Immune Tolerance of CLL Antigens

这个项目的中心假设是肿瘤细胞与宿主免疫系统的相互作用

The central hypothesis of this project is that the interaction of tumor cells with the host immune system results in specific T cell defects in the cancer bearing patients. Although the nature of these T cells defects is poorly understood, repair of these defects will be required to mount effective immune responses required for successful tumor vaccination. In studies modeled in chronic lymphocytic leukemia (CLL) we have documented functional defects in the ability of the T cells to mount anti-tumor responses. Global gene expression profiles of purified CD4 and CDS cells from CLL patients compared to CD4 and CDS cells from age matched healthy donors documented multiple defects. We now seek to characterize the basis for defective T cell function in CLL and repair these defects for future therapeutic intervention. We shall examine this in human samples from patients with CLL and in vivo in the Eu-TCL1 transgenic mouse model of CLL. We shall seek to identify the targets of T cell mediated resposnes against CLL cells and in particualr seek to characterize the nature of the graft versus leukemia effect in CLL. To address these issues we propose the following three specific aims. First, we shall characterize the defects in the CD4 and CDS cells of patients with CLL and in the Eu-TCL1 transgenic mouse model of CLL. Second we shall seek to identify the targets of T cell mediated responses against CLL cells and maximize these responses in vitro and in vivo. Third, we shall identify whether allogeneic T cell responses against CLL cells are targeted against CLL antigens or against minor histocompatibility antigens. Patients fail to mount an immune response against their cancers and cancer cells impair patients' immunity. Using chronic lymphocytic leukemia as a model, we aim to identify how cancer cells impair immune function, repair these immune defects and assess how we can increase immune responses against cancer cells. These findings are likely to lead to improvements in outcome after allogeneic stem cell transplants and to help us to develop cancer vaccines inthis and other cancers.