CD1D REACTIVE T CELLS IN BONE MARROW TRANSPLANTATION

描述：（申请人的摘要）有两个不同的群体， 目前公认的CD 1d反应性T细胞，即“经典”CD 161+（NK 1） 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（BM）T细胞主要由CD 4/CD 8双阴性 (DN)非恒定CD 1d反应性CD 161 + T细胞。BM DN CD 161 + 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）。BMT 在高剂量化疗/放疗之后，对一系列癌症进行化疗/放疗。高 剂量的细胞毒性治疗可以实现更好的肿瘤清除，但 清髓性BMT导致长期造血细胞重建，和 BMT移植物中活化的T淋巴细胞可有助于治疗（“移植物 相对于肿瘤“，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），BMT的严重并发症。正在形成 有证据表明，有可能分别影响BMT的这两种效果。 申请人已经发现，人CD 161+不变T细胞识别CD 1d。 不同的目标相反，人骨髓中的大部分成熟T细胞 优先识别淋巴细胞上的CD 1d，并且是“非不变的”。 外周血祖细胞（PBPC）产品还含有大量的 非恒定CD 1d反应性T细胞的数量。他的初步数据与人类 CD 1d反应性T细胞显示出与小鼠结果的总体相似性， 有相当大的潜力，防止GvH。因此，本申请 是为了确定是否人BM和PBPC来源的CD 1d反应性T细胞采取 可以在体外扩增到治疗相关的数量， 保留改善MLR/GvH的表型潜力。这些临床前 研究是必要的，以评估假设，人类CD 1d反应性T细胞， 细胞具有选择性抑制急性GvH的治疗潜力， 在常规BM和PBPC移植用于癌症的背景下。

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.