Madariaga Maria Lucia L, Shanmugarajah Kumaran, Michel Sebastian G, Villani Vincenzo, Muraglia Glenn M La, Torabi Radbeh, Leonard David A, Randolph Mark A, Colvin Robert B, Yamada Kazuhiko, Madsen Joren C, Cetrulo Curtis L, Sachs David H
Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
Transplantation. 2015 Aug;99(8):1590-1597. doi: 10.1097/TP.0000000000000681.
Achieving tolerance of vascularized composite allografts (VCAs) would improve the risk-to-benefit ratio in patients who undergo this life-enhancing, though not lifesaving, transplant. Kidney cotransplantation along with a short course of high-dose immunosuppression enables tolerance of heart allografts across a full major histocompatibility complex (MHC) mismatch. In this study, we investigated whether tolerance of VCAs across full MHC disparities could be achieved in animals already tolerant of heart and kidney allografts.
Miniature swine that were tolerant of heart and/or kidney allografts long term underwent transplantation of myocutaneous VCA across the same MHC barrier. Before VCA transplant, group 1 (n = 3) underwent class I-mismatched kidney transplantation; group 2 (n = 3) underwent 2 sequential class I-mismatched kidney transplantations; group 3 (n = 2) underwent haploidentical MHC-mismatched heart/kidney transplantation; and group 4 (n = 2) underwent full MHC-mismatched heart/kidney transplantation.
All 3 animals in group 1 and 2 of 3 animals in group 2 showed skin rejection within 85 days; 1 animal in group 2 showed prolonged skin survival longer than 200 days. Animals in groups 3 and 4 showed skin rejection within 30 days and regained in vitro evidence of donor responsiveness.
This is the first preclinical study in which hearts, kidneys, and VCAs have been transplanted into the same recipient. Despite VCA rejection, tolerance of heart and kidney allografts was maintained. These results suggest that regulatory tolerance of skin is possible but not generally achieved by the same level of immunomodulation that is capable of inducing tolerance of heart and kidney allografts. Achieving tolerance of skin may require additional immunomodulatory therapies.
实现血管化复合组织异体移植（VCA）的免疫耐受将改善接受这种虽不能挽救生命但能提高生活质量的移植手术患者的风险效益比。肾脏联合移植以及短期高剂量免疫抑制可使心脏异体移植在完全主要组织相容性复合体（MHC）不匹配的情况下实现免疫耐受。在本研究中，我们调查了在已对心脏和肾脏异体移植产生耐受的动物中，能否实现完全MHC差异的VCA免疫耐受。
长期对心脏和/或肾脏异体移植产生耐受的小型猪接受了跨越相同MHC屏障的肌皮VCA移植。在VCA移植前，第1组（n = 3）接受了I类不匹配的肾脏移植；第2组（n = 3）接受了2次连续的I类不匹配肾脏移植；第3组（n = 2）接受了单倍体MHC不匹配的心脏/肾脏移植；第4组（n = 2）接受了完全MHC不匹配的心脏/肾脏移植。
第1组的所有3只动物和第2组的3只动物中的2只在85天内出现皮肤排斥反应；第2组的1只动物皮肤存活时间延长超过200天。第3组和第4组的动物在30天内出现皮肤排斥反应，并恢复了供体反应性的体外证据。
这是首次将心脏、肾脏和VCA移植到同一受体的临床前研究。尽管出现了VCA排斥反应，但心脏和肾脏异体移植的免疫耐受得以维持。这些结果表明，皮肤的调节性免疫耐受是可能的，但通常不能通过诱导心脏和肾脏异体移植免疫耐受的相同水平的免疫调节来实现。实现皮肤免疫耐受可能需要额外的免疫调节疗法。
