CD4+ T HELPER CELLS AND B CELL TUMOR DORMANCY

CD4+T辅助细胞(TH)亚群在维持 体内处于休眠状态的恶性B细胞改变其生长速度 这些细胞通过分泌独特的细胞因子亚群。休眠 是临床癌症的一大特点，对免疫学的认识 负责获得和维持休眠的机制 如果能长期缓解和治愈，在体内是至关重要的。 癌症患者是要实现的。免疫学知识 负责维持肿瘤休眠的机制将在 对导致休眠重新激活的事件的理解 细胞在体内，因此复发和死于转移性疾病。其目的是 这一建议的目的是确定CD4+T辅助细胞(TH)的作用 细胞免疫学在B细胞瘤休眠中的作用 技术，并通过使用几个具有良好特征的模型 小鼠的肿瘤休眠。所选择的肿瘤系统是小鼠B细胞 白血病/淋巴瘤BCL1，与人类前淋巴细胞极为相似 白血病。现已证实BCL1肿瘤消退 在注射到BALB/c动物体内后自发地 用bcl1独特型免疫。其中40%的动物仍未感染疾病 超过100天，尽管事实是大约2x106 处于休眠状态的BCL1肿瘤细胞藏在它们的脾里。我的工作 假说是T细胞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 动物体内肿瘤生长与休眠的比较。分泌的细胞因子的差异 可能与选择性激活/区分特定的 亚群，正如在许多寄生虫病和T细胞中报告的那样 建立小鼠淋巴瘤模型。为了验证这一假设，CD4+T细胞 克隆人将从上述动物的脾中产生 携带BCL1肿瘤，处于活动或休眠状态。细胞因子 分析这些CD4+TH克隆分泌的IL-2、IL-3、IL-4、 白介素5、白介素10、干扰素-γ、肿瘤坏死因子和粒-巨噬细胞集落刺激因子 和分子水平。每个TH克隆的细胞因子分泌模式将 与未免疫的荷瘤小鼠的模式进行比较。我 会假设白介素4、白介素5、白介素10水平的主要差异 和IFNGamma之间将观察到来自 携带进展性肿瘤的动物与动物来源的TH克隆的比较 他们能够将肿瘤维持在休眠状态。基于 克隆实验结果显示，免疫治疗针对的是不确定 抑制肿瘤生长，可能是通过影响TH1/TH2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、抗细胞因子抗体与“免疫性”CD4+过继转移 细胞。

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.