Rosengard B R, Ojikutu C A, Fishbein J, Kortz E O, Sachs D H
Transplantation Biology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
J Immunol. 1992 Aug 1;149(3):1099-103.
Previous work from this laboratory demonstrated that tolerance to MHC-identical or class I-disparate renal allografts develops in approximately one third of miniature swine without exogenous immunosuppression. A back-cross study indicated that rejection of MHC-identical transplants due to minor Ag was controlled by one or possibly two non-MHC-linked, autosomal dominant Ir genes. According to this hypothesis, and assuming complete penetrance, graft acceptors would be homozygous recessive at the relevant Ir loci, as would their offspring. Alternatively, if the gene(s) were incompletely penetrant, then two acceptors could give rise to a rejector. However, a high rate of MHC-identical graft acceptance would still be expected in the offspring of acceptors even if the Ir gene(s) were incompletely penetrant. To test this hypothesis and to obtain a higher frequency of acceptor animals for studies of tolerance, a program of selective breeding of renal allograft acceptors was begun. In the present paper, we assess the effect of selective breeding on renal graft acceptance. The analysis indicates a marked increase in the rate of MHC-identical graft acceptance, from 27.3% (n = 24) for the earliest of the four chronologic subgroups assessed to 64.5% (n = 33) for the most recent subgroup (p less than 0.0001). Calculations of kinship revealed that the increased acceptance of MHC-identical grafts was not the result of differences between acceptors and rejectors in donor/recipient consanguinity. Class I-disparate grafts (n = 128) were similarly stratified chronologically and compared. Unlike MHC-identical grafts, the rate of acceptance of class I-disparate grafts has not changed over time. We conclude that rejector/acceptor status with respect to class I MHC incompatibility is determined by genetic factors in addition to those that control responses to minor antigen incompatibilities only.
该实验室先前的研究表明，在没有外源性免疫抑制的情况下，约三分之一的小型猪会对 MHC 相同或 I 类不同的肾移植产生耐受。一项回交研究表明，由于次要抗原导致的 MHC 相同移植的排斥反应受一个或可能两个非 MHC 连锁的常染色体显性 Ir 基因控制。根据这一假设，并假设完全外显，移植受体在相关 Ir 位点将是纯合隐性的，其后代也是如此。或者，如果该基因不完全外显，那么两个受体可能产生一个排斥者。然而，即使 Ir 基因不完全外显，受体后代中 MHC 相同移植的高接受率仍有望出现。为了验证这一假设并获得更高频率的受体动物用于耐受性研究，启动了一项肾移植受体的选择性育种计划。在本文中，我们评估了选择性育种对肾移植接受情况的影响。分析表明，MHC 相同移植的接受率显著提高，从评估的四个时间亚组中最早一组的 27.3%（n = 24）增加到最近一组的 64.5%（n = 33）（p < 0.0001）。亲缘关系计算表明，MHC 相同移植接受率的提高不是受体和排斥者在供体/受体血缘关系上差异的结果。I 类不同的移植（n = 128）也按时间顺序进行了类似分层并进行比较。与 MHC 相同的移植不同，I 类不同移植的接受率并未随时间变化。我们得出结论，关于 I 类 MHC 不相容的排斥者/受体状态不仅由控制对次要抗原不相容反应的因素决定，还由遗传因素决定。
