Th1Th2 and Tc1Tc2 T Cell Subsets in Transplantation Therapy

异基因造血干细胞移植，通常被称为“骨髓” 移植”代表了许多患有白血病，淋巴瘤， 多发性骨髓瘤和骨髓增生异常综合征。然而，扩大应用 这些癌症的移植治疗受到两种免疫反应的限制 主要通过T细胞，即移植物抗宿主病（GVHD; T细胞攻击供体细胞 抗患者）和移植物排斥（或宿主抗移植物反应; HVGR）。GVHD是 移植后死亡的主要原因。HVGR导致需要给药 毒性剂量的化疗，并导致目前的限制， 移植到具有来自家族内部或家族内部的密切匹配的供体的个体， 通过国家骨髓捐赠计划我们的实验室专注于新的T细胞移植 设计用于预防GVHD和移植排斥的工程策略。在小鼠模型中，我们有 显示了供体Th 2细胞，其在免疫存在下离体产生， 调节药物雷帕霉素，可以有效地抑制GVHD，同时保留一种成分， 有益的移植物抗肿瘤（GVT）效应;此外，这种Th 2细胞有效地预防 排斥基因完全不匹配的造血干细胞。我们取得了 在将这些发现转化为临床方面取得了重大进展。我们已经开发出一种方法 在雷帕霉素中产生人类Th 2细胞，我们已经开始了一项临床试验， 在难治性恶性血液病患者中研究这些细胞。电流数据 与我们的小鼠数据一致，因为在雷帕霉素中生长的Th 2细胞的受体具有低的比率， 急性GVHD;此外，Th 2细胞的施用允许显著的 减少了实现移植物植入所需的准备性化疗的量， 同种异体移植

Allogeneic hematopoietic stem cell transplantation, often referred to as "bone marrow transplantation", represents a curative therapy for many individuals with leukemia, lymphoma, multiple myeloma, and myelodysplastic syndrome. However, the broadened application of transplantation therapy of these cancers is limited by two immune reactions that are mediated primarily by T cells, namely graft-versus-host disease (GVHD; T cell attack of donor cells against the patient) and graft rejection (or the host-versus-graft response; HVGR). GVHD is the main cause of lethality after transplantation. The HVGR results in the need to administer toxic doses of chemotherapy prior to transplanation, and results in the current limitation of transplantation to individuals having a closely matched donor either from within the family or through the National Marrow Donor Program. Our laboratory focuses on new T cell graft engineering strategies designed to prevent GVHD and graft rejection. In murine models, we have shown that donor Th2 cells, which are generated ex vivo in the presence of the immune modulation drug rapamycin, can potently inhibit GVHD while preserving a component of the beneficial graft-versus-tumor (GVT) effect; furthermore, such Th2 cells effectively prevent the rejection of fully genetically mis-matched hematopoietic stem cells. We have made significant progress in translating these findings to the clinic. We have developed a method for generating human Th2 cells in rapamycin, and we have initiated a clinical trial investigating these cells in patients with refractory hematologic malignancy. Current data are consistent with our murine data, as recipients of Th2 cells grown in rapamycin have a low rate of acute GVHD; furthermore, administration of Th2 cells has allowed for a significant reduction in the amount of preparative chemotherapy required to achieve engraftment of the allograft.