Anti-Inflammatory Strategies in Intrahepatic Islet Transplantation: A Comparative Study in Preclinical Models
Anti-Inflammatory Strategies in Intrahepatic Islet Transplantation: A Comparative Study in Preclinical Models
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DOI：
10.1097/tp.0000000000001925
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发表时间：
2018-02-01
期刊：
影响因子：
6.2
通讯作者：
Piemonti, Lorenzo
中科院分区：
文献类型：
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作者：
Citro, Antonio;Cantarelli, Elisa;Piemonti, Lorenzo
背景资料。识别在胰岛移植患者围手术期不良炎症事件中起关键作用的途径(S)是改善胰岛移植患者治疗和预后的关键一步。最近，我们选择抑制CXCR1/2作为提高胰岛移植后存活的相关策略。在这里，临床上使用最多的抗炎化合物(IL1受体拮抗剂、类固醇和肿瘤坏死因子α抑制剂)单独使用或与CXCR1/2抑制剂联合使用，评估它们改善植入性或延缓移植物排斥反应的能力。为了排除与移植部位有关的偏见，我们使用了成熟的临床前同基因胰岛(C57BL/6中250个等值胰岛)和同种异体胰岛(C57BL6中400个Balb/c等值胰岛)肝内胰岛移植平台。结果。在小鼠身上，我们证实了靶向CXCR1/2通路对于保护胰岛功能和改善植入至关重要。在同种异体移植中，单独使用CXCR1/2抑制剂可以减少移植诱导的白细胞的总体募集，并显著延长移植物排斥反应的时间，无论是作为单一药物还是与免疫抑制联合使用。在MMF+FK-506免疫抑制治疗中，没有其他被测试的抗炎化合物(IL1受体拮抗剂、类固醇和肿瘤坏死因子-α抑制剂)单独或与CXCR1/2抑制剂一起改善胰岛植入并显著延迟移植物排斥反应。结论。这些结果表明，只有CXCR1/2介导的轴在控制胰岛损伤中起关键作用，应该成为提高胰岛移植效率的干预靶点。
Background. The identification of pathway(s) playing a pivotal role in peritransplant detrimental inflammatory events represents the crucial step toward a better management and outcome of pancreatic islet transplanted patients. Recently, we selected the CXCR1/2 inhibition as a relevant strategy in enhancing pancreatic islet survival after transplantation.Methods. Here, the most clinically used anti-inflammatory compounds (IL1-receptor antagonist, steroids, and TNF-alpha inhibitor) alone or in combination with a CXCR1/2 inhibitor were evaluated in their ability to improve engraftment or delay graft rejection. To rule out bias related to transplantation site, we used well-established preclinical syngeneic (250 C57BL/6 equivalent islets in C57BL/6) and allogeneic (400 Balb/c equivalent islets in C57BL6) intrahepatic islet transplantation platforms. Results. In mice, we confirmed that targeting the CXCR1/2 pathway is crucial in preserving islet function and improving engraftment. In the allogeneic setting, CXCR1/2 inhibitor alone could reduce the overall recruitment of transplant-induced leukocytes and significantly prolong the time to graft rejection both as a single agent and in combination with immunosuppression. No other anti-inflammatory compounds tested (IL1-receptor antagonist, steroids, and TNF-alpha inhibitor) alone or in combination with CXCR1/2 inhibitor improve islet engraftment and significantly delay graft rejection in the presence of MMF + FK-506 immunosuppressive treatment. Conclusions. These findings indicate that only the CXCR1/2-mediated axis plays a crucial role in controlling the islet damage and should be a target for intervention to improve the efficiency of islet transplantation.