CANCER GENE THERAPY IN MURINE MODELS USING CELLULAR IL-10--VECTORS/AUTOIMMUNITY

使用细胞 IL-10 在小鼠模型中进行癌症基因治疗——载体/自身免疫

• 批准号: 6237588
• 负责人: HIDEAKI TAHARA
• 金额: $ 16.33万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-09 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6237588
• 关键词: active immunization; autoantigens; autoimmunity; clone cells; cytotoxic T lymphocyte; disease /disorder model; enzyme linked immunosorbent assay; gene therapy; human therapy evaluation; immunocytochemistry; immunomodulators; interleukin 10; laboratory mouse; molecular cloning; neoplasm /cancer immunology; nonhuman therapy evaluation; nucleic acid repetitive sequence; plasmids; polymerase chain reaction; transfection; transfection /expression vector; tumor antigens

IL-10 was initially identified as a cytokine synthesis inhibitory factor (CSIF) affecting several cytokines. It has since been found to have multiple effects including the inhibition of CTL activity primarily through inhibition of monocyte function, i.e. reducing the expression of MHC class II antigens and the secretion of monokines. Thus, IL-10 has been thought to function primarily as an immuno-suppressive cytokine. However, recent studies in vitro and in vivo suggest that cellular IL-10 (cIL-10, either murine IL-10 or human IL-10) exhibits predominantly immunostimulatory effects in vivo. In particular, this appears to be the case in murine tumor models where cIL-10 promotes anti-tumor immune reactivity when high local concentrations of IL-10 can be achieved using either systemic or local delivery methodologies (via gene transfection). In contrast, immunosuppressive effects have been observed in in vivo systems evaluating the local delivery of the viral homologue of cIL-10 (viral IL-10, vIL-10) which exists within the Bam H1 digest (BCRF1) sequence in the Epstein Barr virus (EBV) and exhibits homology to another sequence in the equine herpes virus (EHV) genome. These findings suggest the vIL-10 possesses predominantly immunosuppressive activity, whereas cIL-10 biology is more complex. Interestingly, cIL-10 administration has been reported to accelerate (or its inhibition delays) the onset of autoimmune disease. The human "tumor" antigens defined to date (tyrosinase, Her-1/neu, MAGE-1, gp100 and MART-1) are in fact autoantigens, since they are also expressed in normal tissue and not appear to contain mutations. Thus, means to promote locoregional autoimmunity to tumor, such as expression of high levels of cIL-10 at the tumor site, seem to represent a reasonable approach as in cancer immunotherapy. We propose the following: Specific Aims; Aim I. To examine the in vivo anti-tumor effects of local secretion of cIL-10. Aim II. To define the mechanisms by which cIL-10 (and vIL-10) modulates anti-tumor immunity. Aim III. To develop improved retroviral vector systems allowing for higher level expression of cIL-10.

IL-10最初被鉴定为细胞因子合成抑制因子 （CSIF）影响多种细胞因子。 后来发现， 包括抑制CTL活性在内的多种作用， 通过抑制单核细胞功能，即减少 MHC II类抗原和单核因子的分泌。 因此，IL-10具有 被认为主要起免疫抑制细胞因子的作用。 然而，最近的体外和体内研究表明，细胞IL-10 （cIL-10，鼠IL-10或人IL-10）主要表现出 体内免疫刺激作用。 特别是，这似乎是 小鼠肿瘤模型中cIL-10促进抗肿瘤免疫的病例 当使用以下方法可以实现高局部浓度的IL-10时， 全身或局部递送方法（通过基因转染）。 相反，在体内已经观察到免疫抑制作用， 评价cIL-10的病毒同源物的局部递送的系统 （病毒IL-10，vIL-10），存在于Bam H1消化物（BCRF 1）中 Epstein巴尔病毒（EBV）中的序列，并与另一个序列具有同源性 马疱疹病毒（EHV）基因组中的序列。 这些发现表明 vIL-10主要具有免疫抑制活性，而 cIL-10生物学更复杂。 有趣的是，cIL-10给药 据报道，加速（或其抑制延迟）的发病 自身免疫性疾病 迄今为止定义的人类“肿瘤”抗原 （酪氨酸酶、Her-1/neu、法师-1、gp 100和MART-1）实际上是 自身抗原，因为它们也在正常组织中表达， 似乎含有突变。 因此，促进局部区域的手段 对肿瘤的自身免疫，如在肿瘤组织中高水平的cIL-10表达， 肿瘤部位，似乎代表了一个合理的方法，如在癌症 免疫疗法 具体目标：目标一。审查 局部分泌cIL-10的体内抗肿瘤作用。Aim II.到 定义cIL-10（和vIL-10）调节抗肿瘤的机制 免疫力Aim III.开发改进的逆转录病毒载体系统， cIL-10的高水平表达。