Transplantation biology of human lymphoid progenitors

描述(申请人提供)：为了开发临床方法，以提高造血干细胞(HSC)移植后免疫重建的速度和质量，有必要详细了解植入并产生短期和长期淋巴生成的原始细胞的生物学以及调节这一过程的机制。关于人类的这一过程，许多基本的问题仍然存在。这项建议的总体目标是鉴定和鉴定临床相关来源的原始人类淋巴祖细胞，并确定胸腺外和胸腺外人类淋巴祖细胞在移植后如何植入和分化。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，在骨髓中也发现了类似的群体。人和小鼠CLP之间以及来自不同造血来源的CLP之间存在许多关键差异，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)鉴定和鉴定动员后外周血(MPB)中的人CLP和其他淋巴祖细胞；(2)确定人HSC和淋巴祖细胞在体内稳态和移植后的胸腺植入模式；(3)通过体内和体外操作移植物来确定促进HSC移植后人类T淋巴细胞生成的方法。将使用体外和体内模型相结合的方式来实现这些目标。克隆分析将被用来证明每个被识别的种群的谱系潜力。将评估从MPB、脐带血、骨髓和胸腺中植入CLP和HSC的相对水平和位置以及植入动力学。Notch信号在人类HSC和CLP的淋巴定位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.