TOLERANCE POST IN UTERO TRANSPLANTATION

描述：(申请人摘要)这项研究的长期目标是 开发一种成功的子宫内干细胞移植方法 人类胎儿被诊断患有免疫缺陷疾病，血红蛋白疾病， 或者是先天的新陈代谢障碍。在子宫内小鼠模型中 造血功能正常的小鼠，而70%的移植后， 供体细胞比例较低(0.001%-2%)。然而，大多数植入的动物都是部分 对供体皮肤移植有耐受性；一些人表现出永久性的皮肤移植接受， 少数人没有证据表明他们对皮肤移植有耐受性。的具体目的 此应用程序用于定义负责 子宫诱导对异基因供体细胞的耐受性。假设 将进行检测的有：1)有限数量的同种异体错配 植入子宫的造血干细胞(HSC)可以扩增和 在无缺陷的受者中分化为多个谱系，以及2) 宿主对异基因不相合造血干细胞的耐受是由骨髓介导的 来源的供体树突状细胞(DC)和T细胞。招募的细胞因子 外周血干细胞将被用来确定最佳数量 实现植入所需的细胞，以及胸腺中的植入细胞， 将对脾、淋巴结、血液、肝脏和骨髓进行表型分析。 将进行实验以确定胸腺中的缺失 (或外周)参与了移植小鼠的耐受诱导以及什么 无能发挥着中心和/或外围的作用。评选结果 拟议的实验将导致治疗策略的发展 为了优化供体细胞在出生前和出生后的植入 可能会对移植的其他领域产生影响，特别是， 诱导和维持对固体器官的耐受性。

DESCRIPTION: (Applicant's Abstract) The long-term goal of this research is to develop a successful approach to in utero stem cell transplantation in human fetuses diagnosed with immunodeficiency diseases, hemoglobinopathies, or inborn errors of metabolism. In an in utero murine model of hematopoietically non-defective mice, while 70% engraft, the percent of donor cells is low (.001-2%). However, most engrafted animals are partially tolerant to donor skin grafts; some show permanent skin graft acceptance, and a few have no evidence of tolerance to skin grafts. The specific aim of this application is to define the mechanisms that are responsible for the in utero induction of tolerance to allogeneic donor cells. The hypotheses that will be tested are: 1) The limited number of allogeneic mismatched hematopoietic stem cells (HSC) that engraft in utero can be expanded and differentiate into multilineages in non-defective recipients, and 2) tolerance of the host to allogeneic mismatched HSC is mediated by marrow derived donor dendritic cells (DC) and T cells. Cytokine-recruited peripheral blood stem cells will be used to determine the optimal number of cells required to achieve engraftment, and engrafted cells in the thymus, spleen, lymph node, blood, liver, and marrow will be phenotyped. Experiments will be carried out to determine whether deletion in the thymus (or periphery) is involved in tolerance induction in engrafted mice and what role anergy plays centrally and/or in the periphery. Results of the proposed experiments will lead to the development of therapeutic strategies for the optimization of engraftment of donor cells pre and postnatally and could have an impact on other areas of transplantation, specifically, induction and maintenance of tolerance to solid organs.