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J. Biol. Chem., Vol. 282, Issue 44, 32106-32111, November 2, 2007

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Specific Inhibition of Autoimmune T Cell Transmigration Contributes to Cell Functionality and Insulin Synthesis in Non-obese Diabetic (NOD) Mice^*

From the Burnham Institute for Medical Research, La Jolla, California 92037

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 cells. Therapeutic interventions leading to 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 cell functionality, increases insulin-producing 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.

Received for publication, June 29, 2007 , and in revised form, August 9, 2007.

^* The work reported here was supported by National Institutes of Health Grants AI056385, AI061139, and RR020843 (to A. Y. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Burnham Institute for Medical Research, 10901 North Torrey Pines Rd., La Jolla, CA, 92037. Tel.: 858-713-6271; E-mail: strongin{at}burnham.org.

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