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

移植中的 Th1/Th2 和 Tc1/Tc2 T 细胞亚群

• 批准号: 7068937
• 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/7068937
• 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细胞可以根据其细胞因子分泌谱进行功能定义：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）亚群在体内具有交叉调节作用：在小鼠同种异体骨髓移植的情况下，我们发现 I 型细胞引发移植物抗宿主病（GVHD） ），而 II 型细胞介导减少 GVHD 并抑制 I 型介导的 GVHD。在小鼠模型中，我们还发现针对乳腺癌细胞的移植物抗白血病（GVL）和移植物抗肿瘤（GVT）作用主要是通过I型免疫介导的。尽管 II 型细胞可能对惰性恶性肿瘤或微小残留病具有治疗作用，但可能需要 I 型免疫来治愈更具侵袭性或晚期的疾病。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，包括施用充满 T 细胞的同种异体移植物（I 型免疫）并辅以额外供体 CD4+、Th2 细胞的策略。在一项涉及 n=28 例 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，可促进 I 型和 II 型免疫，并与难治性血液恶性肿瘤患者的显着抗肿瘤反应相关。然而，GVHD 仍然是该方法的限制因素。根据这些信息，我们开发了第二代 Th2 细胞治疗方法，该方法涉及在免疫抑制药物雷帕霉素存在的情况下在体外生成 Th2 细胞。雷帕霉素产生的小鼠 Th2 细胞 (Th2.rapa) 具有增强的促进 II 型免疫和预防 GVHD 的能力；在临床前人类研究中，我们发现 Th2.rapa 细胞的 Th2 细胞因子表型非常丰富。基于这些结果，正在评估一项利用 Th2.rapa 细胞预防 GVHD 的临床试验。除了这种 Th2 细胞同种异体移植增强策略外，我们还在评估纯化的 CD4+Th2 和 CD8+Tc2 细胞在涉及纯化造血干细胞的移植中的使用。这里的重点是进行“T 细胞交换”，即动员的干细胞群中包含的 T 细胞被体外扩增的 Th2/Tc2 细胞取代。在小鼠研究中，我们发现Th2/Tc2群体可以有效预防移植排斥，介导适度的GVT效应，并与大大降低GVHD相关。这种 Th2/Tc2 策略可能特别适用于 HLA 不匹配的移植，因此有望改善约 75% 缺乏 HLA 匹配兄弟姐妹的癌症患者的移植治疗。