Inhibition of membrane type-1 matrix metalloproteinase by cancer drugs interferes with the homing of diabetogenic T cells into the pancreas.
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.
Savinov
Alexei Y
AY
The Burnham Institute, La Jolla, California 92037, USA.
Rozanov
Dmitri V
DV
Golubkov
Vladislav S
VS
Wong
F Susan
FS
Strongin
Alex Y
AY
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D020134:Catalytic Domain; D002469:Cell Separation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D016688:Mice, Inbred NOD; D008856:Microscopy, Fluorescence; D009930:Organic Chemicals / Q000494:pharmacology; D010179:Pancreas / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D018960:Hyaluronan Receptors; C507096:Mmp14 protein, mouse; D009930:Organic Chemicals; C113282:prinomastat; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14