THYMIC TRANSPLANTATION OF STEM CELLS

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实体器官移植中患者发病、器官衰竭和死亡的重要原因。 本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）干细胞植入和持续的外周血微嵌合体（供体细胞在受体血液中共存而不诱导受体免疫攻击）和（2）受体免疫系统的修饰和来自干细胞供体的实体器官移植物的移植物存活时间延长。 这些研究的最终目的是开发一种诱导实体器官移植耐受（接受）的方法，而无需使用终身免疫抑制药物。 在过去的几年中，我们发现胸腺干细胞移植可以导致供体来源的细胞的长期存活，这导致皮肤移植物的接受延长。 我们目前正在评估各种亚型骨髓干细胞的特性，以确定哪些群体是“最好的”胸腺内移植和实现微嵌合体。 这是通过（1）通过细胞表面标志物和功能特征评估干细胞亚型的体外测定和（2）体内实验，将不同干细胞群体移植到实验动物中并监测微嵌合体的发展来完成的。 在过去的一年中获得的结果表明，骨髓来源的干细胞是非常异质性的，并且用于胸腺内移植的特定类型的细胞可能是这种修改受体免疫系统的方法的成功的关键。 未来的研究将评估干细胞移植和微嵌合体对实体器官（心脏）移植物接受性的影响。 这些研究是在灵长类动物中进行的，因为在移植患者中进行测试之前，这些动物为改进这种方法提供了最直接的模型。

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.