Development and analyses of novel animal models for human retrovirus-induced desiases.

人类逆转录病毒引起的疾病的新型动物模型的开发和分析。

• 批准号: 14207010
• 负责人: KYOSHIKI Takashi
• 金额: $ 27.71万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14207010/
• 关键词: retrovirus; HTLV-I; HIV-1; animal model; myelopathy; transgenic; autoimmune disease; thymoma; HIV-I; 免疫制御細胞; レトロウィルス; Cyclin T1

Virus-host interactions were investigated using rat models for human retrovirus-induced diseases.1.HAM rat disease occurred in HTLV-I-infected rats in a strain-dependent manner. In HAM susceptible rats, expression of the INF-γ gene in the spinal cord did not increase after HTLV-I infection, while did in HAM resistant strains. These findings suggest that INF-γ may play a role in prevention at HTLV-1-induced diseases.2.Autoimmune diseases occurred in HTLV-I LTR-env-pX transgenic rats (LTR-env-pX rats). Functional alteration of CD25+CD4+ immunoregulatory T-cells was evident in LTR-env-pX rats before they developed diseases. Expressions of the CTLA-4, GITR, Foxp3, and SOCS family genes in the cells of LTR-env-pX rats were lower than those of wild type rats. Synovial tissues rather than bone marrow cells carrying the transgene may play roles in prolongation of arthritis developed in LTR-env-pX rats.3.Benign epithelial thymoma occurred in lck-pX transgenic rats (lck-pX rats). Thymoma grafted in the subcapsular space of the kidney of lck-pX rats showed malignant transformation. The p16/ARF genes were lost in the transformed tumors, thus suggesting that these molecules may be associated with malignant transformation of HTLV-I-induced neoplasms.4.Rat fibrobalastic cells expressing human CD4 and CXCR-4/CCR5 could be infected with HIV-1. Although HIV-1 provirus was integrated in the genome of these cells, viral expression was not achieved completely. Putative factors including human cyclin T1 and MHC class II transactivator (C2TA) may be needed for viral replication in the cells. To examine interactions of HIV-1 and host in vivo, transgenic rats carrying the human CD4, CXCR4/CCR5, cyclic T1, and C2TA genes were established.

利用人类逆转录病毒引起的疾病的大鼠模型研究了病毒与宿主的相互作用。1.HAM大鼠疾病在HTLV-I感染的大鼠中以毒株依赖性方式发生。在HAM易感大鼠中，INF-γ基因的表达。 HTLV-I感染后脊髓没有增加，而HAM耐药菌株则增加。这些结果表明INF-γ可能在预防HTLV-1诱发的疾病中发挥作用。2.自身免疫性疾病发生在HTLV-I感染后。 HTLV-I LTR-env-pX 转基因大鼠（LTR-env-pX 大鼠）在发生疾病之前，LTR-env-pX 大鼠中 CD25+CD4+ 免疫调节 T 细胞的功能改变是明显的。 LTR-env-pX大鼠细胞中的GITR、Foxp3和SOCS家族基因低于野生型大鼠滑膜组织而非骨髓细胞。携带转基因可能在LTR-env-pX大鼠关节炎的延长中发挥作用。3.lck-pX转基因大鼠（lck-pX大鼠）发生良性上皮性胸腺瘤，移植于lck-肾囊下间隙。 pX大鼠表现出恶性转化，p16/ARF基因在转化的肿瘤中丢失，因此表明这些分子可能与p16/ARF基因的恶性转化有关。 HTLV-I诱导的肿瘤。4.表达人CD4和CXCR-4/CCR5的大鼠成纤维细胞可以被HIV-1感染，尽管HIV-1原病毒已整合到这些细胞的基因组中，但病毒表达并未完全实现。细胞内的病毒复制可能需要包括人细胞周期蛋白 T1 和 MHC II 类反式激活因子 (C2TA) 在内的推定因子。为了检查 HIV-1 与体内宿主的相互作用，携带人类的转基因大鼠。建立了 CD4、CXCR4/CCR5、循环 T1 和 C2TA 基因。

项目成果

Ishizu, A., et al.: "Transduction of dominant negative ATF-1 suppresses the pX gene expression in joint fibroblastic cells derived from HTLV-I transgenic rats"Experimental Molecular Pathology. 74. 309-313 (2003)

Ishizu, A. 等人：“显性失活 ATF-1 的转导抑制了来自 HTLV-1 转基因大鼠的关节成纤维细胞中的 pX 基因表达”实验分子病理学。

Higuchi1 M et al.: "Functional alteration of peripheral CD25+CD4+immunoregulatory T cells in a transgenic rat model of autoimmune diseases"J Autoimmun. 20. 43-49 (2003)

Higuchi1 M 等人：“自身免疫性疾病转基因大鼠模型中外周 CD25 CD4 免疫调节 T 细胞的功能改变”J Autoimmun。

Kawada M et al.: "Vaccination of fusion cells of rat dendritic and carcinoma cells prevents tumor growth in vivo"Int J Cancer. (in press). (2003)

Kawada M 等人：“对大鼠树突状细胞和癌细胞的融合细胞进行疫苗接种可防止体内肿瘤生长”Int J Cancer。

Nakaya H et al.: "In vitro model of suicide gene therapy for alpha-fetoprotein-producing gastric cancer."Anticancer Res. 23. 3795-3800 (2003)

Nakaya H 等人：“针对产生甲胎蛋白的胃癌的自杀基因治疗的体外模型。”抗癌研究。

Sugaya T et al.: "Clonotypic analysis of T cells accumulating at arthriticlesions in HTLV-I env-pX transgenic rats"Exp Mol Pathol. 72. 56-61 (2002)

Sugaya T 等人：“HTLV-I env-pX 转基因大鼠关节炎损伤处 T 细胞积累的克隆型分析”Exp Mol Pathol。