IMMUNOTHERAPY FOR MALIGNANT GLIOMAS

恶性胶质瘤患者目前治疗的局限性， 以及具有明确定义的细胞因子的可用性 免疫调节特性，重新引起了人们对免疫治疗的兴趣。 拟议研究的目的是确定潜在的有效 免疫疗法的形式将在临床试验中进一步研究。这将是 通过检查人脑胶质瘤组织中可能存在的因子来实现 有助于恶性胶质瘤逃避宿主免疫的能力 反应和使用同基因大鼠脑胶质瘤模型评估不同 免疫治疗的策略。 建议的研究将包括两部分： 1)人脑胶质瘤手术标本中的免疫参数 (丢弃的组织)，包括炎症的成分 主要组织相容性复合体(MHC)的表达 将检查抗原和辅助分子(LFA 3) 免疫细胞化学。这将提供一个标准来与 同基因大鼠脑胶质瘤模型的免疫参数。这些免疫 参数也将与临床和组织学特征相关。 假设MHC抗原和附件的相对缺失 分子和抑制诱导剂CD4+、2H4+淋巴细胞的存在可能 有助于恶性胶质瘤逃避宿主的能力 将检查免疫反应。 2)反映免疫学特性的同基因大鼠脑胶质瘤模型 恶性胶质瘤的特征将被用来评估不同的 免疫治疗的策略。原则性策略将涉及使用 细胞因子增加肿瘤细胞上MHC的表达，使它们更多 对T细胞介导的免疫反应敏感。其他战略 这将被审查包括a)克服 脑胶质瘤细胞分泌的免疫抑制因子与白介素2和 肿瘤坏死因子，b)增强淋巴因子激活的杀伤细胞 和白介素2(IL-2)活性，通过诱导HLADR表达 肿瘤细胞和c)使用化疗以消除 抑制性T细胞。

The limitation of current therapy for patients with malignant gliomas, together with the availability of cytokines with well defined immunomodulatory properties, have led to renewed interest in immunotherapy. The purpose of the proposed research is to identify potentially effective forms of immunotherapy for further study in clinical trials. This will be achieved by examining human glioma tissue for factors which may be contributing to the ability of malignant gliomas to evade the host immune response and using a syngeneic rat glioma model to evaluate various strategies of immunotherapy. The proposed research will consist of two parts: 1) The immune parameters within surgical specimens of human glioma tissue (discarded tissue), including the composition of the inflammatory infiltrate, and the expression of major histocompatibility complex (MHC) antigens and the accessory molecules (LFA 3) will be examined immunocytochemically. This will provide a standard for comparison with the immune parameters in the syngeneic rat glioma model. These immune parameters will also be correlated with clinical and histologic features. The hypothesis that the relative absence of MHC antigens and accessory molecules and the presence of suppressor inducer CD4+,2H4+ lymphocytes may be contributing to the ability of malignant gliomas to evade the host immune response will be examined. 2) A syngeneic rat glioma model which reflects the immunologic characteristics of malignant gliomas will be used to evaluate various strategies of immunotherapy. The principle strategy will involve the use of cytokines to increase MHC expression on tumor cells, rendering them more susceptible to T cell mediated immune responses. Additional strategies that will be examined include a) overcoming the effects of immunosuppressive factors released by glioma cells with interleukin-2 and tumor necrosis factor, b) augmenting lymphokine activated killer (LAK) cell and interleukin-2 (IL-2) activity by inducing HLA-DR expression on the tumor cells and c) using chemotherapy directed towards the elimination of suppressor T cells.