THYMIC TRANSPLANTATION OF STEM CELLS

干细胞胸腺移植

• 批准号: 6116369
• 负责人: MARGARET D ALLEN
• 金额: $ 8.67万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6116369
• 关键词: Mammalia; Primates; animal tissue; cardiovascular system; hematology; skin; transplantation

In spite of the development of new immunosuppressive drugs, chronic and acute rejection remains a significant cause of patient morbidity, organ failure, and death in human solid organ transplantation. The goal of this project is to determine whether injection of donor stem cells into the thymus can result in (1) stem cell engraftment and persistent peripheral blood microchimerism (coexistence of donor cells in recipient blood without inducing a recipient immune attack) and (2) modification of the recipient's immune system and prolonged graft survival of solid organ grafts from the stem cell donor. The ultimate objective of these studies is to develop a method of inducing tolerance (acceptance) of a solid organ graft without the use of life-long immunosuppressive drugs. In previous years we showed that intrathymic stem cell implantation could result in long-term survival of donor-derived cells and that this resulted in prolonged skin graft acceptance. We are currently evaluating the characteristics of various sub-types of bone marrow stem cells to determine which populations are "best" for intrathymic transplantation and achieving microchimerism. This is being done by (1) in vitro assays evaluating stem cell sub-types by cell surface markers and functional characteristics and (2) in vivo experiments, transplanting different populations of stem cells into experimental animals and monitoring development of microchimerism. Results obtained during the past year suggest that bone marrow-derived stem cells are very heterogeneous, and that the specific type of cell used for intrathymic transplantation may be critical to the success of this method of modifying the recipient immune system. Future studies will evaluate the effects of stem cell transplantation and microchimerism on the acceptance of a solid organ (heart) graft. These studies are being performed in primates because these animals provide the most direct model for refining this method before it is tested in transplant patients.

尽管开发了新的免疫抑制药物，但慢性和急性排斥反应仍然是人类固体器官移植中患者发病率，器官衰竭和死亡的重要原因。 该项目的目的是确定将供体干细胞注射到胸腺中是否会导致（1）干细胞的植入和持续的外围血液微神经（供体细胞在受体血液中共存而不诱导受体免疫攻击）和（2）修饰受体的免疫系统和从干细胞供体中固体器官移植物的长时间移植物存活。 这些研究的最终目的是开发一种诱导固体器官移植的耐受性（接受）的方法，而无需使用终生的免疫抑制药物。 在过去的几年中，我们表明胸膜干细胞植入可能导致供体衍生细胞的长期存活，这导致了长期的皮肤移植物接受。 我们目前正在评估骨髓干细胞的各种亚类型的特征，以确定哪些人群最适合胸膜内移植和实现微chimerismism。 这是通过（1）通过细胞表面标记和功能特征和（2）在体内实验中评估干细胞亚类型的体外测定方法来完成的，将不同的干细胞种群移植到实验动物中并监测微神经的发展。 在过去的一年中获得的结果表明，骨髓来源的干细胞非常异质，并且用于胸膜内移植的特定细胞类型对于这种修改受体免疫系统的成功的成功可能至关重要。 未来的研究将评估干细胞移植和微核对固体器官（心脏）移植物的接受的影响。 这些研究是在灵长类动物中进行的，因为这些动物为在移植患者进行测试之前提供了最直接的模型。