TLR4 Mediates Early Graft Failure After Intraportal Islet Transplantation
TLR4 Mediates Early Graft Failure After Intraportal Islet Transplantation
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DOI：
10.1111/j.1600-6143.2010.03151.x
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发表时间：
2010-07-01
影响因子：
8.8
通讯作者：
Yin, D. P.
中科院分区：
文献类型：
--
作者：
Gao, Q.;Ma, L. L.;Yin, D. P.
我们先前的研究显示，门静脉内的胰岛栓子阻塞血流并诱发局部炎症反应，导致门静脉内移植后胰岛移植物功能丧失。本研究旨在检测Toll样受体（TLR）激活是否介导早期胰岛移植失败。将同基因胰岛移植物移植到化学诱导的糖尿病小鼠中，TLR缺陷小鼠用作胰岛移植物的供体和/或受体。通过生物发光成像（BLI）、定量RT-PCR（qRT-PCR）和组织学分析胰岛活力、促炎细胞因子、高迁移率族蛋白B1（HMGB 1）和NF-κ B活化。在门静脉内胰岛移植的小鼠中观察到早期胰岛移植失败，促炎细胞因子、HMGB 1表达、NF-κ B活化、caspase-3和TUNEL阳性细胞增加。供体中TLR 4的缺乏抑制了NF-κ B B的活化，减少了促炎细胞因子，提高了胰岛移植物的存活率，但受体中没有。用抗HMGB 1单克隆抗体（mAb，2g 7）阻断HMGB 1可抑制炎症反应，如TNF α和IL-1 β产生减少所证明，并改善胰岛活力。我们得出结论，TLR 4激活介导门静脉内胰岛移植后早期移植物衰竭。抑制TLR 4活化是减轻门静脉内胰岛移植后早期移植物衰竭的一种新策略。
We have previously shown that islet emboli in the portal vein block blood flow and induce local inflammatory reaction, resulting in functional loss of islet grafts following intraportal transplantation. This study was designed to test whether Toll-like receptor (TLR) activation mediates early islet graft failure. Syngeneic islet grafts were transplanted into chemically induced diabetic mice, and TLR deficient mice were used as donors and/or recipients of islet grafts. Islet viability, proinflammatory cytokines, high-mobility group box-1 (HMGB1) and NF-kappa B activation were analyzed by bioluminesce imaging (BLI), quantitative RT-PCR (qRT-PCR) and histology. Early islet graft failure was observed in mice with intraportal islet engrafts with increased proinflammatory cytokines, HMGB1 expression, NF-kappa B activation, caspase-3 and TUNEL positive cells. Deficiency of TLR4 in donor, but not in recipient, inhibited NF-kappa B activation, reduced proinflammatory cytokines and improved viability of islet grafts. Blockade of HMGB1 with anti-HMGB1 monoclonal antibody (mAb, 2g7) inhibited inflammatory reactions, as evidenced by reduced TNF alpha and IL-1 ss production, and improved islet viability. We conclude that TLR4 activation mediates early graft failure following intraportal islet transplantation. Inhibition of TLR4 activation represents a novel strategy to attenuate early graft failure following intraportal islet transplantation.