Division of Cardiac Surgery, Department of Surgery, and Center for Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts, USA.
Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Am J Transplant. 2022 Jan;22(1):28-45. doi: 10.1111/ajt.16809. Epub 2021 Sep 20.
Galactosyl transferase knock-out pig lungs fail rapidly in baboons. Based on previously identified lung xenograft injury mechanisms, additional expression of human complement and coagulation pathway regulatory proteins, anti-inflammatory enzymes and self-recognition receptors, and knock-down of the β4Gal xenoantigen were tested in various combinations. Transient life-supporting GalTKO.hCD46 lung function was consistently observed in association with either hEPCR (n = 15), hTBM (n = 4), or hEPCR.hTFPI (n = 11), but the loss of vascular barrier function in the xenograft and systemic inflammation in the recipient typically occurred within 24 h. Co-expression of hEPCR and hTBM (n = 11) and additionally blocking multiple pro-inflammatory innate and adaptive immune mechanisms was more consistently associated with survival >1 day, with one recipient surviving for 31 days. Combining targeted genetic modifications to the lung xenograft with selective innate and adaptive immune suppression enables prolonged initial life-supporting lung function and extends lung xenograft recipient survival, and illustrates residual barriers and candidate treatment strategies that may enable the clinical application of other organ xenografts.
半乳糖基转移酶敲除猪肺在狒狒中迅速衰竭。基于先前确定的肺异种移植物损伤机制，在各种组合中测试了额外表达人补体和凝血途径调节蛋白、抗炎酶和自身识别受体，以及敲低β4Gal 异种抗原。在与 hEPCR（n=15）、hTBM（n=4）或 hEPCR.hTFPI（n=11）中的任何一种联合应用时，均观察到短暂的 GalTKO.hCD46 肺功能的生命支持作用，但异种移植物中的血管屏障功能丧失和受体中的全身炎症通常在 24 小时内发生。hEPCR 和 hTBM 的共表达（n=11）以及额外阻断多种炎症固有和适应性免疫机制与>1 天的存活更相关，其中一名受体存活了 31 天。将针对肺异种移植物的靶向基因修饰与选择性固有和适应性免疫抑制相结合，可延长初始的生命支持肺功能并延长肺异种移植物受体的存活时间，并说明了可能实现其他器官异种移植临床应用的剩余障碍和候选治疗策略。
