Department of Surgery, Division of Transplantation, University of Wisconsin, Madison, WI, United States of America.
Department of Surgery, Division of Transplantation, Duke University, Durham, NC, United States of America.
Transplant Rev (Orlando). 2021 Apr;35(2):100586. doi: 10.1016/j.trre.2020.100586. Epub 2020 Oct 17.
Ex vivo machine perfusion (EVMP) has gained revitalized interest in recent years due to the increasing use of marginal organs which poorly tolerate the standard preservation method static cold storage (SCS). EVMP improves on SCS in a number of ways, most notably by the potential for reconditioning of the donor organ prior to transplantation without the ethical concerns associated with organ modulation before procurement. Immunomodulatory therapies administered during EVMP can influence innate and adaptive immune responses to reduce production of inflammatory molecules and polarize tissue-resident immune cells to a regulatory phenotype. The targeted inhibition of an inflammatory response can reduce ischemia-reperfusion injury following organ reoxygenation and therefore reduce incidence of graft dysfunction and rejection. Numerous approaches to modulate the inflammatory response have been applied in experimental models, with the ultimate goal of clinical translatability. Strategies to target the innate immune system include inhibiting inflammatory signaling pathways, upregulating anti-inflammatory mediators, and decreasing mitochondrial damage while those which target the adaptive immune system include mesenchymal stromal cells. Inhibitory RNA approaches target both the innate and adaptive immune systems with a focus on MHC knock-down. Future studies may address issues of therapeutic agent delivery through use of nanoparticles and explore novel strategies such as targeting co-inhibitory molecules to educate T-cells to a tolerogenic state. In this review, we summarize the cellular and acellular contributors to allograft dysfunction and rejection, discuss the strategies which have been employed pre-clinically during EVMP to modulate the donor organ immune environment, and suggest future directions for immunomodulatory EVMP studies.
近年来，由于边缘供体器官的使用日益增加，而这些器官对标准保存方法——静态冷保存（SCS）的耐受性较差，因此体外机器灌注（EVMP）重新引起了人们的兴趣。EVMP 在许多方面优于 SCS，最显著的是在移植前有潜力对供体器官进行调理，而不会产生与获取前器官调节相关的伦理问题。EVMP 期间给予的免疫调节治疗可以影响固有和适应性免疫反应，减少炎症分子的产生，并使组织驻留免疫细胞向调节表型极化。靶向抑制炎症反应可以减少器官再氧合后的缺血再灌注损伤，从而降低移植物功能障碍和排斥反应的发生率。许多调节炎症反应的方法已在实验模型中应用，最终目标是实现临床转化。靶向固有免疫系统的策略包括抑制炎症信号通路、上调抗炎介质和减少线粒体损伤，而靶向适应性免疫系统的策略包括间充质基质细胞。抑制性 RNA 方法靶向固有和适应性免疫系统，重点是 MHC 敲低。未来的研究可能会通过使用纳米颗粒解决治疗剂递送的问题，并探索靶向共抑制分子使 T 细胞向耐受性状态教育等新策略。在这篇综述中，我们总结了同种异体移植物功能障碍和排斥的细胞和无细胞贡献者，讨论了在 EVMP 中临床前用于调节供体器官免疫环境的策略，并为免疫调节 EVMP 研究提出了未来的方向。
