TOLERANCE TO VASCULARIZED ALLOGRAFTS IN MINISWINE

描述：部分近亲繁殖的小型猪提供了一个独特的大 移植免疫学研究的动物模型。这个 MHC纯合子和MHC内重组单倍型的可用性 使研究选择性匹配对I类的影响成为可能 和/或移植免疫参数的II类基因座。 跨两个单倍型I或I类的同种异体肾移植的未经治疗的受者 在所有病例中，II类MHC屏障都会发生急性排斥反应。在.期间 在之前的项目期间，研究人员建立了治疗方案 包括12天疗程的环孢素A，其耐受率为100% 在I类不匹配的同种异体肾移植中，71%的II类不匹配的肾移植 同种异体肾移植，但不会诱导两个单倍型完全耐受 MHC障碍，这表明该方案诱导的耐受是 通过共享至少一种MHC抗原来促进。的主要目标是 目前的建议是确定这种情况的机制 耐受性是被诱导和维持的。具体地说，调查人员 将1)确定移植物的存在是否需要 保持对同种异体肾移植的耐受性，如果是，维持多长时间；2)研究 肾移植前后胸腺切除的疗效观察 关于耐受性的诱导；3)研究涉及的外周机制 在诱导和维持耐受性方面，这可能解释了 MHC抗原共享的明显要求。初步数据为 表示耐受性持续至少一个月，但 不是在同种异体肾被移除后无限期的，而且 胸腺参与了诱导耐受的机制，因为 胸腺切除导致排斥危机和不稳定的长期 宽容。这两项发现都表明，供体细胞的迁移 和/或胸腺抗原参与了耐受机制。 调查人员将试图确定 耐受诱导和维持阶段的供体抗原 通过免疫组织化学和聚合酶链式反应技术。希望能有一个 对耐受性诱导机制的理解 这个模型系统中的血管化移植物将允许发展 诱导特异性耐受性的适当临床方案 人类的同种异体器官移植。

DESCRIPTION: Partially inbred miniature swine provide a unique large animal model for the studies of transplantation immunology. The availability of MHC homozygous and intra-MHC recombinant haplotypes have made it possible to study the effects of selective matching for class I and/or class II loci on parameters of transplantation immunity. Untreated recipients of renal allografts across two-haplotype class I or class II MHC barriers undergo acute rejection in all cases. During the previous project period the investigators established a treatment regimen involving a 12-day course of Cyclosporin A which led to tolerance in 100% of class I mismatched renal allografts and in 71% of class II mismatched renal allografts, but does not induce tolerance across two-haplotype full MHC barriers, suggesting that induction of tolerance by this regimen is facilitated by sharing of at least one MHC antigen. The major goal of the present proposal is to determine the mechanism by which such tolerance is induced and maintained. Specifically, the investigators will 1) determine whether the presence of the graft is required to maintain tolerance to renal allografts, and if so, for how long; 2) study the effect of thymectomy prior to or subsequent to kidney transplantation on induction of tolerance; and 3) study peripheral mechanisms involved in the induction and maintenance of tolerance which may explain the apparent requirement for MHC antigen sharing. Preliminary data are presented indicating that tolerance persists for at least one month, but not indefinitely after the renal allograft is removed, and that the thymus is involved in the mechanism by which tolerance is induced, since thymectomy leads to rejection crises and to less stable long-term tolerance. Both of these findings suggest that migration of donor cells and/or antigen to the thymus is involved in the mechanism of tolerance. The investigators will attempt to determine the precise localization of donor antigen during the induction and maintenance phases of tolerance by immunohistochemical and PCR techniques. It is hoped that an understanding of the mechanisms by which tolerance is induced to vascularized grafts in this model system will permit development of appropriate clinical protocols for induction of specific tolerance to organ allografts in human beings.