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: 6354617
• 负责人: HIDEAKI TAHARA
• 金额: $ 16.84万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6354617
• 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最初被确定为细胞因子合成抑制因子