CXCR1/2 inhibition enhances pancreatic islet survival after transplantation
CXCR1/2 inhibition enhances pancreatic islet survival after transplantation
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DOI：
10.1172/jci63089
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发表时间：
2012-10-01
影响因子：
15.9
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
虽然长期以来被认为是1型糖尿病的有希望的治疗选择，但胰岛细胞转化受到移植组织的免疫系统排斥的阻碍。识别调节移植后有害炎症事件的途径将改善移植患者的管理和结果。在这里，我们发现CXCR 1/2趋化因子受体及其配体是移植后胰岛存活的关键负性决定因素。胰岛释放丰富的CXCR 1/2配体（CXCL 1和CXCL 8）。因此，肝内CXCL 1和循环CXCL 1和CXCL 8强烈诱导胰岛输注后不久。小鼠CXCL 1-CXCR 1/2轴的遗传和药理学阻断改善了肝内胰岛移植，并减少了胰岛输注后多形核白细胞和NKT细胞的肝内募集。在人类中，CXCR 1/2变构抑制剂瑞帕里辛在一项2期随机、开放标签的先导性研究中改善了单次输注同种异体胰岛的结局。这些发现表明，CXCR 1/2介导的途径是胰岛损伤的调节剂，应该成为干预的目标，以提高移植的疗效。
Although long considered a promising treatment option for type 1 diabetes, pancreatic islet cell transformation has been hindered by immune system rejection of engrafted tissue. The identification of pathways that regulate post-transplant detrimental inflammatory events would improve management and outcome of transplanted patients. Here, we found that CXCR1/2 chemokine receptors and their ligands are crucial negative determinants for islet survival after transplantation. Pancreatic islets released abundant CXCR1/2 ligands (CXCL1 and CXCL8). Accordingly, intrahepatic CXCL1 and circulating CXCL1 and CXCL8 were strongly induced shortly after islet infusion. Genetic and pharmacological blockade of the CXCL1-CXCR1/2 axis in mice improved intrahepatic islet engraftrnent and reduced intrahepatic recruitment of polymorphonuclear leukocytes and NKT cells after islet infusion. In humans, the CXCR1/2 allosteric inhibitor reparixin improved outcome in a phase 2 randomized, open-label pilot study with a single infusion of allogeneic islets. These findings indicate that the CXCR1/2-mediated pathway is a regulator of islet damage and should be a target for intervention to improve the efficacy of transplantation.