STEM CELLS FOR TOLERANCE INDUCTION

用于耐受诱导的干细胞

• 批准号: 6655693
• 负责人: NORMA S. KENYON
• 金额: $ 92.27万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6655693
• 关键词: cooperative study; immune tolerance /unresponsiveness; stem cell transplantation; transplantation immunology

DESCRIPTION (provided by applicant): With the continued introduction of new agents capable of intervening at different stages in the generation of an immune response, significant progress has been made in the field of transplantation over the past decade. One of the major challenges facing the field today concerns definition of protocols that result in the establishment of a state of donor specific tolerance, thus obviating the need for life-long immunosuppression of the recipient. Several strategies proven successful for tolerance induction in rodent models have not translated-well to pre-clinical models or man. Bone marrow transplantation and the establishment of mixed hematopoietic chimerism can lead to tolerance to allogeneic organs and ceils, as well as prevention or amelioration of autoimmune disease in rodents. Clinical application of this strategy has been hampered by the requirement for intensive conditioning of the recipient in order to attain donor HSC engraftment across MHC barriers. Variables associated with the ability to overcome this challenge are being defined in a rapid manner in basic research models. In this program project, we aim to bring together and test, in a rigorous pre-clinical model, several approaches that have been demonstrated to facilitate donor HSC engraftment in rodents. In Project I, the following concepts will be tested: I) can intraportal infusion of donor hematopoietic cells and/or MSCs lead to recruitment of peripheral regulatory mechanisms that predispose the host to become tolerant to islet allografts, 2) does intraportal transplantation of stromal cells result in the establishment of a microenvironment within the liver that facilitates donor HSC engraftment (augmented by i.v. HSC infusion), and 3) do HSC repopulate host tissues, thus leading to recruitment of central deletional mechanisms that, combined with peripheral regulatory processes, will lead to a state of robust tolerance. In Project 2, we propose to: I) manipulate donor stem cells to engineer a graft that exerts immunoregulatory effects on the host, 2) determine whether stem cells of the bone marrow microenvironment can be manipulated to further enhance graft survival, and 3) address issues related to residual host T and B cells in relation to late graft loss. Overlapping both projects 1 and 2 are newly emerging concepts regarding the role of regulatory cells in the induction and maintenance of tolerance (project 3). Animals transplanted in Projects 1 (islet) and 2 (kidney) will be studied in Project 3 to identify and analyze putative regulatory cells in monkeys with stable allografts, and we will then utilize this information to refine our transplant strategies. Core A will provide MSCs for transplantation in Projects 1 and 2.

描述（由申请人提供）：随着继续介绍 新的代理人能够干预在不同阶段的产生， 免疫反应，在免疫领域取得了重大进展， 近十年来，移植。面临的主要挑战之一， 今天的领域涉及导致建立的协议的定义 供体特异性耐受的状态，从而避免了终身需要 免疫抑制受体。几种策略被证明是成功的， 啮齿动物模型中的耐受性诱导尚未很好地证实至临床前 骨髓移植及混合模型的建立 造血嵌合体可导致对同种异体器官和细胞的耐受性， 以及预防或改善啮齿动物的自身免疫性疾病。 该策略的临床应用受到以下要求的阻碍： 接受者的强化调节以获得供体HSC 跨MHC屏障的移植。与以下能力相关的变量： 克服这一挑战的方法正在基础研究中迅速确定 模型在这个项目中，我们的目标是汇集和测试，在一个 严格的临床前模型，已被证明， 促进供体HSC在啮齿动物中的植入。在项目I中， 概念将被测试：I）可以门静脉内输注供体造血 细胞和/或MSC导致外周调节机制的募集， 易使宿主对胰岛移植物产生耐受性，2） 门静脉内移植基质细胞导致建立一个 促进供体HSC植入的肝脏内微环境 （通过静脉内HSC输注增强），和3）HSC是否重新填充宿主组织，因此 导致中央委派机制的招募， 外周调节过程，将导致一种稳健的耐受状态。在 项目2，我们建议：I）操纵供体干细胞来设计移植物 对宿主发挥免疫调节作用，2）确定是否干细胞 可以操纵骨髓微环境的细胞，以进一步 提高移植物存活率，以及3）解决与残留宿主T和B相关的问题 与晚期移植物丢失有关。与项目1和项目2重叠的是 新出现的概念，调节细胞的作用， 容忍的诱导和维持（项目3）。动物移植 项目1（胰岛）和项目2（肾脏）将在项目3中进行研究，以确定和 分析稳定同种异体移植物的猴子中的假定调节细胞， 将利用这些信息来完善我们的移植策略。芯A 将为项目1和项目2的移植提供MSC。