STEM CELLS FOR TOLERANCE INDUCTION

用于耐受诱导的干细胞

• 批准号: 7092156
• 负责人: NORMA S. KENYON
• 金额: $ 84.9万
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7092156
• 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(申请人提供)：继续介绍 新的代理人能够在不同的阶段干预在产生 在免疫反应方面，在免疫领域取得了重大进展。 在过去的十年中进行了移植。面临的主要挑战之一是 今天的领域涉及导致建立 一种供者特有的耐受性状态，从而消除了终生 受者的免疫抑制。事实证明，以下几种策略是成功的 啮齿动物模型的耐受诱导尚未很好地转化为临床前 模特还是男人。骨髓移植与混合型骨髓移植的建立 造血嵌合体可以导致对同种异体器官和细胞的耐受， 以及预防或改善啮齿动物的自身免疫性疾病。 这一策略的临床应用受到了以下要求的阻碍 为了获得供者的造血干细胞，对受者进行密集的条件调节 跨越MHC障碍的嫁接。与以下能力相关的变量 克服这一挑战在基础研究中正在迅速得到定义 模特们。在这个计划项目中，我们的目标是在一个 严格的临床前模型，几种方法已被证明 促进供者HSC在啮齿动物体内的植入。在项目I中，以下是 将测试的概念：一)门脉内能否输注供者的造血 细胞和/或MSCs导致外周调节机制的招募 使宿主对同种异体胰岛移植物产生耐受性，2) 门脉内移植基质细胞导致建立 促进供者HSC植入的肝脏内微环境 (增加了静脉注射。HSC输注)，以及3)HSC是否重新填充宿主组织，从而 导致中央删除机制的招募，与 外围监管过程，将导致一种稳健的容忍状态。在……里面 项目2，我们建议：i)操纵捐赠者干细胞来设计移植物 对宿主施加免疫调节作用，2)决定干细胞 骨髓微环境的细胞可以被操纵以进一步 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 细胞与移植物晚期丢失有关。重叠的项目1和2都是 关于调节细胞在体内的作用的新概念 诱导和维持耐受性(项目3)。动物被移植到 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 分析有稳定同种异体移植物的猴子体内可能的调节细胞，我们 然后将利用这些信息来改进我们的移植策略。核心A 将在项目1和2中提供骨髓间充质干细胞进行移植。

项目成果

Cellular therapies for type 1 diabetes.

1 型糖尿病的细胞疗法。

• DOI: 10.1055/s-2008-1042430
• 发表时间: 2008
• 期刊: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
• 作者: Lee,DD;Grossman,E;Chong,AS
• 通讯作者: Chong,AS