带血管蒂骨皮瓣移植诱导同种异体器官移植免疫耐受的方法与机制研究

Currently organ allograft transplantation has emerged as an effective clinic procedure for end-stage organ failure patients. However, to successfully induce allograft tolerance, thus avoid lifelong immunosuppressive therapy and their deleterious side-effects, remain a major challenge worldwide. Current successful approaches to induce long-term stable mixed chimerism and allograft tolerance by using bone marrow cell transplantation require host conditioning with lethal irradiation and cytotoxic drugs. The concerns about the safety of cytotoxic drugs and/or irradiation have impeded the widespread clinic application of these strategies for organ transplantation. Based on our recent findings that the donor bone marrow stem cell microenvironment, the niche, play a important role in the establishment of stable mixed chimerism and transplant tolerance, we hypothesize, a central hypothesis of this study, the vascularized donor bone marrow, which inherently contain donor stem cell niches for sustained donor-derived SC production and renewal, facilitates stable mixed chimerism and allograft tolerance without recipient myeloablation. It may provide a unique opportunity for achieving clinic organ transplant tolerance. In this study we will explore a novel strategy for inducing renal allograft tolerance by concomitant vascularized donor-specific osteomyocutaneous graft transplantation, as well as novel immunomodulatory fusion proteins in nonhuman primate models. The granted understanding of the roles and mechanisms of donor derived stem cell niche in stable MC and transplant tolerance using the unique vascularized bone marrow allograft model and the development of novels strategies to induce allograft tolerance is likely to have an important impact on clinic organ transplantation.

当前异体器官移植已成为挽救晚期器官衰竭患者生命的有效临床手段，然而避免长期使用大剂量免疫抑制剂带来的严重合并症，成功诱导移植耐受，仍然是世界范围的严重挑战。现行的骨髓细胞移植诱导稳定嵌合体和器官移植耐受的方法，需使用大剂量放射治疗和细胞毒性药物诱导, 严重阻碍了该方案的推广。 基于近期对供体骨髓干细胞微环境-Niche在啮齿类复合组织移植耐受作用的研究，本课题组提出新的假设:带血管供体骨移植提供了供体骨髓干细胞和维持其持续产生和自我更新的微环境，为成功建立稳定嵌合体和器官移植耐受提供了机遇。本课题将应用灵长类大动物建立肾脏移植联合带血管蒂骨皮瓣移植模型，短期使用常规免疫抑制剂并联合使用新型生物免疫调节融合蛋白进行免疫耐受诱导，通过监测移植物存活,嵌合体形成,及细胞和体液免疫状态，进一步验证这一设想并探讨其机理。同时探讨带血管蒂骨皮瓣对预警早期内脏移植物排斥的作用。为临床应用提供可靠的依据。

当前异体器官移植已成为挽救晚期器官衰竭患者生命的有效临床手段，然而避免长期使用大剂量免疫抑制剂带来的严重合并症，成功诱导移植耐受，仍然是世界范围的严重挑战。现行的骨髓细胞移植诱导稳定嵌合体和器官移植耐受的方法，需使用大剂量放射治疗和细胞毒性药物诱导, 严重阻碍了该方案的推广。 基于近期对供体骨髓干细胞微环境-Niche在啮齿类复合组织移植耐受作用的研究，本课题提出新的假设:带血管供体骨移植提供了供体骨髓干细胞和维持其持续产生和自我更新的微环境，为成功建立稳定嵌合体和器官移植耐受提供了机遇。基于目前移植免疫方面研究的现实情况，我们从4个方面对带血管蒂骨皮瓣复合组织移植在非人灵长类大动物中诱导免疫耐受的作用进行了研究并完成了相关工作：1.建立了带血管蒂骨皮瓣复合组织非人类灵长类大动物模型；2.成功建立了非人类灵长类大动物移植后嵌合体的检测方法；3.探索出一套适合带血管蒂骨皮瓣复合组织联合肾移植的免疫诱导和免疫抑制剂使用方案；4.揭示了带血管蒂骨皮瓣复合组织移植在诱导肾移植后免疫耐受中的作用及机制，同时探讨了带血管蒂骨皮瓣对预警早期内脏移植物排斥的作用。