Ciubotariu R, Liu Z, Colovai A I, Ho E, Itescu S, Ravalli S, Hardy M A, Cortesini R, Rose E A, Suciu-Foca N
College of Physicians and Surgeons of Columbia University, New York 10032, USA.
J Clin Invest. 1998 Jan 15;101(2):398-405. doi: 10.1172/JCI1117.
The role of the indirect allorecognition pathway in acute allograft rejection has been documented both in organ recipients and in experimental models. However, it is unknown whether self-restricted recognition of donor alloantigens also contributes to chronic allograft rejection. The aim of this study was to determine the relationship between allopeptide reactivity, epitope spreading, and chronic rejection. Using synthetic peptides corresponding to the hypervariable region of 32 HLA-DR alleles, we have followed the specificity of self-restricted T cell alloresponses to the donor in a population of 34 heart allograft recipients. T cells from sequential samples of blood collected from the patients up to 36 mo after transplantation were studied in limiting dilution analysis for allopeptide reactivity. The incidence of coronary artery vasculopathy (CAV) was significantly higher in patients who displayed persistent alloreactivity late after transplantation than in patients who showed no alloreactivity after the first 6 mo after transplantation. Both intra- and intermolecular spreading of epitopes was observed with an increased frequency in patients developing CAV in less than 2 yr, compared with patients without CAV; this suggests that diversification of the immune response against the graft contributes to chronic rejection. These data provide a strategy for identifying patients at risk of developing CAV and a rationale for therapeutic intervention aimed to prevent the progression of the rejection process.
间接同种异体识别途径在急性同种异体移植排斥反应中的作用已在器官移植受者和实验模型中得到证实。然而，供体同种异体抗原的自身限制性识别是否也会导致慢性同种异体移植排斥反应尚不清楚。本研究的目的是确定同种异体肽反应性、表位扩展与慢性排斥反应之间的关系。我们使用与32个HLA-DR等位基因高变区对应的合成肽，在34名心脏同种异体移植受者群体中追踪了自身限制性T细胞对供体的同种异体反应特异性。对患者移植后长达36个月连续采集的血样中的T细胞进行有限稀释分析，以研究其对同种异体肽的反应性。移植后晚期仍表现出持续同种异体反应性的患者，其冠状动脉血管病变（CAV）的发生率显著高于移植后最初6个月内未表现出同种异体反应性的患者。与无CAV的患者相比，在不到2年时间内发生CAV的患者中，表位的分子内和分子间扩展频率均增加；这表明针对移植物的免疫反应多样化会导致慢性排斥反应。这些数据为识别有发生CAV风险的患者提供了一种策略，并为旨在防止排斥反应进程的治疗干预提供了理论依据。
