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

Alexei Y. Savinov, Dmitri Rozanov, Alex Y. Strongin

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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, Kd-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 β 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.

Original languageEnglish (US)
Pages (from-to)1793-1801
Number of pages9
JournalFASEB Journal
Volume20
Issue number11
DOIs
StatePublished - Sep 2006
Externally publishedYes

Fingerprint

Matrix Metalloproteinase 14
Rejuvenation
T-cells
insulin-dependent diabetes mellitus
islets of Langerhans
Cell membranes
Medical problems
Type 1 Diabetes Mellitus
Islets of Langerhans
cell membranes
Peptide Hydrolases
proteinases
T-lymphocytes
Cell Membrane
T-Lymphocytes
Matrix Metalloproteinase Inhibitors
Endothelium
endothelium
adhesion
Insulin

Keywords

  • CD44
  • IDDM
  • Monoclonal antibody
  • MT1-MMP

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Mechanistic insights into targeting T cell membrane proteinase to promote islet β-cell rejuvenation in type 1 diabetes. / Savinov, Alexei Y.; Rozanov, Dmitri; Strongin, Alex Y.

In: FASEB Journal, Vol. 20, No. 11, 09.2006, p. 1793-1801.

Research output: Contribution to journalArticle

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