Lee R S, Yamada K, Houser S L, Womer K L, Maloney M E, Rose H S, Sayegh M H, Madsen J C
The Transplantation Biology Research Center and Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3276-81. doi: 10.1073/pnas.051584498.
Graft loss from chronic rejection has become the major obstacle to the long-term success of whole organ transplantation. In cardiac allografts, chronic rejection is manifested as a diffuse and accelerated form of arteriosclerosis, termed cardiac allograft vasculopathy. It has been suggested that T-cell recognition of processed alloantigens (allopeptides) presented by recipient antigen-presenting cells through the indirect pathway of allorecognition plays a critical role in the development and progression of chronic rejection. However, definitive preclinical evidence to support this hypothesis is lacking. To examine the role of indirect allorecognition in a clinically relevant large animal model of cardiac allograft vasculopathy, we immunized MHC inbred miniature swine with synthetic polymorphic peptides spanning the alpha(1) domain of an allogeneic donor-derived swine leukocyte antigen class I gene. Pigs immunized with swine leukocyte antigen class I allopeptides showed in vitro proliferative responses and in vivo delayed-type hypersensitivity responses to the allogeneic peptides. Donor MHC class I disparate hearts transplanted into peptide-immunized cyclosporine-treated pigs not only rejected faster than unimmunized cyclosporine-treated controls (mean survival time = 5.5 +/-1.7 vs. 54.7 +/-3.8 days, P < 0.001), but they also developed obstructive fibroproliferative coronary artery lesions much earlier than unimmunized controls (<9 vs. >30 days). These results definitively link indirect allorecognition and cardiac allograft vasculopathy.
慢性排斥导致的移植物丢失已成为全器官移植长期成功的主要障碍。在心脏同种异体移植中，慢性排斥表现为一种弥漫性且加速发展的动脉硬化形式，称为心脏同种异体移植血管病变。有研究表明，受体抗原呈递细胞通过间接同种异体识别途径呈递的加工后的同种异体抗原（同种异体肽）被T细胞识别，在慢性排斥的发生和发展中起关键作用。然而，缺乏确凿的临床前证据来支持这一假设。为了研究间接同种异体识别在临床上相关的心脏同种异体移植血管病变大型动物模型中的作用，我们用跨越同种异体供体来源的猪白细胞抗原I类基因α(1)结构域的合成多态性肽免疫MHC近交系小型猪。用猪白细胞抗原I类同种异体肽免疫的猪对同种异体肽表现出体外增殖反应和体内迟发型超敏反应。将供体MHC I类不同的心脏移植到经肽免疫并接受环孢素治疗的猪体内，其排斥速度不仅比未免疫且接受环孢素治疗的对照组更快（平均存活时间=5.5±1.7天对54.7±3.8天，P<0.001），而且它们出现阻塞性纤维增生性冠状动脉病变的时间也比未免疫的对照组早得多（<9天对>30天）。这些结果明确地将间接同种异体识别与心脏同种异体移植血管病变联系起来。
