Reconstitution of Regulatory T Cells after Allogeneic Stem Cell Transplantation

项目2的总体目标将是描述异基因造血干细胞移植后调节性T细胞的重建，并确定这些重要的调节元件在移植物抗宿主病发展中的作用。许多实验室最近使用各种模型系统进行的研究表明，调节性T细胞(Treg)在抑制自身免疫中发挥重要作用，并且Treg缺陷能够增强肿瘤免疫。 自身免疫力。几个实验室也开始研究Treg在人类异基因造血干细胞移植后GVHD发生中的潜在作用。遗憾的是，最初的研究提供了相互矛盾的结果，Treg在GVL和GVHD的调节中的作用尚不确定。我们实验室的初步结果表明，Treg重构缺陷实际上与慢性移植物抗宿主病的发生有关。在对接受异基因造血干细胞移植的患者进行的综合前瞻性分析中，我们的研究将确定Treg是否在异基因干细胞接受者T细胞重建的调节中发挥重要作用。通过表型分析和功能分析，这些研究将确定Treg重建缺陷是否有助于慢性移植物抗宿主病的发生和持续。进一步的研究还将检验影响Treg重建的机制以及在体内调节Treg的可能方法。我们还建议启动供体Treg过继治疗的临床试验，这些供体Treg已被分离并在体外扩大。与该计划项目中的其他研究人员合作，这些实验将导致开发有选择地增强异基因造血干细胞移植后有益反应或有选择地消除毒性反应的新方法。这些实验将在4个特定的目标下进行：1.确定慢性GVHD是否与异基因HSCT后调节性T细胞重建延迟有关。 2.明确异基因HSCT后调节性T细胞重建的机制。 3.明确异基因造血干细胞移植后体内调节性T细胞的调节机制。 4.评价调节性T细胞过继细胞治疗的毒性和免疫学效应。

The overall goal of Project 2 will be to characterize the reconstitution of regulatory T cells after allogeneic HSCT and to define the role of these important regulatory elements in the development of GVHD. Recent studies from many laboratories using a variety of model systems have demonstrated that regulatory T cells (Treg) play an important role in the suppression of autoimmunity and that deficiencies of Treg are capable of enhancing tumor immunity as well as autoimmunity. Several laboratories have also begun to examine the potential role of Treg in the development of GVHD following allogeneic HSCT in humans. Unfortunately, initial studies have provided conflicting results and the role of Treg in the modulation of GVL and GVHD is uncertain. Preliminary results from our laboratory suggest that deficient reconstitution of Treg is, in fact, associated with the development of chronic GVHD. In a comprehensive prospective analysis of patients undergoing allogeneic HSCT, our studies will determine whether Treg play a significant role in the modulation of T cell reconstitution in the allogeneic stem cell recipient. Using both phenotypic and functional assays, these studies will determine whether deficient reconstitution of Treg contributes to the development and persistence of chronic GVHD. Further studies will also examine mechanisms affecting the reconstitution of Treg and potential methods for modulating Treg in vivo. We also propose to initiate clinical trials of adoptive therapy with donor Treg that have been isolated and expanded in vitro. Working with other investigators in this Program Project, these experiments will lead to the development of new methods for selectively enhancing beneficial responses or selectively abrogating toxic responses after allogeneic HSCT. These experiments will be carried out in 4 Specific Aims: 1. To determine whether chronic GVHD is associated with delayed reconstitution of regulatory T cells after allogeneic HSCT. 2. To define the mechanisms of reconstitution of regulatory T cells after allogeneic HSCT. 3. To define mechanisms for modulation of regulatory T cells in vivo after allogeneic HSCT. 4. To evaluate the toxicity and immunologic effects of adoptive cellular therapy with regulatory T cells.