Immune Tolerance of CLL Antigens

该项目的中心假设是肿瘤细胞与宿主免疫系统的相互作用 结果在癌症患者中出现了特异性T细胞缺陷。尽管这些T细胞缺陷的本质 人们对此知之甚少，需要修复这些缺陷才能产生所需的有效免疫反应 为了成功接种肿瘤疫苗。在以慢性淋巴细胞白血病(CLL)为模型的研究中，我们 已证实T细胞在启动抗肿瘤反应的能力方面存在功能缺陷。全球基因 慢性淋巴细胞性白血病患者外周血中纯化的CD4和CDS细胞的表达谱 年龄匹配的健康捐赠者记录了多种缺陷。我们现在试图描述以下基础： CLL中T细胞功能的缺陷，并修复这些缺陷，为未来的治疗干预。我们将研究一下 这是在来自CLL患者的人类样本和体内EU-TCL1转基因小鼠模型中的CLL。 我们将寻求确定T细胞介导的针对CLL细胞的反应的靶点，特别是寻求 描述慢性淋巴细胞性白血病中移植物抗白血病效应的性质。为了解决这些问题，我们建议 遵循三个具体目标。首先，我们将描述患者的CD4和CDS细胞的缺陷。 用CLL和Eu-TCL1转基因小鼠模型进行比较。第二，我们将努力确定以下目标 T细胞介导针对CLL细胞的反应，并在体外和体内最大限度地发挥这些反应。第三，我们 应确定针对CLL细胞的同种异体T细胞反应是否针对CLL抗原或 抗次要的组织相容性抗原。 患者无法对他们的癌症产生免疫反应，癌细胞会损害患者的免疫力。 以慢性淋巴细胞白血病为模型，我们的目标是确定癌细胞如何损害免疫功能， 修复这些免疫缺陷，并评估我们如何提高对癌细胞的免疫反应。 这些发现可能会导致异基因干细胞移植后结果的改善，并 帮助我们开发治疗这种癌症和其他癌症的癌症疫苗。

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.