BARRIERS TO ALLOGENIC TRANSPLANTATION OF PURIFIED HEMATOPOIETIC STEM CELLS

异基因骨髓移植(BMT)目前是 多种血液病的主要治疗选择 恶性肿瘤、遗传性造血障碍和某些先天疾病 新陈代谢错误。对于白血病和其他肿瘤疾病， 现在人们认识到异基因骨髓移植的一个重要好处是 移植物抗白血病(GVL)效应。不幸的是，越是普遍 同种异体骨髓移植的应用仍然受到严重限制 移植物抗宿主病(GVHD)的并发症 长期免疫抑制的病态效应和失败问题 关于嫁接的。这项提案中描述的实验旨在 在克服这些障碍方面通过移植纯化的 造血干细胞(HSC)。这种方法的基本原理是 纯化的造血干细胞缺乏成熟的成分，使移植物 对宿主产生反应，从而植入这样的细胞 不会引起GVHD，而在没有GVHD的情况下需要长期 免疫抑制将被消除。一个重要的附带好处 源于异基因造血干细胞的成功移植，是 由此产生的嵌合体个体具有免疫耐受性 到随后的捐献者匹配的细胞输注。因此，在以下情况下 造血干细胞移植将有可能为供者群体输注 已被选择来授予GVL效果(但不是 GVHD)，没有宿主对这些肿瘤的抵抗力问题 抑制单元格。 在我们实验室以前的研究中，我们分离并鉴定了 一种纯化的小鼠造血干细胞群体。这些细胞 能够自我更新，产生所有的血统，并且 它们的辐射防护能力提高了约2000倍 受到致命照射的小鼠。我们最近成功地实现了 这些细胞跨越主要免疫屏障的植入已经开始 定义实现耐久植骨的一些要求。 该提案中概述的实验的主要目标如下 主要内容如下：(1)了解细胞和分子基础 对异基因造血干细胞和骨髓移植的抵抗； 开发基于原理的疗法，允许稳定的同种异体造血干细胞 寄主发病率低的嫁接；(3)鉴定和克隆 细胞群，以及来自细胞的受体 GVL，这样就有可能生产“定制化”产品 未来针对肿瘤疾病的移植。 项目V中的研究与在其他项目中进行的实验有关 子项目。

Allogeneic bone marrow transplantation (BMT) currently constitutes the major therapeutic treatment option for a number of hematological malignancies, inherited disorders of hematopoiesis and certain in-born errors of metabolism. For leukemias and other neoplastic diseases, it is now appreciated that an important benefit of allogeneic BMT is a graft-vs-leukemia (GVL) effect. Unfortunately, the more widespread application of allogeneic BMT remains severely limited by the complications of graft-versus-host disease (GVHD), the associated morbid effects of long-term immunosuppression and problems of failure of engraftment. The experiments described in this proposal are aimed at overcoming these obstacles by the transplantation of purified hematopoietic stem cells (HSCs). The rationale for this approach is that purified HSCs lack the mature elements which allow the graft to mount a response against the host, thus engraftment of such cells will not cause GVHD, and in the absence of GVHD the need for long-term immunosuppression will be eliminated. An important adjunctive benefit derived from the successful transplantation of allogeneic HSCs, is that the resultant chimeric individuals are immunologically tolerant to subsequent donor-matched cell infusions. Thus, in the context of HSC engraftment it will be possible to infuse populations of donor derived cells that have been selected to confer GVL effects (but not GVHD) without the problems of host resistance to these tumor suppressing cells. In previous studies from our laboratory we isolated and characterized a purified hematopoietic stem cell population from mice. These cells are capable of self-renewal, give rise to all blood lineages, and are approximately 2000-fold enriched for their ability to radioprotect lethally irradiated mice. We have recently successfully achieved engraftment of these cells across major immune barriers and have begun to define some of the requirements to achieve durable engraftment. The major goals of the experiments outlined in this proposal are as follows: (1) To understand the cellular and molecular basis of resistance to allogeneic HSC and bone marrow transplants; (2) to develop rationale based therapies that allow stable allogeneic HSC engraftment with limited host morbidity; (3) to characterize and clone the cell populations, as well as the receptors from cells that confer GVL, so that it may become possible to produce "customized" transplants for neoplastic diseases in the future. Research in Project V is related to experiments performed in other subprojects.