Targeting the T‑cell membrane type-1 matrix metalloproteinase‑CD44 axis in a transferred type 1 diabetes model in NOD mice

Savinov,Alexei  Y.; Strongin,Alex  Y.

doi:10.3892/etm.2012.821

Targeting the T‑cell membrane type-1 matrix metalloproteinase‑CD44 axis in a transferred type 1 diabetes model in NOD mice

Authors:
- Alexei Y. Savinov
- Alex Y. Strongin
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Affiliations: Sanford Research, University of South Dakota, Sioux Falls, SD 57105, USA, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA
Published online on: November 20, 2012 https://doi.org/10.3892/etm.2012.821
Pages: 438-442

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Abstract

This study tested the hypothesis that membrane‑tethered type‑1 matrix metalloproteinase (MT1-MMP)-induced proteolysis of T cell CD44 is important for defining the migration and function of autoreactive T cells, including diabetogenic, insulin-specific and Kd-restricted IS-CD8+ cells. To confirm the importance of MT1-MMP proteolysis of CD44 in type 1 diabetes (T1D), the anti-diabetic effects of three MMP inhibitors (3(S)-2,2-dimethyl-4[4-pyridin-4-yloxy-benzenesulfonyl]-thiomorpholine-3-carboxylic acid hydroxamate [AG3340], 2-(4-phenoxyphenylsulfonylmethyl)thiirane [SB-3CT] and epigallocatechin-3-gallate [EGCG]) were compared using an adoptive diabetes transfer model in non-obese diabetic (NOD) mice. Only AG3340 was capable of inhibiting both the activity of MT1-MMP and the shedding of CD44 in T cells; and the transendothelial migration and homing of IS-CD8+ T cells into the pancreatic islets. SB-3CT and EGCG were incapable of inhibiting T cell MT1-MMP efficiently. As a result, AG3340 alone, but not SB-3CT or EGCG, delayed the onset of transferred diabetes in NOD mice. In summary, the results of the present study emphasize that the MT1-MMP-CD44 axis has a unique involvement in T1D development. Accordingly, we suggest that a potent small‑molecule MT1-MMP antagonist is required for the design of novel therapies for T1D.

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