STEM CELLS FOR TOLERANCE INDUCTION

用于耐受诱导的干细胞

• 批准号: 6919116
• 负责人: NORMA S. KENYON
• 金额: $ 101.45万
• 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/6919116
• 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）：继续介绍 能够在不同阶段介入的新代理 免疫反应，在领域取得了重大进展 过去十年的移植。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 特定于捐助者的耐受状态，从而消除了对终身的需求 接受者的免疫抑制。几种证明成功的策略 啮齿动物模型中的耐受性诱导尚未转换为临床前 模特或人。骨髓移植和混合的建立 造血嵌合可能会导致对同种异体器官和天花板的耐受性， 以及啮齿动物自身免疫性疾病的预防或改善。 该策略的临床应用已受到要求的要求 为了获得捐助者HSC，接收者的密集调理 跨MHC障碍的植入。与能力相关的变量 克服这一挑战正在基础研究中迅速定义 型号。在这个程序项目中，我们旨在将 严格的临床前模型，已经证明了几种 促进啮齿动物中的供体HSC植入。在项目I中，以下 将测试概念：i）供体造血的体内输注 细胞和/或MSC导致募集外围调节机制 容易耐受胰岛同种异体移植物的耐受性，2） 基质细胞的体内移植导致建立A 肝脏内的微环境有助于供体HSC植入 （由I.V. HSC输注增强）和3）DO HSC重新填充宿主组织，因此 导致招募中央缺失机制，并结合 外围调节过程将导致耐受性的状态。在 项目2，我们建议：i）操纵供体干细胞来设计移植物 这对宿主发挥免疫调节作用，2）确定是否茎 可以操纵骨髓微环境的细胞以进一步 提高移植物的生存，3）解决与残留宿主T和B有关的问题 与晚期移植物损失有关的细胞。重叠两个项目1和2是 关于调节细胞在 耐受性的诱导和维持（项目3）。动物移植 项目1（胰岛）和2（肾脏）将在项目3中进行研究，以识别和 分析具有稳定同种异体移植物的猴子中推定的调节细胞，我们 然后，将利用这些信息来完善我们的移植策略。核心A。 将在项目1和2中提供用于移植的硕士学位。