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介导的免疫反应的限制 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 在移植前使用毒性剂量的化疗，从而导致目前的 限制移植到具有密切匹配的供体的个体， 家庭或通过国家骨髓捐赠者计划。我们的实验室专注于新的T细胞 旨在预防GVHD和移植排斥反应的移植工程策略。在小鼠模型中， 我们已经证明，在免疫原存在下离体产生的供体Th 2细胞， 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， 同种异体移植这种同种异体Th 2细胞目前正在两个临床方案中进行评估。 在第一个方案中，NIH临床中心方案#04-C-0055，难治性 血液恶性肿瘤如白血病、淋巴瘤和多发性骨髓瘤正在接受 补充供体Th 2细胞的低强度移植;目前，大约 100名患者接受了该方案的治疗。在第二个方案中，NIH临床 中心方案#08-C-0088，难治性和转移性肾细胞癌患者 接受补充有供体Th 2的多次输注的低强度移植 细胞值得注意的是，这两个协议都是以多中心的方式实施的， 位于新泽西的哈肯萨克大学作为多中心研究中心。

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 thereby 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. Such allogeneic Th2 cells are currently being evaluated on two clinical protocols. In the first protocol, NIH Clinical Center Protocol #04-C-0055, patients with refractory hematologic malignancy such as leukemia, lymphoma, and multiple myeloma are receiving a low-intensity transplant that is supplemented with donor Th2 cells; currently, approximately 100 patients have received therapy on this protocol. In the second protocol, NIH Clinical Center Protocol #08-C-0088, patients with refractory and metastatic renal cell carcinoma are receiving a low-intensity transplant that is supplemented with multiple infusions of donor Th2 cells. Of note, both of these protocols are being implemented in a multi-center manner, with Hackensack University in New Jersey serving as the multi-center site.