α1-antitrypsin monotherapy prolongs islet allograft survival in mice
α1-antitrypsin monotherapy prolongs islet allograft survival in mice
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DOI：
10.1073/pnas.0505579102
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发表时间：
2005-08-23
影响因子：
11.1
通讯作者：
Dinarello, CA
中科院分区：
文献类型：
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作者：
Lewis, EC;Shapiro, L;Dinarello, CA
胰岛移植在1型糖尿病患者中应用非糖尿病免疫抑制治疗显示出良好的效果。然而，长期研究表明，除了损害移植受者的免疫系统外，胰岛的生存能力也受到了损害。在这里，我们证明，在没有免疫抑制剂的情况下，临床级别的人α1-抗胰蛋白酶(HAAT)(主要的血清丝氨酸蛋白酶抑制剂)的单一治疗可以延长移植的同种异体糖尿病小鼠的胰岛移植物存活和正常血糖，一直持续到抗HAAT抗体的产生。与未经处理或白蛋白控制处理的移植受体相比，后者在第10天排斥胰岛，AAT处理的小鼠在整个治疗过程中表现出细胞渗透减少和移植物内胰岛素的完整产生。使用腹膜渗透模型，我们证明AAT使同种异体成纤维细胞诱导的自然杀伤细胞流入减少89%，CD3阳性细胞流入减少44%，硫代乙醇酸盐诱导的中性粒细胞迁移减少66%。ATT还延长了链脲佐菌素诱导的β细胞毒性后小鼠的胰岛存活率。在体外，检测了几种胰岛对IL-1β/干扰素-γ刺激的反应。在AAT存在的情况下，胰岛显示出更高的活性和可诱导的胰岛素分泌。胰岛释放的一氧化氮减少了36%，巨噬细胞炎症蛋白1α减少了82%，表面MHC II类分子的表达减少了63%。IL-1β/干扰素-γ刺激的胰岛细胞释放的肿瘤坏死因子α减少了99%，同时CD45阳性的胰岛细胞膜上的TNFa积聚增加了8倍。根据已有的安全记录和AAT的非糖尿病潜能，这些数据表明AAT作为胰岛移植患者的辅助治疗可能是有益的。
Islet transplantation for type 1 diabetic patients shows promising results with the use of nondiabetogenic immunosuppressive therapy. However, in addition to compromising the immune system of transplant recipients, long-term studies demonstrate that islet viability is impaired. Here, we demonstrate that, in the absence of immunosuppressive agents, monotherapy with clinical-grade human alpha 1-antitrypsin (hAAT), the major serum serine-protease inhibitor, prolongs islet graft survival and normoglycemia in transplanted allogeneic diabetic mice, lasting until the development of anti-hAAT antibodies. Compared to untreated or albumin-control-treated graft recipients, which rejected islets at day 10, AAT-treated mice displayed diminished cellular infiltrates and intact intragraft insulin production throughout treatment. Using peritoneal infiltration models, we demonstrate that AAT decreases allogeneic fibroblast-elicited natural-killer-cell influx by 89%, CD3-positive cell influx by 44%, and thioglycolate-elicited neutrophil emigration by 66%. ATT also extended islet viability in mice after streptozotocin-induced beta cell toxicity. In vitro, several islet responses to IL-1 beta/IFN gamma stimulation were examined. In the presence of AAT, islets displayed enhanced viability and inducible insulin secretion. Islets also released 36% less nitric oxide and 82% less macrophage inflammatory protein 1 alpha and expressed 63% fewer surface MHC class II molecules. TNF alpha release from IL-1 beta/IFN gamma-stimulated islet cells was reduced by 99%, accompanied by an 8-fold increase in the accumulation of membrane TNFa on CD45-positive islet cells. In light of the established safety record and the nondiabetogenic potential of AAT, these data suggest that AAT may be beneficial as adjunctive therapy in patients undergoing islet transplantation.