Robust allograft tolerance in non-human primates

项目总结 混合造血嵌合体是诱导同种异体和异种移植免疫耐受的一种很有前途的方法。我们 初步研究表明，将扩增的受体调节性T细胞（TCRs）添加到同种异体移植物中， 骨髓移植在非人灵长类动物中产生更持久的混合嵌合体。这是 得到了小鼠体内数据的支持。在人类中，Treg也具有预防移植物抗宿主的潜力。 移植物抗宿主病（GVHD）是异基因造血细胞移植后的主要并发症， 排斥或促进移植实体器官的耐受性。对小鼠的研究表明， 嵌合状态与强的全身耐受性有关，所述耐受性允许具有挑战性的同种异体移植物存活。在我们 目前的研究集中在将扩增的受体调节性T细胞（TCFs）加入非清髓性 异基因骨髓移植以诱导持久的混合嵌合体并由此诱导稳健的同种异体移植物 临床前食蟹猴模型中的耐受性。然而，根据目前的协议，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， 嵌合体，排除了延迟移植供体肾脏作为耐受性的一个强大的测试。的设备 将允许从活体供体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，有效递送免疫抑制药物的输注泵， 可以提高手术效率的器械（荧光检查台、牵开器系统）可以基本上 改善母项目的结果和成果。 自从我们在哥伦比亚建立非人类灵长类动物移植项目以来， 哥伦比亚大学医学中心（CISC）的NHP项目和其他NHP项目的增长。我们的研究是 在器官移植的许多领域，包括骨髓、肝、肾、肺、胰岛细胞和 皮肤和其他临床相关的人类疾病领域。许多调查人员在CNOC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， 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与我们的进展， 主要目标，但也将提高其他NIH资助的研究人员在哥伦比亚的研究成果。

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.