Savinov Alexei Y, Strongin Alex Y
Burnham Institute for Medical Reserach, La Jolla, CA 92037, USA.
Vitam Horm. 2009;80:541-62. doi: 10.1016/S0083-6729(08)00618-3.
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.
1型糖尿病的发病机制始于自身免疫性T杀伤细胞的激活，随后这些细胞归巢至胰岛。穿透胰岛后，T细胞直接接触并破坏产生胰岛素的β细胞。本综述概述了将T细胞膜型-1基质金属蛋白酶（MT1-MMP）和信号黏附CD44受体与T细胞跨内皮迁移以及随后迁移细胞归巢至胰岛联系起来的动态相互作用。MT1-MMP调节致糖尿病T细胞中CD44的功能。通过调节T细胞CD44的功能，MT1-MMP介导T细胞从黏附于内皮细胞转变为跨内皮迁移，从而控制T细胞归巢至胰岛的速率。因此，T细胞MT1-MMP-CD44轴控制疾病的严重程度。使用已在癌症患者中进行临床测试的高度特异性和强效合成抑制剂抑制MT1-MMP对CD44的蛋白水解作用，可降低T细胞的跨内皮迁移速率和归巢。结果是T细胞的净致糖尿病效率降低，NOD小鼠的β细胞数量和胰岛素产生得以恢复。后者是人类1型糖尿病一种可靠且广泛使用的模型。总体而言，现有实验证据表明，对人类1型糖尿病患者进行T细胞MT1-MMP抑制剂临床试验有合理的机制依据。
