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”，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一种根治疗法。然而，移植治疗的广泛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；供者细胞对患者的T细胞攻击)和移植物排斥反应(或宿主抗移植物反应；HVGR)。移植物抗宿主病是移植后死亡的主要原因。HVGR导致需要在移植前实施毒性剂量的化疗，从而导致目前移植仅限于拥有接近匹配的捐赠者的个人，无论是来自家庭内部还是通过国家骨髓捐赠者计划。我们的实验室专注于新的T细胞移植工程策略，旨在防止GVHD和移植物排斥反应。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的情况下体外产生的供体Th2细胞，可以有效地抑制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细胞有效地防止完全基因错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。我们已经开发出一种在雷帕霉素中产生人Th2细胞的方法，并启动了一项临床试验，研究这些细胞在难治性血液系统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细胞的接受者急性移植物抗宿主病的发生率很低；此外，给药Th2细胞可以显著减少实现同种异体移植物植入所需的准备化疗量。这种同种异体Th2细胞目前正在两种临床方案上进行评估。在第一个方案中，NIH临床中心方案#04-C-0055，白血病、淋巴瘤和多发性骨髓瘤等难治性血液病患者正在接受低强度移植，并辅以供者Th2细胞；目前，约有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，难治性和转移性肾癌患者正在接受低强度移植，并辅之以多次输注供体Th2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，新泽西州的哈肯萨克大学作为多中心站点。

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.