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.
