CD1D REACTIVE T CELLS IN BONE MARROW TRANSPLANTATION

描述：(申请人摘要)有两个截然不同的群体 目前公认的CD1d反应性T细胞，即“经典”CD161(NK1) 不变TCR-α阳性‘NK T细胞’和‘非不变’多克隆T细胞 细胞。小鼠骨髓T细胞以CD4/CD8双阴性为主 (DN)不稳定的CD1d反应性CD161T细胞。骨髓DN CD161 T细胞可以 体内抑制骨髓移植后移植物抗宿主病(GVH) 移植(BMT)和体外混合淋巴细胞反应(MLR)。BMT 在大剂量化疗/放射治疗之后，一系列癌症被用于治疗。高 细胞毒治疗是否能实现更好的肿瘤清除，但 清髓剂。骨髓移植导致长期的造血细胞重建，以及 BMT移植物中活化的T淋巴细胞可以帮助治疗(‘移植物 对肿瘤‘，GVT)。然而，同种异体反应性T细胞也可引起急性移植物 与宿主病(GVH)相比，GVH是BMT的严重并发症。有一个正在出现的 有证据表明，有可能分别影响骨髓移植的这两种效应。 申请人发现人类CD161不变T细胞识别CD1d 目标多样。相比之下，人骨髓中很大一部分成熟T细胞 优先识别淋巴样细胞上的CD1d，并具有非不变性。 外周血祖细胞(PBPC)产品还含有大量 非恒定CD1d反应性T细胞的数量。他与人类的初步数据 CD1d反应性T细胞与小鼠和 预防生殖器疱疹的潜力相当大。因此，此应用程序 是为了确定人类骨髓和外周血来源的CD1d反应性T细胞 At可以在体外扩增到治疗相关的数字，同时 保留表型潜力以改善MLR/GVH。这些临床前研究 有必要对人类CD1d反应性T细胞的假设进行评估 细胞具有选择性抑制急性GVH的治疗潜力 传统的骨髓和外周血干细胞移植治疗癌症的背景。

DESCRIPTION: (Applicant's Abstract) There are two distinct populations of CD1d-reactive T cells currently recognized, the 'classical' CD161+ (NK1) invariant TCR-alpha positive 'NK T cells' and 'non-invariant' polyclonal T cells. Murine bone marrow (BM) T cells are dominated by CD4/CD8-double negative (DN) non-invariant CD1d-reactive CD161+ T cells. BM DN CD161+ T cells can suppress both graft versus host disease (GvH) in vivo following bone marrow transplantation (BMT), and mixed lymphocyte reactions (MLR) in vitro. BMT following high dose chemo-/radiotherapy is used for a range of cancers. High dose cytotoxic treatments achieve better tumor clearance, but are myeloablative. BMT results in long term hematopoietic cell reconstitution, and activated T lymphocytes in the BMT graft can contribute to therapy ('graft versus tumor', GvT). However, allo-reactive T cells can also cause acute graft versus host disease (GvH), a serious complication of BMT. There is emerging evidence that it is possible to separately influence these two effects of BMT. The applicant has found that human CD161+ invariant T cells recognize CD1d on diverse targets. In contrast, a large fraction of mature T cells in human BM preferentially recognize CD1d on lymphoid cells and are "non-invariant". Peripheral blood progenitor cell (PBPC) product also contains substantial numbers of non-invariant CD1d-reactive T cells. His preliminary data with human CD1d-reactive T cells show overall similarity to results in the mouse and considerable potential for protection against GvH. Therefore, this application is to determine whether human BM and PBPC-derived CD1d-reactive T cells taken at harvest can be expanded in vitro to therapeutically relevant numbers whilst retaining the phenotype potential to ameliorate MLR/GvH. These preclinical studies are necessary to evaluate the hypothesis that human CD1d-reactive T cells have the therapeutic potential to selectively suppress acute GvH in the context of conventional BM and PBPC transplants for cancer.