreatic islets and ensuing destruction of insulin-producing b cells. Interaction between activated lymphocytes and endothelial cells in the islets is the hallmark of the homing process. Initial adhesion, firm adhesion and diapedesis of lymphocytes are the three crucial steps involved in the homing process. Cell-surface receptors including integrins, selectins and hyaluronate receptor CD44 mediate the initial steps of homing. Diapedesis relies on a series of proteolytic events mediated by matrix metalloproteinases. Here, molecular mechanisms governing transendothelial migration of the diabetogenic effector cells are discussed and resulting pharmacological strategies are considered.Drug discovery today 07/2010; 15(13-14):531-9. DOI:10.1016/j.drudis.2010.05.013 · 6.63 Impact Factor
Article: Chapter 11.5 Clays and Human Health