Matrix metalloproteinases, T cell homing and beta-cell mass in type 1 diabetes.
The pathogenesis of type 1 diabetes begins with the activation of autoimmune T killer cells and is followed by their homing into the pancreatic islets. After penetrating the pancreatic islets, T cells directly contact and destroy insulin-producing beta cells. This review provides an overview of the dynamic interactions which link T cell membrane type-1 matrix metalloproteinase (MT1-MMP) and the signaling adhesion CD44 receptor with T cell transendothelial migration and the subsequent homing of the transmigrated cells to the pancreatic islets. MT1-MMP regulates the functionality of CD44 in diabetogenic T cells. By regulating the functionality of T cell CD44, MT1-MMP mediates the transition of T cell adhesion to endothelial cells to the transendothelial migration of T cells, thus, controlling the rate at which T cells home into the pancreatic islets. As a result, the T cell MT1-MMP-CD44 axis controls the severity of the disease. Inhibition of MT1-MMP proteolysis of CD44 using highly specific and potent synthetic inhibitors, which have been clinically tested in cancer patients, reduces the rate of transendothelial migration and the homing of T cells. Result is a decrease in the net diabetogenic efficiency of T cells and a restoration of beta cell mass and insulin production in NOD mice. The latter is a reliable and widely used model of type I diabetes in humans. Overall, existing experimental evidence suggests that there is a sound mechanistic rationale for clinical trials of the inhibitors of T cell MT1-MMP in human type 1 diabetes patients.
Savinov
Alexei Y
AY
Burnham Institute for Medical Reserach, La Jolla, CA 92037, USA.
Strongin
Alex Y
AY
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D051381:Rats; D013601:T-Lymphocytes / Q000502:physiology*
D020782:Matrix Metalloproteinases