Strategies for Prenatal Stem Cell Tranplantation

描述：（研究者摘要）子宫内造血干细胞 移植（IUHSC Tx）是一种有前途的治疗方法，用于治疗 各种先天性血液病的症状然而，在缺乏一个 正常细胞的选择性优势，临床和实验努力， IUHSCTx导致有限的或不可检测的植入，支持 在造血竞争中存在植入的主要障碍 收件人。该项目的长期目标是在临床上开发 将植入增加到治疗水平的适用策略。克服 植入屏障将允许增加IUHSCTx的临床应用 相对于 目前可用的疗法。该提案的具体目标是：1.到 优化供体细胞亚群，用于子宫内HSC后的植入 移植有关归巢、递交及植入的规定， 对胎儿肝脏了解甚少。供体细胞群体的特征不同 植活效率使用新的策略，特定的供体细胞群 将比较它们的早期植入动力学， 移植细胞的再增殖能力和移植后的竞争能力 IUHSCTx的等效重新填充人口。这将提供深入了解 特定供体群体在IUHSCTx后移植的相对能力， 移植的HSC的初始数量的相对重要性，与 捐助者群体的竞争能力，以实现高水平 雕刻2.为了研究基于免疫的策略对 增强产前植入，并增加嵌合体水平 出生后该具体目标有三个目标：1）识别和验证 特异性供体来源的细胞群， 没有移植物抗宿主病（GVHD）的富集HSC的移植; 2） 研究产前免疫策略以抑制GVHD并改善 IUHSC Tx后非富集供体群体的植入;和3）测试 出生后免疫方法的有效性，以减少或消除 在通过IUHSCTx耐受的混合嵌合受体中的宿主造血。 本提案中的研究旨在确定和测试战略， 增加IUHSCTx后的植入。这将允许应用此 一个广泛的产前诊断的遗传疾病的方法。

DESCRIPTION: (Investigator's abstract) In utero hematopoietic stem cell transplantation (IUHSCTx) is a promising therapeutic approach for the treatment of a variety of congenital hematologic disorders. However, in the absence of a selective advantage for normal cells, clinical and experimental efforts at IUHSCTx have resulted in limited or no detectable engraftment, supporting the existence of major barriers to engraftment in the hematopoietically competitive recipient. The long-term objective of this project is to develop clinically applicable strategies to increase engraftment to therapeutic levels. Overcoming the engraftment barrier would allow increased clinical application of IUHSCTx with the potential for reduced morbidity, mortality, and cost, relative to currently available therapy. The specific aims of this proposal are: 1. To optimize donor cell subpopulations for engraftment after in utero HSC transplantation. The requirements for homing, lodgement and engraftment to the fetal liver are poorly understood. Donor cell populations differ in their engraftment efficiency. Using novel strategies, specific donor cell populations will be compared for their early kinetics of engraftment, the relative repopulating ability of engrafted cells, and the competitive capacity after IUHSCTx of equivalent repopulating populations. This will provide insight into the relative ability of specific donor populations to engraft after IUHSCTx and into the relative importance of initial number of HSC engrafted, versus the competitive capacity of the donor population, for the achievement of high level engrafment. 2. To investigate the efficacy of immune based strategies to enhance engraftment prenatally, and to increase levels of chimerism postnatally. This Specific Aim has three goals: 1) To identify and validate specific donor derived cell populations that can facilitate prenatal engraftment of enriched HSC without graft versus host disease (GVHD); 2) to investigate prenatal immunotherapeutic strategies to suppress GVHD and improve engraftment of non-enriched donor populations after IUHSCTx; and 3) to test the efficacy of immunotherapeutic approaches after birth to reduce or eliminate host hematopoiesis in the mixed chimeric recipient made tolerant by IUHSCTx. The studies in this proposal are designed to identify and test strategies to increase engraftment after IUHSCTx. This would allow application of this approach to a broad range of prenatally diagnosed genetic disorders.