HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Savinov, A. Y. Articles by Strongin, A. Y. Search for Related Content PubMed PubMed Citation Articles by Savinov, A. Y. Articles by Strongin, A. Y.

Mechanistic insights into targeting T cell membrane proteinase to promote islet ß-cell rejuvenation in type 1 diabetes

Burnham Institute for Medical Research, La Jolla, California, USA

¹Correspondence: Burnham Institute for Medical Research, 10901 North Torrey Pines Rd., La Jolla, CA 92037, USA. E-mail: strongin{at}burnham.org

It has been well established that invasion-promoting membrane type-1 matrix metalloproteinase (MT1-MMP), a multifunctional membrane-tethered enzyme, functions in cancer cells as a mediator of pericellular proteolysis and directly cleaves several cell surface receptors, including CD44. In this report, we confirm that adhesion of diabetogenic T cells promotes the activation of endogenous MT1-MMP. Activated protease then cleaves CD44 in adherent T cells. We have validated that the T cell CD44 receptor is critical for the adhesion of diabetogenic insulin-specific, CD8-positive, K^d-restricted cells to the matrix as well as for the subsequent transmigration of the adherent T cells through the endothelium and homing of the transmigrated T cells into the pancreatic islets. We have determined that the inhibition of MT1-MMP by low dosages of AG3340 (a subnanomolar range hydroxamate inhibitor of MMPs that has been widely tested in cancer patients) inhibited both T cell MT1-MMP activity and MT1-MMP-dependent shedding of CD44, immobilized T cells on the endothelium, repressed the homing of diabetogenic T cells into the pancreatic islets, reduced insulitis and mononuclear cell infiltration, and promoted either the recovery or the rejuvenation of the functional insulin-producing ß cells in diabetic NOD mice with freshly developed type I diabetes (IDDM). We believe our data constitute a mechanistic and substantive rationale for clinical trials of selected MT1-MMP inhibitors in the therapy of IDDM in humans.—Savinov, A. Y., Rozanov, D. V., Strongin, A. Y. Mechanistic insights into targeting T cell membrane proteinase to promote islet ß-cell rejuvenation in type 1 diabetes.

Key Words: IDDM • monoclonal antibody • CD44 • MT1-MMP

This article has been cited by other articles:

				J.-A. Cho, P. Osenkowski, H. Zhao, S. Kim, M. Toth, K. Cole, A. Aboukameel, A. Saliganan, L. Schuger, R. D. Bonfil, et al. The Inactive 44-kDa Processed Form of Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) Enhances Proteolytic Activity via Regulation of Endocytosis of Active MT1-MMP J. Biol. Chem., June 20, 2008; 283(25): 17391 - 17405. [Abstract] [Full Text] [PDF]

				A. Y. Savinov, D. V. Rozanov, and A. Y. Strongin Specific Inhibition of Autoimmune T Cell Transmigration Contributes to beta Cell Functionality and Insulin Synthesis in Non-obese Diabetic (NOD) Mice J. Biol. Chem., November 2, 2007; 282(44): 32106 - 32111. [Abstract] [Full Text] [PDF]