Dissecting the instant blood-mediated inflammatory reaction in islet xenotransplantation.
Dissecting the instant blood-mediated inflammatory reaction in islet xenotransplantation.
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DOI：
10.1111/j.1399-3089.2008.00482.x
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发表时间：
2008-07
影响因子：
3.9
通讯作者：
Nilsson B
中科院分区：
文献类型：
--
作者：
Goto M;Tjernberg J;Dufrane D;Elgue G;Brandhorst D;Ekdahl KN;Brandhorst H;Wennberg L;Kurokawa Y;Satomi S;Lambris JD;Gianello P;Korsgren O;Nilsson B
猪胰岛移植到非人灵长类动物体内后，移植组织会立即发生大量破坏。猪胰岛引发的有害的即时血液介导的炎症反应（IBMIR）很可能是这种组织损失的原因；这种反应也可能介导受体的适应性免疫反应，从而需要高强度的免疫抑制方案。
低分子量硫酸葡聚糖（LMW - DS）和补体抑制剂坎普他汀（Compstatin）被用于一系列体外和体内研究，旨在剖析胰岛移植非人灵长类动物模型中的异种IBMIR。将成年猪胰岛（10,000 IEQs/kg）经门静脉移植到三对食蟹猴体内，这些食蟹猴分别接受了LMW - DS或肝素（对照）治疗，并对IBMIR的影响进行了表征。还将猪胰岛在人血浆中进行体外培养，以评估LMW - DS和坎普他汀对补体的抑制作用。
形态学评分和免疫组化染色显示，在对照（肝素处理）动物中观察到的严重胰岛破坏以及血小板、巨噬细胞、中性粒细胞和T细胞浸润，在LMW - DS处理的猴子中未出现。在接受LMW - DS治疗的猴子中，凝血和补体激活均显著减少，但在胰岛表面仍发现IgM和补体片段。这种残留的补体激活在体外可被坎普他汀抑制。
在这个非人灵长类动物模型中，异种IBMIR的特征是抗体立即结合，引发有害的补体激活，随后的凝血反应又导致进一步的补体激活。LMW - DS（体内和体外）和坎普他汀（体外）在抑制这种IBMIR方面的有效性，为可用于消除猪 - 人临床胰岛移植中IBMIR的方案提供了基础。
A massive destruction of transplanted tissue occurs immediately following transplantation of pancreatic islets from pig to non-human primates. The detrimental instant blood-mediated inflammatory reaction (IBMIR), triggered by the porcine islets, is a likely explanation for this tissue loss; this reaction may also be responsible for mediating an adaptive immune response in the recipient that requires a heavy immunosuppressive regimen. Low molecular weight dextran sulfate (LMW-DS) and the complement inhibitor Compstatin were used in a combination of in vitro and in vivo studies designed to dissect the xenogeneic IBMIR in a non-human primate model of pancreatic islet transplantation. Adult porcine islets (10,000 IEQs/kg) were transplanted intraportally into three pairs of cynomolgus monkeys that had been treated with LMW-DS or heparin (control), and the effects on the IBMIR were characterized. Porcine islets were also incubated in human blood plasma in vitro to assess complement inhibition by LMW-DS and Compstatin. Morphological scoring and immunohistochemical staining revealed that the severe islet destruction and platelet, macrophage, neutrophilic granulocyte, and T-cell infiltration observed in the control (heparin-treated) animals were abrogated in the LMW-DS-treated monkeys. Both coagulation and complement activation were significantly reduced in monkeys treated with LMW-DS, but IgM and complement fragments were still found on the islet surface. This residual complement activation could be inhibited by Compstatin in vitro. The xenogeneic IBMIR in this non-human primate model is characterized by an immediate binding of antibodies that triggers deleterious complement activation and a subsequent clotting reaction that leads to further complement activation. The effectiveness of LMW-DS (in vivo and in vitro) and Compstatin (in vitro) in inhibiting this IBMIR provides the basis for a protocol that can be used to abrogate the IBMIR in pig-human clinical islet transplantation.
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