CD4+ T HELPER CELLS AND B CELL TUMOR DORMANCY

CD4 T 辅助细胞和 B 细胞肿瘤休眠

• 批准号: 2096486
• 负责人: NANCY E. STREET
• 金额: $ 10.72万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2096486
• 关键词: B lymphocyte; CD4 molecule; clone cells; colony stimulating factor; complementary DNA; enzyme linked immunosorbent assay; gene expression; helper T lymphocyte; interferons; interleukin 2; interleukin 3; interleukin 4; interleukin 5; laboratory mouse; lymphoma; messenger RNA; neoplastic growth; polymerase chain reaction; protein biosynthesis; tumor necrosis factor alpha

Subsets of CD4+ T helper (TH) cells play a major role in maintaining malignant B cells in a dormant state in vivo altering the rate of growth of these cells through the secretion of unique subsets of cytokines. Dormancy is a major feature of clinical cancer and understanding the immunological mechanisms that are responsible for acquisition and maintenance of dormancy in vivo is critically important if long-lasting remission and cure of cancer patients is to be achieved. Knowledge of the immunological mechanisms responsible for maintaining tumor dormancy will be invaluable in the understanding of the events that cause the reactivation of dormant cells in vivo and hence relapse and death from metastatic disease. The aim of this proposal is to determine the role that CD4+ T helper (TH) cells play in B cell tumor dormancy through the use of cellular immunologic techniques and through the use of several well-characterized models of tumor dormancy in mice. The tumor system chosen is the murine B cell leukemia/lymphoma BCL1 which closely resembles a human prolymphocytic leukemia. It has been established that the BCL1 tumor regresses spontaneously after injection into BALB/c animals that are subsequently immunized with the BCL1 idiotype. 40% of these animals remain disease free for greater than 100 days despite the fact that approximately 2 x 106 dormant BCL1 tumor cells are harbored in their spleens. My working hypothesis is that differences in secretion of particular cytokines by T helper cell clones generated from tumor bearing mice will contribute to tumor growth vs dormancy in the animals. Differences in secreted cytokines may correlate with selective activation/differentiation of a particular TH subset, as has been reported in numerous parasitic diseases and a T cell lymphoma model in mice. In order to test this hypothesis, CD4+ T cell clones will be generated from the spleens of the above-described animals bearing BCL1 tumor, either in an active or a dormant state. The cytokines secreted by these CD4+ TH clones will be analyzed, including IL2, IL3, IL4, IL5, IL10, IFNgamma, tumor necrosis factor and GM-CSF, at both the protein and molecular level. The cytokine secretion patterns of each TH clone will be compared to the patterns seen in non-immunized tumor bearing mice. I would hypothesize that major differences in the levels of IL4, IL5, IL10 and IFNgamma will be observed between the TH clones derived from the animals bearing progressive tumor vs those TH clones derived from animals who are able to maintain the tumor in a dormant state. Based on the results of the TH cloning experiments, immunotherapy aimed at indefinite growth suppression of the tumor, perhaps by affecting the ratio of TH1/TH2 cell in vivo, will be initiated. Plans for immunotherapy include exogenous cytokines, anti-cytokine antibodies and adoptive transfer of "immune" CD4+ cells.

CD 4 + T辅助细胞（TH）的亚群在维持免疫应答中起主要作用。 在体内处于休眠状态的恶性B细胞， 这些细胞通过分泌独特的细胞因子亚群。 休眠 是临床癌症的一个主要特征， 负责获得和维持休眠的机制 如果长期缓解和治愈， 癌症患者是可以做到的。 免疫学知识 负责维持肿瘤休眠的机制将是非常宝贵的， 对导致休眠的重新激活的事件的理解 细胞在体内，并因此复发和死于转移性疾病。 目的 这项建议的目的是确定CD 4 + T辅助细胞（TH）的作用， 通过使用细胞免疫学在B细胞肿瘤休眠中发挥作用 技术，并通过使用几个良好的表征模型， 小鼠的肿瘤休眠。 选择的肿瘤系统是鼠B细胞 白血病/淋巴瘤BCL 1，与人类幼淋巴细胞非常相似 白血病 已经确定BCL 1肿瘤消退 在注射到BALB/c动物中后自发地， 用BCL 1独特型免疫。 这些动物中有40%保持无病 超过100天，尽管事实上，大约2 x 106 休眠的BCL 1肿瘤细胞藏在它们的脾脏中。 我的工作 假设是T分泌特定细胞因子的差异 从荷瘤小鼠产生的辅助细胞克隆将有助于 肿瘤生长与休眠的关系。 分泌的细胞因子的差异 可能与特定TH的选择性激活/分化相关 亚群，如在许多寄生虫病和T细胞 小鼠淋巴瘤模型。 为了验证这一假设，CD 4 + T细胞 克隆将从上述动物的脾脏产生 携带BCL 1肿瘤，处于活动或休眠状态。 细胞因子 将分析这些CD 4 + TH克隆分泌的IL 2，IL 3，IL 4， IL 5、IL 10、IFN γ、肿瘤坏死因子和GM-CSF，在两种蛋白质水平上， 分子水平。 每个TH克隆的细胞因子分泌模式将 与未免疫的荷瘤小鼠中观察到的模式进行比较。 我 假设IL 4、IL 5、IL 10水平的主要差异 和IFN γ将在来源于 携带进行性肿瘤的动物与来自动物的TH克隆 能够使肿瘤保持休眠状态 基于 TH克隆实验的结果，免疫治疗的目的是不确定的 肿瘤的生长抑制，可能通过影响TH 1/TH 2的比例 细胞在体内，将被启动。 免疫治疗计划包括外源性 细胞因子、抗细胞因子抗体和“免疫”CD 4+的过继转移 细胞