Low molecular weight dextran sulfate prevents the instant blood-mediated inflammatory reaction induced by adult porcine islets
Low molecular weight dextran sulfate prevents the instant blood-mediated inflammatory reaction induced by adult porcine islets
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DOI：
10.1097/01.tp.0000114872.26990.4f
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发表时间：
2004-03-15
期刊：
影响因子：
6.2
通讯作者：
Nilsson, B
中科院分区：
文献类型：
--
作者：
Goto, M;Johansson, H;Nilsson, B
背景。临床胰岛异种移植的主要障碍之一是有害的即时血液介导的炎症反应（IBMIR），当胰岛暴露于血液时，它会导致血小板迅速结合到胰岛表面，激活凝血和补体系统，并使白细胞浸润胰岛。
方法。本研究在使用人血的体外管路环试验以及使用糖尿病无胸腺小鼠的体内模型中，评估低分子量硫酸葡聚糖（LMW - DS）对猪胰岛诱导的IBMIR的影响。
结果。体外实验表明，在0.01 mg/mL的LMW - DS存在时，血小板消耗、凝血和补体激活已经减少，并且在0.1 mg/mL时，LMW - DS可阻止BMIR。免疫组织化学研究显示，在最高剂量下白细胞浸润被消除。体内实验表明，在接受LMW - DS治疗的受体中，移植的猪胰岛存活时间显著延长，并且对移植胰岛的形态学检查显示IBMIR减少，这与体外研究结果相似。
结论。鉴于LMW - DS已用于临床研究且无严重不良反应，它有潜力作为一种药物候选物，可控制猪胰岛经门静脉移植时诱导的强烈先天免疫反应。
Background. One of the main obstacles to clinical islet xenotransplantation is the injurious instant blood-mediated inflammatory reaction (IBMIR) that causes rapid binding of platelets to the islet surface, activation of the coagulation and complement systems, and leukocyte infiltration of the islets when the islets are exposed to blood.Methods. This study assesses the effect of low molecular weight dextran sulfate (LMW-DS) on IBMIR induced by porcine islets in an in vitro tubing loop assay using human blood and in an in vivo model using diabetic athymic mice.Results. In vitro experiments demonstrated that platelet consumption, coagulation, and complement activation were already reduced in the presence of LMW-DS at 0.01 mg/mL, and that at 0.1 mg/mL, LMW-DS prevented BMIR. Immunohistochemical investigation showed that the leukocyte infiltration was abrogated at the highest dose. In vivo experiments showed that the transplanted pig islets survived for a significantly longer period in recipients treated with LMW-DS, and morphologic examination of transplanted islets showed a reduction in IBMIR analogous to that demonstrated by in vitro studies.Conclusions. Given that LMW-DS has been used in clinical studies without serious adverse reactions, it has potential as a drug candidate that can control the strong innate immune response induced by pig islets when transplanted through the portal vein.