GENE TRANSFER FOR TRANSPLANT TOLERANCE

诱导特定的移植耐受，导致一种状态 在接受来自特定捐赠者类型的组织时 维持其他方面的正常免疫反应性，是 移植研究。同种异体肾移植 各种捐赠者/受赠者的组合已经证明了压倒性的 主要组织相容性复合体(MHC)配型的重要性 血管移植物诱导特异性耐受的第II类区域 小型猪，从临床上可能得出类似的结论 学习。在前一个项目期间，我们演示了 通过逆转录病毒介导的Il类基因的转移 自体骨髓细胞可替代同种异体骨 骨髓移植诱导特异性移植耐受的实验研究 随后的完全不匹配的同种异体肾移植。令人惊讶的是，具体的 通过转移Il DR类成功地实现了容差 孤身一人。尽管同种异体DR转基因的表达水平很低 仅限于一小部分骨髓来源的细胞，与DR匹配 单独似乎控制了对显示在 带血管的器官。鉴于DR强大的耐受作用 在这个模型中，我们假设类II依赖诱导 宽容是一种显性现象，它可能通过身份认同来调节 至少一种II类产品，并且只需要低信号 水平(可能是多肽)存在于适当的骨髓来源 造血系统重建早期的细胞类型。 为了检验这一假说，我们在这次更新中提出：L)检验 单凭对二类DQ的认同感是否也能控制容忍度 微创微创血管器官移植的诱导 猪；2)研究导致长期持续的可能机制 无反应；3)表征骨髓来源的细胞类型 通过II类基因治疗诱导耐受；以及4)检查 外源基因长期表达与外源基因表达的相关性 持久的宽容。从这些研究中获得的信息将是 在定义第II类分子的作用模式方面至关重要 并将允许设计适当的方案 未来血管器官耐受性的基因治疗方法 在人类身上。

The induction of specific transplantation tolerance, a state resulting in the acceptance of tissues from a particular donor type while maintaining otherwise normal immune reactivity, is a major goal of transplantation research. Transplantation of kidney allografts between various donor/recipient combinations have demonstrated the overwhelming importance of matching for the major histocompatibility complex (MHC) class II region in inducing specific tolerance to vascularized grafts in miniature swine, and similar conclusions may be drawn from clinical studies. During the previous project period we demonstrated that transfer of class Il genes, through retrovirus-mediated transduction of autologous bone marrow cells, could substitute for allogeneic bone marrow transplantation in inducing specific transplantation tolerance to subsequent fully mismatched renal allografts. Surprisingly, specific tolerance was successfully achieved by transferring the class Il DR locus alone. Although expression of the allogeneic DR transgene was low and limited to a fraction of bone marrow-derived cells, matching for DR alone appeared to control immunity to alloantigens displayed on the vascularized organ. In view of the powerful tolerogenic effects of DR in this model we hypothesize that induction of class II-dependent tolerance is a dominant phenomenon which may be mediated by identity for at least one class II product, and which only requires a low signal level (possibly peptides) present on an appropriate bone marrow-derived cell type in the early phase of the hematopoietic system reconstitution. In order to test this hypothesis we propose in this renewal to: l) Test whether identity to class II DQ alone can also control tolerance induction to primarily vascularized organ transplants in miniature swine; 2) Examine possible mechanisms leading to long-lasting unresponsiveness; 3) Characterize the bone marrow-derived cell type which induces tolerance via class II gene therapy; and 4) Examine the correlation between long-term expression of the transferred genes and long-lasting tolerance. Information obtained from these studies will be critical in defining the mode of action of the class II molecules in tolerance induction and will permit the design of appropriate protocols for future gene therapy approaches to tolerance of vascularized organs in man.