Th1/Th2 and Tc1/Tc2 T Cell Subsets in Transplantation Th

移植中的 Th1/Th2 和 Tc1/Tc2 T 细胞亚群

• 批准号: 6948127
• 负责人: DANIEL FOWLER
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6948127
• 关键词: T lymphocyte; autologous transplantation; bone marrow purging; bone marrow transplantation; cell population study; cellular immunity; chronic lymphocytic leukemia; clinical research; cytokine; graft versus host disease; helper T lymphocyte; hematopoietic stem cells; hematopoietic tissue transplantation; histocompatibility; histocompatibility typing; homologous transplantation; human subject; human therapy evaluation; laboratory mouse; sirolimus; stem cell transplantation; transplant rejection; transplantation immunology

Immune T cells can be functionally defined in terms of their cytokine secretion profile: CD4+, Th1 and CD8+, Tc1 cells primarily secrete IL-2 and IFN-g, whereas CD4+, Th2 and CD8+, Tc2 cells primarily secrete IL-4, IL-5, IL-10, and IL-13. These Th1/Tc1 (type I) and Th2/Tc2 (type II) subsets are cross-regulatory in vivo: in the setting of murine allogeneic bone marrow transplantation, we have found that type I cells initiate graft-versus-host disease (GVHD), whereas type II cells mediate reduced GVHD and inhibit type I-mediated GVHD. In murine models, we have also found that graft-versus-leukemia (GVL) and graft-versus-tumor (GVT) effects against breast cancer cells are primarily mediated through type I immunity. Although type II cells may be therapeutic for indolent malignancy or minimal residual disease, it is likely that type I immunity will be required to cure more aggressive or advanced disease. As such, we are currently evaluating methods to utilize type I immunity in the allogeneic transplantation setting, including a strategy that administers a T cell replete allograft (type I immunity) that is supplemented by additional donor CD4+, Th2 cells. In an initial clinical trial involving n=28 Th2 cell recipients, we established a dose of Th2 cells that promoted both type I and type II immunity and was associated with significant anti-tumor responses in patients with refractory hematologic malignancy; however, GVHD remained a limiting factor to this approach. In light of this information, we have developed a second generation approach to Th2 cell therapy that involves Th2 cell generation in vitro in the presence of the immune suppression drug rapamcyin. Rapamycin generated murine Th2 cells (Th2.rapa) have an enhanced capacity to promote type II immunity and to prevent GVHD; in pre-clinical human studies, we identified that Th2.rapa cells are greatly enriched for the Th2 cytokine phenotype. Based on these results, a clinical trial utilizing Th2.rapa cells is being evaluated for GVHD prevention. In addition to this Th2 cell allograft augmentation strategy, we are also evaluating the use of purified CD4+Th2 and CD8+Tc2 cells in transplants involving purified hematopoietic stem cells. The focus here is to perform a "T cell exchange", whereby the T cells contained within mobilized stem cell populations are replaced the the in vitro expanded Th2/Tc2 cells. In murine studies, we have found that the Th2/Tc2 population can effectively prevent graft rejection, mediate a modest GVT effect, and is associated with greatly reduced GVHD. This Th2/Tc2 strategy may have particular application for HLA mis-matched transplantation, and hopefully therefore improve transplantation therapy for the approximate 75% of cancer patients that lack an HLA matched sibling.

免疫T细胞的功能可以根据它们的细胞因子分泌特征来定义：CD4+、Th1和CD8+、Tc1细胞主要分泌IL-2和IFN-g，而CD4+、Th2和CD8+、Tc2细胞主要分泌IL-4、IL-5、IL-10和IL-13。这些Th1/Tc1 （I型）和Th2/Tc2 （II型）亚群在体内是交叉调节的：在小鼠同种异体骨髓移植的环境中，我们发现I型细胞启动移植物抗宿主病（GVHD），而II型细胞介导GVHD减少并抑制I型介导的GVHD。在小鼠模型中，我们还发现移植物抗白血病（GVL）和移植物抗肿瘤（GVT）对乳腺癌细胞的作用主要是通过I型免疫介导的。虽然II型细胞可以治疗惰性恶性肿瘤或微小残留疾病，但可能需要I型免疫来治疗更具侵袭性或晚期疾病。因此，我们目前正在评估在同种异体移植环境中利用I型免疫的方法，包括一种管理T细胞充满的同种异体移植物（I型免疫）的策略，该策略由额外的供体CD4+， Th2细胞补充。在一项涉及n=28名Th2细胞受体的初步临床试验中，我们确定了一定剂量的Th2细胞可以促进I型和II型免疫，并与难治性血液恶性肿瘤患者的显著抗肿瘤反应相关；然而，GVHD仍然是这种方法的限制因素。根据这些信息，我们已经开发了第二代Th2细胞治疗方法，包括在免疫抑制药物雷帕霉素的存在下体外生成Th2细胞。雷帕霉素生成的小鼠Th2细胞（Th2.rapa）具有增强的促进II型免疫和预防GVHD的能力；在临床前人体研究中，我们发现Th2。rapa细胞的Th2细胞因子表型显著富集。基于这些结果，一项利用Th2的临床试验。rapa细胞正在被评估用于预防GVHD。除了这种Th2细胞同种异体移植增强策略外，我们还在评估纯化CD4+Th2和CD8+Tc2细胞在涉及纯化造血干细胞的移植中的应用。这里的重点是执行“T细胞交换”，即动员干细胞群中包含的T细胞被体外扩增的Th2/Tc2细胞所取代。在小鼠研究中，我们发现Th2/Tc2群体可以有效地预防移植物排斥反应，介导适度的GVT效应，并与GVHD的大幅降低有关。这种Th2/Tc2策略可能对HLA不匹配移植有特殊的应用，并有望因此改善大约75%缺乏HLA匹配兄弟姐妹的癌症患者的移植治疗。