Transplantation biology of human lymphoid progenitors

描述（由申请人提供）：为了开发将提高造血干细胞（HSC）移植后免疫重建速度和质量的临床方法，有必要详细了解移植并产生短期和长期淋巴样产生的原始细胞的生物学以及调节该过程的机制。关于人类的这一过程，仍有许多基本问题。本提案的总体目标是鉴定和表征临床相关来源的HSC中的原始人淋巴祖细胞，并确定移植后如何操作胸腺外和胸腺人淋巴祖细胞的植入和分化。我们最近在脐带血中鉴定并鉴定了一个人类共同类人猿祖细胞（CLP）群体，并在骨髓中鉴定了一个类似的群体。人和鼠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，这强调了研究来自临床相关来源的人类细胞的重要性。我们的具体目标是：（1）鉴定和表征动员外周血（MPB）中的人CLP和其他淋巴祖细胞;（2）确定稳态期间和移植后人HSC和淋巴祖细胞的胸腺植入模式;（3）确定通过移植物的体内和体外操作来增强HSC移植后人T淋巴细胞生成的方法。将使用体外和体内模型的组合来实现这些目标。将使用克隆试验来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的相对水平和植入部位以及植入动力学。将确定Notch信号传导在来自人HSC和CLP的淋巴定型和扩增中的作用。

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.