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不同 系统. 它们存在于免疫特权状态， 宿主对恶性胶质瘤免疫应答的机制 并不完全理解。 恶性神经胶质瘤逃避宿主防御， 部分原因是由于中枢神经系统缺乏常规的神经递质， 系统限制了对脑肿瘤的初级免疫反应， 分泌因子，如TGF-β 2，抑制全身和局部免疫 反应性 T细胞增殖能力降低的患者 胶质瘤和T细胞IL-2受体缺陷可能导致克隆性无能 以及外周淋巴细胞对脑肿瘤抗原的耐受性。 此外，本发明还 调节肿瘤血管上关键粘附分子的表达 内皮细胞可能限制淋巴细胞迁移到中枢神经系统 肿瘤的 然而，促进宿主免疫耐受的因素 是相对的，而不是绝对的，宿主免疫的决定因素 反应性 研究人员假设有效的脑肿瘤 抗原加工和呈递可以通过使用 基因修饰的表达细胞因子的神经胶质瘤疫苗， 因此，疫苗将产生有效的全身免疫， 反应和促进抗肿瘤活性，在周边以及在 中枢神经系统 白细胞介素-4（IL-4）是一种多效性细胞因子， 内皮细胞，促进树突状细胞活化和增殖， 作为T细胞生长因子 在使用9 L胶质肉瘤的初步研究中， 细胞系，以及研究者已经稳定转染的9 L细胞系 小鼠白细胞介素-4基因，他们已经表明，IL-4促进抗肿瘤 在Fischer大鼠中，IL-4抗9 L胶质瘤的活性， 效应是T细胞依赖性的，并且带有9 L-IL 4肿瘤的Fischer大鼠 随后对脑内或皮下攻击产生免疫力 9 L胶质肉瘤细胞。 为了验证他们的假设，他们提出：（1） 研究9 L肿瘤浸润淋巴细胞的表型和功能 胶质瘤及其对细胞因子的反应;（2）分析其机制 调节淋巴细胞浸润到脑肿瘤中;和（3）评估 脑肿瘤疫苗在增强宿主免疫应答中的作用 恶性神经胶质瘤 这项提案的长期目标是了解 更好地调节对肿瘤的特异性免疫应答的机制， 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.