Aquaporin 4 blockade improves survival of murine heart allografts subjected to prolonged cold ischemia
Aquaporin 4 blockade improves survival of murine heart allografts subjected to prolonged cold ischemia
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DOI：
10.1111/ajt.14624
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发表时间：
2018-05-01
影响因子：
8.8
通讯作者：
Valujskikh, Anna
中科院分区：
文献类型：
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作者：
Ayasoufi, Katayoun;Kohei, Naoki;Valujskikh, Anna
长期冷缺血储存（CIS）是移植结果不良的主要危险因素。现有的策略努力使移植器官中的缺血再灌注损伤最小化，但需要新的方法来改善边缘同种异体移植物的结果并扩大适合移植的供体器官库。水通道蛋白（AQP）是一个促进体内平衡、组织损伤和炎症的水通道家族。我们测试了抑制AQP 4是否能提高8小时CIS条件下MHC完全不匹配的小鼠心脏移植物的存活率。在供体心脏收集和储存期间以及移植后短时间内给予小分子AQP 4抑制剂可改善供体移植细胞的活力，减少供体反应性T细胞应答，并在没有其他免疫抑制的情况下延长同种异体移植物存活。此外，AQP 4抑制与细胞毒性T淋巴细胞相关抗原4-IG在延长8小时CIS心脏同种异体移植物的存活方面具有协同作用。AQP 4阻断显著降低体外T细胞增殖和细胞因子产生，表明改善的移植物存活至少部分是通过对供体反应性T细胞的直接作用介导的。这些结果确定水通道蛋白作为一个有前途的目标，减少供体特异性同种异体反应性和提高生存的高风险的器官transplants.Using一个强大的心脏同种异体移植排斥反应的小鼠模型，这项研究提供了第一个证据表明，水通道蛋白水通道调节适应性同种异体免疫，可以有针对性地改善移植结果。
Prolonged cold ischemia storage (CIS) is a leading risk factor for poor transplant outcome. Existing strategies strive to minimize ischemia-reperfusion injury in transplanted organs, yet there is a need for novel approaches to improve outcomes of marginal allografts and expand the pool of donor organs suitable for transplantation. Aquaporins (AQPs) are a family of water channels that facilitate homeostasis, tissue injury, and inflammation. We tested whether inhibition of AQP4 improves the survival of fully MHC-mismatched murine cardiac allografts subjected to 8hours of CIS. Administration of a small molecule AQP4 inhibitor during donor heart collection and storage and for a short-time posttransplantation improves the viability of donor graft cells, diminishes donor-reactive T cell responses, and extends allograft survival in the absence of other immunosuppression. Furthermore, AQP4 inhibition is synergistic with cytotoxic T lymphocyte-associated antigen 4-Ig in prolonging survival of 8-hour CIS heart allografts. AQP4 blockade markedly reduced T cell proliferation and cytokine production in vitro, suggesting that the improved graft survival is at least in part mediated through direct effects on donor-reactive T cells. These results identify AQPs as a promising target for diminishing donor-specific alloreactivity and improving the survival of high-risk organ transplants.Using a robust mouse model of heart allograft rejection, this study provides the first evidence that aquaporin water channels regulate adaptive alloimmunity and can be targeted to improve transplant outcome.