Th1Th2 and Tc1Tc2 T Cell Subsets in Transplantation Therapy

同种异体造血干细胞移植，通常被称为“骨髓移植”，是许多白血病、淋巴瘤、多发性骨髓瘤和骨髓增生异常综合征患者的根治性治疗方法。然而，这些癌症的移植治疗的扩大应用受到两种主要由T细胞介导的免疫反应的限制，即移植物抗宿主病（GVHD；供体细胞攻击患者的T细胞）和移植物排斥反应（或宿主抗移植物反应；HVGR）。GVHD是移植后死亡的主要原因。HVGR导致需要在移植前进行毒性剂量的化疗，并导致目前对具有来自家庭内部或通过国家骨髓捐赠计划的密切匹配供体的个人进行移植的限制。我们的实验室专注于新的T细胞移植工程策略，旨在防止GVHD和移植排斥。在小鼠模型中，我们已经证明，在免疫调节药物雷帕霉素存在下体外产生的供体Th2细胞可以有效抑制GVHD，同时保留有益的移植物抗肿瘤（GVT）效应的一部分；此外，这种Th2细胞有效地防止了基因完全不匹配的造血干细胞的排斥反应。我们在将这些发现转化为临床方面取得了重大进展。我们已经开发了一种在雷帕霉素中产生人类Th2细胞的方法，我们已经启动了一项临床试验，研究这些细胞在难治性血液恶性肿瘤患者中的作用。目前的数据与我们的小鼠数据一致，因为在雷帕霉素中生长的Th2细胞受体的急性GVHD发生率较低；此外，Th2细胞的施用使得实现同种异体移植物移植所需的预备化疗量显著减少。

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.