CHARACTERISTICS OF T CELLS MEDIATING TUMOR IMMUNOTHERAPY

描述：(申请人摘要)肿瘤反应性领养转移 T淋巴细胞介导已建立的恶性肿瘤的消退。在动物身上 在模型中，肿瘤引流淋巴结(LN)是致敏T细胞的丰富来源 可以在体外被激活以获得效应器功能的细胞。在这 肿瘤致敏T淋巴细胞的产生在LN中的应用 这一群体的丰富和效应细胞功能的分析将 被调查。明确的过继免疫治疗小鼠肿瘤模型 将被用来检验抗原提呈细胞 将肿瘤抗原转移到引流性LN。包括GM-CSF在内的几种佐剂 将瘤旁注射以研究LN T细胞的增强作用 敏化。在引流层，抗原免疫的T细胞发生改变 几种膜标志物的水平，其中包括CD62L(L-选择素)，这将 用于从无关的T细胞中浓缩肿瘤致敏细胞。这个 细胞因子与肿瘤细胞接触产生及治疗 疗效将在分离的T细胞亚群中进行分析。调停 肿瘤消退T细胞必须与肿瘤接触并转移细胞渗入 甚至在免疫特权部位，如中枢神经系统的肿瘤。 转移的T细胞归巢到肿瘤和效应机制将是 在携带颅内肿瘤的小鼠身上进行了分析。细胞黏附分子 介导T细胞与肿瘤血管系统的黏附将被定义 通过原位表达，在从肿瘤中分离的T细胞上，以及通过 阻断单抗对肿瘤侵袭的干扰。T细胞介导的肿瘤 回归是高度具体的，选择性贩运的贡献 或者肿瘤反应细胞对这种特异性的保留将被确定。 虽然体外激活的T细胞在标准的51Cr中不具有细胞溶解作用 释放实验表明，它们与肿瘤接触时确实会产生细胞因子。这个 体内细胞因子的产生和辅助细胞在体内的参与 肿瘤消退的中介作用将被研究。

DESCRIPTION: (Applicant's Abstract) The adoptive transfer of tumor-reactive T lymphocytes mediates regression of established malignancies. In animal models, tumor-draining lymph nodes (LN) are a rich source of sensitized T cells that can be activated ex vivo to acquire effector function. In this application the generation of tumor-sensitized T lymphocytes in LN, enrichment of this population, and analysis of effector cell function will be investigated. Well defined murine tumor models of adoptive immunotherapy will be utilized to test the hypothesis that antigen presenting cells transfer tumor antigens to draining LN. Several adjuvants including GM-CSF will be injected paratumorally to study augmentation of LN T cell sensitization. In the draining LN, antigen primed T cells display altered levels of several membrane markers, among them CD62L (L-selectin), that will be used to enrich tumor-sensitized cells from irrelevant T cells. The production of cytokines upon contact with tumor cells and therapeutic efficacy will be analyzed in the segregated T cell subsets. To mediate tumor regression T cells must contact tumor and transferred cells infiltrate tumors even in immune privileged sites such as the central nervous system. The homing of transferred T cells to tumor and effector mechanisms will be analyzed in mice bearing intracranial tumors. The cell adhesion molecules that mediate adherence of T cells to the tumor vasculature will be defined by their expression in situ, on T cells isolated from tumors, and by interference with tumor infiltration by blocking mAb. T cell mediated tumor regression is highly specific and the contribution of selective trafficking or retention of tumor-reactive cells to this specificity will be determined. Although ex vivo activated T cells are not cytolytic in the standard 51Cr release assay, they do produce cytokines upon contact with tumor. The production of cytokines in vivo, and the participation of accessory cells in mediation of tumor regression will be investigated.