Wang Jingjing, Sun Zhen, Gou Wenyu, Adams David B, Cui Wanxing, Morgan Katherine A, Strange Charlie, Wang Hongjun
Department of Surgery, Medical University of South Carolina, Charleston, SC.
MedStar Georgetown University Hospital, Washington, DC.
Diabetes. 2017 Apr;66(4):970-980. doi: 10.2337/db16-1036. Epub 2017 Jan 9.
Islet cell transplantation has limited effectiveness because of an instant blood-mediated inflammatory reaction (IBMIR) that occurs immediately after cell infusion and leads to dramatic β-cell death. In intraportal islet transplantation models using mouse and human islets, we demonstrated that α-1 antitrypsin (AAT; Prolastin-C), a serine protease inhibitor used for the treatment of AAT deficiency, inhibits IBMIR and cytokine-induced inflammation in islets. In mice, more diabetic recipients reached normoglycemia after intraportal islet transplantation when they were treated with AAT compared with mice treated with saline. AAT suppressed blood-mediated coagulation pathways by diminishing tissue factor production, reducing plasma thrombin-antithrombin complex levels and fibrinogen deposition on islet grafts, which correlated with less graft damage and apoptosis. AAT-treated mice showed reduced serum tumor necrosis factor-α levels, decreased lymphocytic infiltration, and decreased nuclear factor (NF)-κB activation compared with controls. The potent anti-inflammatory effect of AAT is possibly mediated by suppression of c-Jun N-terminal kinase (JNK) phosphorylation. Blocking JNK activation failed to further reduce cytokine-induced apoptosis in β-cells. Taken together, AAT significantly improves islet graft survival after intraportal islet transplantation by mitigation of coagulation in IBMIR and suppression of cytokine-induced JNK and NF-κB activation. AAT-based therapy has the potential to improve graft survival in human islet transplantation and other cellular therapies on the horizon.
胰岛细胞移植的有效性有限，因为在细胞输注后会立即发生即时血液介导的炎症反应（IBMIR），并导致大量β细胞死亡。在使用小鼠和人类胰岛的门静脉内胰岛移植模型中，我们证明了α-1抗胰蛋白酶（AAT；普洛莱斯坦-C），一种用于治疗AAT缺乏症的丝氨酸蛋白酶抑制剂，可抑制IBMIR和细胞因子诱导的胰岛炎症。在小鼠中，与用生理盐水治疗的小鼠相比，接受AAT治疗的糖尿病受体在门静脉内胰岛移植后更多地达到了正常血糖水平。AAT通过减少组织因子的产生、降低血浆凝血酶-抗凝血酶复合物水平以及胰岛移植物上的纤维蛋白原沉积来抑制血液介导的凝血途径，这与较少的移植物损伤和细胞凋亡相关。与对照组相比，接受AAT治疗的小鼠血清肿瘤坏死因子-α水平降低、淋巴细胞浸润减少且核因子（NF）-κB激活减少。AAT的强效抗炎作用可能是通过抑制c-Jun氨基末端激酶（JNK）磷酸化介导的。阻断JNK激活未能进一步降低细胞因子诱导的β细胞凋亡。综上所述，AAT通过减轻IBMIR中的凝血以及抑制细胞因子诱导的JNK和NF-κB激活，显著提高了门静脉内胰岛移植后胰岛移植物的存活率。基于AAT的疗法有可能提高人类胰岛移植和其他即将出现的细胞疗法中的移植物存活率。
