Robust allograft tolerance in non-human primates

项目总结 混合造血型嵌合体是诱导同种异种移植耐受的一种有前景的方法。我们的 初步研究表明，将扩增的受体调节性T细胞(Tregs)添加到异基因 骨髓移植在非人类灵长类动物中导致了更持久的混合嵌合体。这是 由小鼠体内的数据支持。在人类中，Treg也具有预防移植物抗宿主的潜力 异基因造血细胞移植后的主要并发症--移植物抗宿主病(GVHD) 对移植的实体器官的排斥或促进耐受性。对小鼠的研究表明，耐久的混合 嵌合体与强大的系统耐受性有关，这种耐受性允许具有挑战性的同种异体移植物存活。在我们的 目前我们的研究集中在将扩增的受体调节性T细胞(Tregs)添加到非清髓性 异基因骨髓移植诱导持久的混合嵌合体，从而获得健壮的同种异体移植物 临床前食蟹猴模型的耐受性。然而，在目前的协议中，我们发现 我们必须对供体动物实施安乐死，以获得足够的骨髓细胞，以实现高水平的 嵌合体，排除了将供体肾脏延迟移植作为耐受性的有力测试。具有以下特点的设备 允许从活体捐赠者中分离动员的造血干细胞将克服这一障碍。 此外，一种用于保护性隔离的生物限制装置将减少感染并发症 免疫抑制的受体动物，高效输送免疫抑制药物的输液泵和 可提高手术效率的器械(透视台、牵引器系统)可显著提高手术效率 改进父项目的结果和成果。 自从我们在哥伦比亚大学建立了非人类灵长类移植项目以来，已经有了主要的 哥伦比亚大学医学中心(CUMC)的这一项目和其他NHP项目的增长。我们的研究是 在许多器官移植领域稳步发展，包括骨髓、肝、肾、肺、胰岛细胞和 皮肤和其他与临床相关的人类疾病领域。CUMC的许多调查人员正在密切合作 共同将异种移植耐受性带入临床现实。在这个令人兴奋的增长时期，拟议的 通过这笔赠款提出的最先进的设备不仅将帮助我们成功地在我们的 主要目标，但也将加强其他国家卫生研究院资助的哥伦比亚大学研究人员的研究成果。

Project Summery Mixed hematopoietic chimerism is a promising approach to inducing allograft and xenograft tolerance. Our preliminary studies have shown that the addition of expanded recipient regulatory T cells (Tregs) to allogeneic bone marrow transplantation results in more durable mixed chimerism in non-human primates. This is supported by in vivo data in mice. In humans, Treg also have potential for the prevention of graft-versus-host disease (GVHD), a major complication after allogeneic hematopoietic cell transplantation, and for preventing rejection or promoting tolerance of transplanted solid organs. Studies in mice indicate that durable mixed chimerism is associated with strong systemic tolerance that permits survival of challenging allografts. In our current study we focus on the addition of expanded recipient regulatory T cells (Tregs) to non-myeloablative allogeneic bone marrow transplantation to induce durable mixed chimerism and thereby robust allograft tolerance in the pre-clinical cynomolgus macaque model. However, with the current protocol we have found that we must euthanize the donor animal to obtain sufficient bone marrow cells to achieve high levels of chimerism, precluding delayed transplantation of donor kidneys as a robust test of tolerance. Equipment that would permit pheresis of mobilized hematopoietic stem cells from live donors would overcome this obstacle. Furthermore, a bioconfinement device for protective isolation that would reduce infectious complications in immunosuppressed recipient animals, infusion pumps that efficiently deliver immunosuppressive drugs and instruments that would enhanced the surgical efficiency (fluoroscopic table, retractor system) may substantially improve the results and outcome of the parent project. Since our establishment of the non-human primate transplant program at Columbia, there has been major growth of this and other NHP programs at Columbia University Medical Center (CUMC). Our research is advancing steadily in many areas of organ transplant including bone marrow, liver, kidney, lung, islet cells and skin and other areas of clinically relevant human diseases. Many investigators at CUMC are working closely together to bring xenotransplantation tolerance to clinical reality. In this exciting time of growth, the proposed state-of-the-art equipment proposed through this grant will not only help us to successfully progress with our primary goals but will also enhance research outcomes of other NIH-funded investigators at Columbia.