GENE TRANSFER FOR TRANSPLANT TOLERANCE

特异性移植耐受的诱导， 在接受来自特定供体类型的组织时， 维持正常的免疫反应性，是免疫治疗的主要目标。 移植研究同种异体肾移植术 各种捐赠者/接受者组合已经证明了压倒性的 主要组织相容性复合体（MHC）匹配的重要性 II类区域诱导对血管化移植物的特异性耐受， 小型猪，从临床上也可以得出类似的结论。 问题研究 在上一个项目期间，我们证明， II类基因的转移，通过逆转录病毒介导的 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 随后进行完全不匹配的肾移植。 令人惊讶的是，具体 通过转移II DR级，成功实现了公差 locus单独 尽管同种异体DR转基因的表达较低， 并且仅限于一部分骨髓来源的细胞，与DR匹配 似乎单独控制对显示在细胞表面的同种抗原的免疫。 血管化器官 鉴于DR具有强大的致耐受性作用， 在该模型中，我们假设诱导II类依赖性 容忍是一种主要现象，这种现象可能是由身份所介导的， 至少一个II类产品，并且仅需要低信号 水平（可能是肽）存在于适当的骨髓源性 在造血系统重建的早期阶段的细胞类型。 为了检验这一假设，我们在本次更新中提出：1）检验 单独对II类DQ的鉴别是否也能控制耐受性 诱导主要血管化的微型器官移植 猪; 2）检查导致持久的可能机制 无反应性; 3）表征骨髓来源的细胞类型 其通过II类基因疗法诱导耐受性;以及4）检查 转移基因的长期表达与 持久的宽容。从这些研究中获得的信息将 在定义II类分子的作用模式方面至关重要， 耐受性诱导，并将允许设计适当的方案 为将来的基因治疗方法，以耐受血管化器官 在人身上。

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.