PROGRAM PROJECT IN ALLOGENEIC STEM CELL TRANSPLANTATION

近年来，我们对造血系统内免疫功能和细胞相互作用的基本理解有了显著提高。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，以开发人类造血干细胞移植的新策略。这种方法，我们通常称之为移植工程，是基于我们的能力，选择性地操纵特定群体的未成熟和成熟细胞，并选择性地移植这些细胞在不同的时间在一个协调的方式。移植工程有望减少与移植相关的毒性，同时促进移植干细胞及其多样化后代的植入和功能。我们的研究人员将通过3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，以检查从干细胞移植物中耗尽成熟供体T细胞，然后在造血移植后的稍后时间输注选择性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措施，以确定这些体外操作在体内的影响。免疫重建的实验室测量结果将与临床结局相关。在项目2中，我们将开发新的方法，用于从造血祖细胞体外产生具有不同库的成熟多克隆T细胞。初步结果表明，这将是可行的，以开发人工系统，支持人类T细胞新生在体外。这些三维生物基质系统将用于建立产生不同的幼稚T细胞群体所需的体外参数，并检查混合嵌合体对T细胞新生的影响。如果成功的话，生物基质系统也可以让我们在体外扩大T细胞库的多样性，并在体内增强T细胞重建。在项目3中，我们描述了体内移植物抗宿主病（GVHD）和移植物抗白血病（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。总之，该计划项目中的拟议研究将集中在更好地了解成人T细胞新生，并定义免疫机制和供体免疫应答对受体细胞的靶抗原。希望这些研究将改善接受异基因干细胞移植的恶性血液病患者的结局，并为非恶性造血系统疾病患者的干细胞移植提供新的方法。

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.