IMMUNOBIOLOGICAL RESPONSES TO RAT BRAIN TUMOR VACCINES

描述(申请人描述)：中枢神经系统肿瘤 在解剖学和生物学上与其他器官的癌症截然不同 系统。它们以免疫特权状态存在，并且 恶性胶质瘤的宿主免疫应答机制 是不完全理解的。恶性胶质瘤逃避宿主防御，在 部分是因为中枢神经中没有传统的淋巴管 系统限制了对脑瘤的初级免疫反应，因为胶质瘤 分泌因子，如转化生长因子-β2，抑制全身和局部免疫 反应性。慢性阻塞性肺疾病患者T细胞增殖能力降低 胶质瘤和T细胞IL-2受体缺陷可能导致克隆性无能 和外周血淋巴细胞对脑肿瘤抗原的耐受性。此外， 肿瘤血管上关键黏附分子的调控表达 内皮细胞可能限制淋巴细胞向中枢神经系统的迁移 肿瘤。尽管如此，促进宿主免疫耐受的因素 是宿主免疫的相对决定因素，而不是绝对决定因素 反应性。研究人员假设有效的脑瘤 抗原处理和呈递可以通过使用 表达细胞因子的转基因胶质瘤疫苗等 因此，疫苗将产生有效的系统免疫。 在外周和外周血中促进抗肿瘤活性 中枢神经系统。 白介素4(IL-4)是一种激活血管的多效性细胞因子 内皮细胞，促进树突状细胞的激活和增殖，并为 作为T细胞生长因子。在使用9L胶质肉瘤的初步研究中 细胞系，以及研究人员已稳定转染的9L细胞系 小鼠白介素4基因，他们已经表明白介素4促进抗肿瘤 IL-4对Fischer大鼠9L胶质肉瘤的抑制作用 作用依赖于T细胞，而携带9L-IL4肿瘤的Fischer大鼠 随后形成对脑内或皮下挑战的免疫力 与9L胶质肉瘤细胞共培养。为了验证他们的假设，他们提出：(1) 9L肿瘤浸润性淋巴细胞表型和功能的研究 胶质肉瘤及其对细胞因子的反应；(2)分析其作用机制 调节淋巴细胞对脑肿瘤的渗透；以及(3)评估 脑瘤疫苗在增强宿主免疫应答中的作用 恶性胶质瘤。这项提议的长期目标是理解 完善肿瘤特异性免疫反应的调控机制 并将这些知识转化为更有效的 恶性神经胶质肿瘤的生物治疗。

DESCRIPTION (Applicant's Description): Tumors of the central nervous system are anatomically and biologically distinct from cancers of other organ systems. They exist in an immunologically privileged state, and the mechanisms governing host immunologic responses to malignant glial neoplasms are incompletely understood. Malignant gliomas elude host defenses, in part, because the absence of conventional lymphatics in the central nervous system limits primary immune responses to brain tumors and because gliomas secrete factors, such as TGF-Beta2, which suppress systemic and local immune reactivity. The reduced T cell proliferative capacity in patients with gliomas and defects in the T cell IL-2 receptor may lead to clonal anergy and peripheral lymphocyte tolerance of brain tumor antigens. Further, modulated expression of critical adhesion molecules on tumor vascular endothelium may limit lymphocyte migration into central nervous system tumors. Nonetheless, the factors which promote host immunologic tolerance of gliomas are relative, not absolute, determinants of host immune reactivity. The investigators hypothesize that efficient brain tumor antigen processing and presentation can be accomplished through the use of genetically modified, cytokine expressing glioma vaccines and that such vaccines, as a consequence, will generate effective systemic immune responses and promote anti-tumor activity in the periphery as well as in the central nervous system. Interleukin-4 (IL-4) is a pleiotropic cytokine which activates vascular endothelia, promotes dendritic cell activation and proliferation, and serves as a T-cell growth factor. In preliminary studies using the 9L gliosarcoma cell line, and a 9L cell line the investigators have stably transfected with the murine interleukin-4 gene, they have shown that IL-4 promotes anti-tumor activity against 9L gliosarcomas in Fischer rats, that IL-4 anti-tumor effects are T-cell dependent, and that Fischer rats bearing 9L-IL4 tumors subsequently develop immunity to intracerebral or subcutaneous challenges with 9L gliosarcoma cells. To test their hypotheses, they propose: (1) to study the phenotype and function of tumor infiltrating lymphocytes in 9L gliosarcomas and their response to cytokines; (2) to analyze the mechanisms regulating lymphocyte infiltration into brain tumors; and (3) to evaluate the role of brain tumor vaccines in augmenting host immunologic responses to malignant gliomas. The long-term goal of this proposal is to understand better the mechanisms regulating specific immune responses to tumors of the central nervous system and to translate this knowledge into more effective biologic therapies of malignant glial neoplasms.