Madsen J C, Yamada K, Allan J S, Choo J K, Erhorn A E, Pins M R, Vesga L, Slisz J K, Sachs D H
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Transplantation. 1998 Feb 15;65(3):304-13. doi: 10.1097/00007890-199802150-00002.
The mechanisms and treatment of cardiac allograft vasculopathy (CAV) remain elusive. We have used partially inbred miniature swine to determine the role of class I MHC antigens in the pathogenesis of CAV and to determine whether acquired tolerance to donor antigen can prevent the development of CAV in large animals.
Previous studies demonstrated that miniature swine treated with 12 days of cyclosporine (CsA) after the transplantation of MHC class I-disparate kidney allografts all became tolerant to the donor kidneys and survived indefinitely. In the present study, heart allografts were transplanted across the same MHC class I disparity in CsA-treated swine.
Unlike kidney allografts, heart allografts were rejected in 33-55 days. By postoperative day 28, all cardiac allografts had developed the intimal proliferation characteristic of CAV. When hearts and kidneys from the same donors were transplanted simultaneously into class I-disparate, CsA-treated recipients, the hosts became tolerant to their cardiac allografts and survived long-term. Furthermore, none of the hearts from the combined heart/kidney recipients developed evidence of CAV. Thus, this report demonstrates that: (1) MHC class I antigens play an important role in the pathogenesis of CAV, (2) the specific unresponsiveness to donor class I antigen induced by a class I-disparate kidney protects a heart transplanted from the same organ donor, and (3) the induction of acquired tolerance prevents the development of CAV.
These findings in a preclinical system establish the significance of antigen-dependent mechanisms in the pathogenesis of CAV and underscore the importance of achieving tolerance in clinical transplantation.
心脏移植血管病变（CAV）的发病机制和治疗方法仍不清楚。我们使用部分近交系小型猪来确定I类主要组织相容性复合体（MHC）抗原在CAV发病机制中的作用，并确定对供体抗原的获得性耐受是否可以预防大型动物发生CAV。
先前的研究表明，在移植I类MHC不匹配的肾脏异体移植物后，用环孢素（CsA）治疗12天的小型猪均对供体肾脏产生耐受并长期存活。在本研究中，在接受CsA治疗的猪中进行了跨越相同I类MHC差异的心脏异体移植。
与肾脏异体移植不同，心脏异体移植在33 - 55天内被排斥。到术后第28天，所有心脏异体移植均出现了CAV特有的内膜增生。当将来自同一供体的心脏和肾脏同时移植到I类不匹配、接受CsA治疗的受体中时，宿主对其心脏异体移植产生耐受并长期存活。此外，联合进行心脏/肾脏移植的受体的心脏均未出现CAV的迹象。因此，本报告表明：（1）I类MHC抗原在CAV的发病机制中起重要作用；（2）I类不匹配的肾脏诱导的对供体I类抗原的特异性无反应性可保护来自同一器官供体的心脏移植；（3）获得性耐受的诱导可预防CAV的发生。
临床前系统中的这些发现确立了抗原依赖性机制在CAV发病机制中的重要性，并强调了在临床移植中实现耐受的重要性。
