CD1D REACTIVE T CELLS IN BONE MARROW TRANSPLANTATION

骨髓移植中的 CD1D 反应性 T 细胞

• 批准号: 6498002
• 负责人: MARK A EXLEY
• 金额: $ 17万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6498002
• 关键词: CD1 molecule; T lymphocyte; bone marrow transplantation; clinical research; enzyme linked immunosorbent assay; graft versus host disease; homologous transplantation; human subject; interleukin 4; mixed lymphocyte reaction test; neoplasm /cancer immunotherapy

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.

描述：（申请人的摘要）有两个不同的种群 目前公认的 CD1d 反应性 T 细胞，即“经典”CD161+ (NK1) 不变的 TCR-α 阳性“NK T 细胞”和“非不变”多克隆 T 细胞。小鼠骨髓 (BM) T 细胞以 CD4/CD8 双阴性为主 (DN) 非不变的 CD1d 反应性 CD161+ T 细胞。 BM DN CD161+ T 细胞可以 抑制骨髓移植后体内移植物抗宿主病 (GvH) 移植（BMT）和体外混合淋巴细胞反应（MLR）。骨髓移植 高剂量化疗/放疗后用于治疗一系列癌症。高的 剂量细胞毒性治疗可实现更好的肿瘤清除，但 清髓性。 BMT 导致长期造血细胞重建，并且 BMT 移植物中活化的 T 淋巴细胞有助于治疗（“移植物 与肿瘤'，GvT）。然而，同种异体反应性 T 细胞也可引起急性移植物 抗宿主病 (GvH)，这是 BMT 的严重并发症。有新兴的 有证据表明可以单独影响 BMT 的这两种效果。 申请人发现人类CD161+不变T细胞识别CD1d 多样化的目标。相比之下，人类骨髓中很大一部分成熟 T 细胞 优先识别淋巴细胞上的 CD1d，并且是“非不变的”。 外周血祖细胞（PBPC）产品还含有大量 非不变 CD1d 反应性 T 细胞的数量。他与人类的初步数据 CD1d 反应性 T 细胞与小鼠和小鼠的结果总体相似 对抗 GvH 的巨大潜力。因此，本申请 是为了确定是否提取了人类 BM 和 PBPC 衍生的 CD1d 反应性 T 细胞 收获时可以在体外扩大到治疗相关的数量，同时 保留改善 MLR/GvH 的表型潜力。这些临床前 有必要进行研究来评估人类 CD1d 反应性 T 的假设 细胞具有选择性抑制急性 GvH 的治疗潜力 传统 BM 和 PBPC 移植治疗癌症的背景。