Inhibition of membrane type-1 matrix metalloproteinase by cancer drugs interferes with the homing of diabetogenic T cells into the pancreas.

Abstract

We have discovered that clinically tested inhibitors of matrix metalloproteinases can control the functional activity of T cell membrane type-1 matrix metalloproteinase (MT1-MMP) and the onset of disease in a rodent model of type 1 diabetes in non-obese diabetic mice. We determined that MT1-MMP proteolysis of the T cell surface CD44 adhesion receptor affects the homing of T cells into the pancreas. We also determined that both the induction of the intrinsic T cell MT1-MMP activity and the shedding of cellular CD44 follow the adhesion of insulin-specific, CD8-positive, Kd-restricted T cells to the matrix. Conversely, inhibition of these events by AG3340 (a potent hydroxamate inhibitor that was widely used in clinical trials in cancer patents) impedes the transmigration of diabetogenic T cells into the pancreas and protects non-obese diabetic mice from diabetes onset. Overall, our studies have divulged a previously unknown function of MT1-MMP and identified a promising novel drug target in type I diabetes.

• Authors: Alexei Y Savinov, Dmitri V Rozanov, Vladislav S Golubkov, F Susan Wong, Alex Y Strongin
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 280 Issue 30 Pg. 27755-8 (Jul 29 2005) ISSN: 0021-9258 [Print] United States
• PMID: 15944163 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Enzyme Inhibitors
• Hyaluronan Receptors
• Mmp14 protein, mouse
• Organic Chemicals
• prinomastat
• Matrix Metalloproteinases, Membrane-Associated
• Metalloendopeptidases
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 14

Topics

• Animals
• Antibodies, Monoclonal (metabolism)
• Blotting, Western
• CD8-Positive T-Lymphocytes (immunology)
• Catalytic Domain
• Cell Separation
• Enzyme Inhibitors (pharmacology)
• Flow Cytometry
• Hyaluronan Receptors (biosynthesis)
• Matrix Metalloproteinase 14
• Matrix Metalloproteinase 2 (biosynthesis)
• Matrix Metalloproteinases, Membrane-Associated
• Metalloendopeptidases (antagonists & inhibitors)
• Mice
• Mice, Inbred NOD
• Microscopy, Fluorescence
• Organic Chemicals (pharmacology)
• Pancreas (metabolism)
• T-Lymphocytes (immunology, metabolism)
• Time Factors