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

免疫T细胞可根据其细胞因子分泌谱在功能上定义为：CD4+、Th1和CD8+，Tc1细胞主要分泌IL-2和干扰素-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：在小鼠异基因骨髓移植的背景下，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型细胞可能对惰性恶性肿瘤或微小残留疾病有治疗作用，但I型免疫很可能需要用来治愈更具侵袭性的疾病或晚期疾病。因此，我们目前正在评估在异基因移植环境中利用I型免疫的方法，包括一种策略，即管理T细胞完全同种异体移植(I型免疫)，并补充额外的捐赠者CD4+，Th2细胞。在一项涉及28名Th2细胞接受者的初步临床试验中，我们确定了一种剂量的Th2细胞，该剂量同时促进了I型和II型免疫，并与难治性血液病患者的显著抗肿瘤反应有关；然而，GVHD仍然是这一方法的限制因素。根据这些信息，我们开发了Th2细胞治疗的第二代方法，包括在免疫抑制药物Rapamcyin存在的情况下在体外产生Th2细胞。雷帕霉素诱导的小鼠Th2细胞(Th2.Rapa)具有增强的促进II型免疫和预防GVHD的能力；在临床前的人类研究中，我们发现Th2.Rapa细胞极大地丰富了Th2细胞因子的表型。基于这些结果，利用Th2.Rapa细胞进行的预防GVHD的临床试验正在进行评估。除了这种Th2细胞移植增强策略外，我们还在评估纯化的CD4+Th2和CD8+Tc2细胞在涉及纯化的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”，即动员的干细胞群体中包含的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群体可以有效地防止移植物排斥反应，调节适度的GVT效应，并与GVHD显著降低有关。这种Th2/Tc2策略可能在人类白细胞抗原不匹配的移植中有特殊的应用，因此有望改善大约75%缺乏人类白细胞抗原匹配同胞的癌症患者的移植治疗。

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.