BARRIERS TO ALLOGENIC TRANSPLANTATION OF PURIFIED HEMATOPOIETIC STEM CELLS

异基因骨髓移植（BMT）目前构成了 一些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性疾病 新陈代谢的错误。 对于白血病和其他肿瘤疾病， 现在认识到同种异体BMT的重要益处是 移植物抗白血病（GVL）效应。 不幸的是， 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影响和失败的问题 移植。 本提案中描述的实验旨在 在克服这些障碍的移植纯化 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， 产生针对宿主的反应，因此这些细胞的植入将 不会引起GVHD，在没有GVHD的情况下，需要长期 免疫抑制将被消除。 一个重要的预防性好处是 来源于同种异体HSC的成功移植， 所得到的嵌合体个体是免疫耐受的， 随后的供体匹配细胞输注。 因此，在 HSC植入将有可能将供体群体 已经被选择以赋予GVL效应的衍生细胞（但不 GVHD）而不存在宿主对这些肿瘤的抗性的问题 抑制细胞 在我们实验室以前的研究中，我们分离并表征了 来自小鼠的纯化的造血干细胞群。 这些细胞 能够自我更新，产生所有血统， 大约2000倍的放射防护能力 致命辐射的小鼠。 我们最近成功地 这些细胞的植入跨越主要的免疫屏障，并已开始 以确定实现持久植入的一些要求。 本提案中概述的实验的主要目标如下： （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;（2） 开发基于合理性的治疗方法， 移植与有限的主机发病率;（3）表征和克隆 细胞群，以及来自细胞的受体， GVL，以便可以生产“定制” 肿瘤性疾病的器官移植 项目五的研究与其他国家的实验有关。 次级项目。

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.