PROGRAM PROJECT IN ALLOGENEIC STEM CELL TRANSPLANTATION

近年来，我们对造血系统中的免疫功能和细胞相互作用的基本了解有了显著的提高。我们的假设是，这些进展可以与体外细胞处理和免疫功能评估的新方法相结合，为人类造血干细胞移植开发新的策略。这种方法，我们通常称之为移植工程，是基于我们有能力选择性地操纵特定的未成熟和成熟细胞群体，并在不同的时间以协调的方式选择性地移植这些细胞。移植工程承诺减少与移植相关的毒性，同时促进移植干细胞及其不同后代的植入和功能。我们的研究人员将通过三个项目的一系列综合研究来完成。项目1进行了一系列临床试验，以检测从干细胞移植中耗尽成熟供者T细胞，然后在造血植入后的稍后时间输入选择性T细胞亚群的临床和免疫学效果。结合这些临床试验，我们将利用T细胞重建和复杂性的新测量来确定这些体外操作在体内的效果。免疫重建实验室措施的结果将与临床结果相关。在项目2中，我们将开发新的方法，从造血祖细胞体外产生具有不同谱系的成熟多克隆T细胞。初步结果表明，在体外开发支持人类T细胞新生的人工系统是可行的。这些三维生物矩阵系统将被用来建立在体外产生不同群体的原始T细胞所需的参数，并检测混合嵌合体对T细胞新生的影响。如果成功，BioMatrix系统还可能允许我们在体外扩大T细胞谱系的多样性，并增强体内T细胞的重建。在项目3中，我们描述了移植物抗宿主病(GVHD)和体内移植物抗白血病(GVL)反应的靶抗原。更好地定义这些靶抗原将使我们能够开发出选择性缺失或扩增介导这两种反应的特定T细胞群的方法。综上所述，该计划项目中拟议的研究将集中于更好地了解成人T细胞新生，并确定供体免疫反应针对受体细胞的免疫学机制和靶抗原。希望这些研究能改善接受异基因干细胞移植的恶性血液病患者的预后，并为非恶性血液病患者的干细胞移植开辟新的途径。

Our basic understanding of immune function and cellular interactions within the hematopoietic system has improved dramatically in recent years. It is our hypothesis that these advances can be coupled with new methods for ex vivo cell processing and assessment of immune function to develop new strategies for human hematopoietic stem cell transplantation. This approach, which we have generally termed graft engineering, is based on our ability to selective manipulate specific populations of immature and mature cells and to selective transplant these cells at different times in a coordinated fashion. Graft engineering promises to reduce the toxicities associated with transplantation while facilitating the engraftment and function of engrafted stem cells and their diverse progeny. Our investigators will be accomplished through a series of integrated studies in 3 projects. Project 1 undertakes a series of clinical trials to examine the clinical and immunologic effects of depleting mature donor T cells from the stem cell graft followed by infusion of selective subsets of T cells at later times after hematopoietic engraftment. In conjunction with these clinical trials we will utilize novel measures of T cell reconstitution and complexity to determine the effects of these in vitro manipulations in vivo. Results of laboratory measures of immune reconstitution will be correlated with clinical outcomes. In Project 2, we will develop new methods for ex vivo generation of mature polyclonal T cell with diverse repertoire from hematopoietic progenitors. Preliminary results suggest that it will be feasible to develop artificial systems that support human T cell neogenesis in vitro. These 3 dimensional biomatrix systems will be used to establish in vitro parameters required for the generation of diverse populations of na ve T cells and to examine the effects of mixed chimerism on T cell neogenesis. If successful, the biomatrix systems may also allow us to expand the diversity of the T cell repertoire in vitro and enhance T cell reconstitution in vivo. In Project 3, we characterize the target antigens for graft-versus-host disease (GVHD) and the graft-versus leukemia (GVL) response in vivo. Better definition of these target antigens will allow us to develop methods for selective deletion or expansion of specific T cell populations that mediate these two responses. Taken together, the proposed studies in this program project will focus on developing a better understanding of T cell neogenesis in adults and on defining the immunologic mechanisms and target antigens of the donor immune response against recipient cells. It is hoped that these studies will lead to improved outcomes for patients with hematologic malignancies undergoing allogeneic stem cell transplantation and will also lead to new approaches for stem cell transplantation in patients with non-malignant hematopoietic diseases.