Transplantation biology of human lymphoid progenitors

描述（由申请人提供）：为了开发临床方法来提高造血干细胞移植后免疫重建的速度和质量，有必要详细了解移植和产生短期和长期淋巴细胞的原始细胞的生物学以及这一过程的调节机制。关于人类的这一过程，还有许多基本问题有待解决。本提案的总体目标是在临床相关的HSC来源中识别和表征原始人类淋巴样祖细胞，并确定如何在移植后操纵胸腺外和胸腺人类淋巴样祖细胞的植入和分化。我们最近在脐带血中发现并鉴定了人类共同淋巴祖细胞（CLP）群体，并在骨髓中发现了类似的群体。人和小鼠CLP之间以及不同造血来源的CLP之间存在许多关键差异，这强调了从临床相关来源研究人类细胞的重要性。我们的具体目标是：(1)鉴定和表征动员外周血（MPB）中的人类CLP和其他淋巴样祖细胞；(2)确定人造血干细胞和淋巴样祖细胞在体内稳态和移植后的胸腺植入模式；(3)确定通过体内和体外操作移植物来增强人造血干细胞移植后T淋巴生成的方法。体外和体内模型的结合将用于实现这些目标。克隆测定将用于证明所鉴定的每个群体的谱系潜力。将评估来自MPB、脐带血、骨髓和胸腺的CLP和HSC的相对水平和移植位置以及移植动力学。Notch信号在人类HSC和CLP的淋巴细胞承诺和扩增中的作用将被确定。

DESCRIPTION (provided by applicant): To develop clinical approaches that will improve the speed and quality of immune reconstitution after Hematopoietic Stem Cell (HSC) transplantation, it is necessary to understand in detail the biology of the primitive cells that engraft and generate short-term and long- term lymphoid production and the mechanisms by which this process is regulated. Many fundamental questions remain about this process in humans. The overall goals of this proposal are to identify and characterize primitive human lymphoid progenitors in clinically relevant sources of HSC and to determine how engraftment and differentiation of extrathymic and thymic human lymphoid progenitors can be manipulated after transplantation. We have recently identified and characterized a human Common Lymphoid Progenitor (CLP) population in umbilical cord blood and have identified a similar population in bone marrow. A number of critical differences exist between human and murine CLP, and between CLP from different hematopoietic sources emphasizing the importance of studying human cells from clinically relevant sources. Our Specific Aims are (1) To identify and characterize human CLP and other lymphoid progenitors in Mobilized Peripheral Blood (MPB); (2) To determine the thymic engraftment pattern of human HSC and lymphoid progenitors during homeostasis and after transplantation; and (3) To determine methods to enhance human T lymphopoiesis after HSC transplantation by in vivo and in vitro manipulation of the graft. A combination of in vitro and in vivo models will be used to accomplish these aims. Clonal assays will be used to prove the lineage potential of each population identified. The relative levels and sites of engraftment and the kinetics of engraftment of CLP and HSC from MPB, cord blood, bone marrow and thymus will be assessed. The role of Notch signaling in lymphoid commitment and expansion from human HSC and CLP will be determined.