DEVELOPMENT AND PERSISTENCE OF IMMUNITY IN SCID CHIMERAS

SCID 嵌合体中免疫的发展和持续

基本信息

批准号：
6624525
负责人：
REBECCA H BUCKLEY
金额：
$ 26.33万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-12-01 至 2004-04-30
项目状态：
已结题

项目摘要

The research proposed in this application is designed to investigate the ontogeny and persistence of T, B, and NK cell function in infants and children with well-characterized (at both the cellular and molecular levels) human services combined immunodeficiency (SCID) who are or who become haploidentical stem cell chimeras. The unique study population will consist of 66 surviving SCIDs (and any subsequent chimeras) who have been given bone marrow stem cells without pre-transplant cytoreduction or post- transplant GVHD prophylaxis. The first aim is to examine the phenotypes, functions and genetic origins of T cells in SCID recipients of haploidentical T cell-depleted parental marrow stem cells at specified intervals post-transplantation. Two hypotheses will be tested initially: a) that the neonatal SCID thymus is able to mature normal stem cells to be phenotypically and functionally normal T cells more rapidly that thymi from older SCIDs and b) that the number and time of development of CD4+/CD45RA+ T cells post-transplantation will be predictive of more sustained and effective T cell function. The second aim is to assess the phenotype, functions and genetic origins of B cells in these chimeras as a function of time post-transplantation and type of SCID. Three hypotheses will be tested initially: a) that persistence of immature B cell phenotypes correlates with abnormal B cell development post- transplantation, b) that abnormal B cell function post-transplantation is related to the underlying molecular defect leading to SCID, and c) that the development of normal B cell function is due to the presence of donor B cells or to double parental T cell chimerism. The third aim is to assess the functions and genetic origins of NK cells longitudinally, testing the hypothesis that abnormal NK function post-transplantation is due to failure to signal through the gamma chain of the IL-15 receptor and that will only be seen in certain forms of SCID. NK function will be assessed in K562/51 Cr release assays, and purified NK cells will be analyzed for donor or host origin as indicated above. The studies in the first three aims will also reveal new information about T,B, and NK cell ontogeny not available in any other human experimental system. The fourth aim is to investigate the molecular bases of the 29% of these SCID chimeras for whom the cause remains unknown. The hypothesis to be tested is that the phenotypes of these patients' lymphocytes and/or their response or failure to respond to IL-2 will provide clues that will lead to the discovery of their underlying defects. These could include known or as yet undescribed defects, such as IL-7 or IL-7Ralpha mutations, or defects in signaling molecules such as LAT.

本申请中提出的研究旨在调查婴儿和婴儿中 T、B 和 NK 细胞功能的个体发育和持续性具有良好特征的儿童（在细胞和分子方面）水平）人类服务联合免疫缺陷（SCID）谁是或谁成为单倍体干细胞嵌合体。独特的研究人群将由 66 个幸存的 SCID（以及任何后续的嵌合体）组成，它们已被未经移植前细胞减灭术或移植后给予骨髓干细胞移植GVHD预防。第一个目的是检查表型， SCID 受体 T 细胞的功能和遗传起源指定的半相合 T 细胞耗尽的亲代骨髓干细胞移植后的间隔。最初将测试两个假设： a) 新生儿 SCID 胸腺能够使正常干细胞成熟表型和功能正常的 T 细胞比胸腺更快来自较旧的 SCID 和 b) 的开发数量和时间移植后 CD4+/CD45RA+ T 细胞将预测更多持续有效的 T 细胞功能。第二个目标是评估这些嵌合体中 B 细胞的表型、功能和遗传起源是移植后时间和 SCID 类型的函数。三个假设最初将测试：a) 未成熟 B 细胞的持续性表型与异常 B 细胞发育后相关移植，b) 移植后 B 细胞功能异常与导致 SCID 的潜在分子缺陷有关，并且 c) 正常 B 细胞功能的发育是由于供体的存在 B细胞或双亲T细胞嵌合。第三个目标是评估纵向研究 NK 细胞的功能和遗传起源，测试假设移植后 NK 功能异常是由于未能通过 IL-15 受体的伽玛链发出信号仅在某些形式的 SCID 中可见。将评估 NK 功能在 K562/51 Cr 释放测定中，将分析纯化的 NK 细胞供体或宿主来源如上所述。前三项研究目标还将揭示有关 T、B 和 NK 细胞个体发育的新信息可用于任何其他人体实验系统。第四个目标是研究 29% SCID 嵌合体的分子基础原因尚不清楚。要检验的假设是这些患者淋巴细胞的表型和/或其反应或失败响应 IL-2 将提供线索，从而导致发现他们的根本缺陷。这些可能包括已知或尚未描述的缺陷，例如 IL-7 或 IL-7Rα 突变，或信号传导缺陷分子，如 LAT。