Donor Pretreatment With IL-1 Receptor Antagonist Attenuates Inflammation and Improves Functional Potency in Islets From Brain-Dead Nonhuman Primates.
Donor Pretreatment With IL-1 Receptor Antagonist Attenuates Inflammation and Improves Functional Potency in Islets From Brain-Dead Nonhuman Primates.
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DOI：
10.3727/096368914x681045
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发表时间：
2015
影响因子：
3.3
通讯作者：
Fernandez LA
中科院分区：
文献类型：
--
作者：
Danobeitia JS;Hanson MS;Chlebeck P;Park E;Sperger JM;Schwarznau A;Fernandez LA
大多数胰腺和胰岛移植物是从脑死亡(BD)的捐赠者那里恢复的。在这项研究中，我们描述了非人类灵长类供者脑死亡在胰腺和胰岛引起的早期炎症反应，并在移植前评估了靶向抗炎干预对胰岛保护的效果。脑死亡供者被监测6小时，并被分配到三个试验组。第1组：BD-UT(BD-UT)组(n=7)，第2组：BD+供体IL-1ra预处理组(n=6)，第3组：非BD动物对照组(n=7)。我们观察到脑死亡诱导后，IL-1ra依赖减少骨髓中性粒细胞的动员和激活，并显著减少CD68+白细胞在胰腺和胰岛的聚集。供者经IL-1ra处理后，趋化因子β、IL-6、MCP-1和MIP-1α的表达显著降低，循环中性粒细胞和胰岛内巨噬细胞的活化明显减弱。结果，IL-1ra显著改善了使用最小胰岛质量进行移植的小鼠的存活率、线粒体膜极性和胰岛植入。这些结果表明，早期针对脑死亡供者炎症的免疫调节可能是一种有效的治疗策略，可以在移植前改善胰岛的质量和功能。
Most pancreas and islet grafts are recovered from brain-dead (BD) donors. In this study we characterized the early inflammatory response induced by brain death in pancreata and islets from non-human primate donors and evaluated the effect of targeted anti-inflammatory intervention in the protection of pancreatic islets prior to transplantation. Brain-dead donors were monitored for 6 hours and assigned to three experimental groups. Group 1: BD-untreated donors (BD-UT) (n=7), Group 2: BD + donor pre-treatment with IL-1ra (n=6) and Group 3: Non-BD animals serving as controls (n=7). We observed an IL-1ra dependent reduction in the mobilization and activation of neutrophils from bone marrow and a significantly reduced accumulation of CD68+ leukocytes in the pancreas and islets after brain death induction. Donor treatment with IL-1ra significantly decreased chemokine mRNA expression (MCP-1, IL-8 and MIP-1a) and attenuated the activation of circulating neutrophils and intra-islet macrophages as demonstrated by a reduction in intracellular IL-1β, IL-6, MCP-1 and MIP-1α expression. As a result, IL-1ra dramatically improved viability, mitochondrial membrane polarity and islet engraftment in mice transplanted using a minimal islet mass. These results suggest that early immunomodulation targeting inflammation in the brain-dead donor may represent an effective therapeutic strategy to improve islet quality and function prior to transplantation.