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Development of model mice of adult T-cell leukemia for evaluation of new therapeutic agents

开发成人 T 细胞白血病模型小鼠以评估新治疗药物

基本信息

批准号：
15500300
负责人：
OHSUGI Takeo
金额：
$ 2.05万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15500300/
关键词：
HTLV-I ATL mice SCID mice animal model HTLV-1

项目摘要

We established small-animal models that is appropriate to assess therapeutic agents for adult T-cell leukemia (ATL).1.SCID mice modelWe developed an improved severe combined immunodeficiency (SCID) mouse model for ATL. Five-week-old SCID mice in which natural killer (NK) cell activity had been eliminated were inoculated intraperitoneally with the HTLV-I-infected cell lines, TL-Om1, MT-1, MT-2 and HUT-102. No engraftment of TL-Om1 cells and little tumorigenesis of MT-1 cells were detected 40 days after injection. In contrast, inoculation of mice with MT-2 and HUT-102 cells elicited high mortality, 100% frequency of gross tumor formation, and tumor cell infiltration of various organs, all of which were reduced by co-administration of DHMEQ during the inoculation. Moreover, tumors from mice treated with DHMEQ had a high frequency of apoptosis. These results suggest that DHMEQ induces apoptosis in HTLV-I-transformed cells in vivo, resulting in inhibition of tumor formation and organ infilt … More ration, thereby enhancing survival.2.HTLV-I Tax transgenic miceTax gene product of HTLV-I encoded may be responsible for the development of diseases caused by this virus. We established a series of novel transgenic mice carrying the tax gene under the control of a mice lymphocyte-specific protein tyrosine kinase (p56lck) proximal or distal promoter. Several lines of Lck-proximal-tax mice showed dermatitis, however we did not demonstrate the expression of Tax in these lesions. The mice expressing Tax controlled by Lck distal promoter in mature thymocytes and peripheral T lymphocytes developed T-cell lymphoma and leukemia. The mice showed the development of marked splenomegaly, hepatomegaly and lymphadenopathy. Histological examination showed diffuse, large-cell lymphomas involving spleen, lymph nodes, liver, thymus, bone marrow, kidney, lung, meninges and skin. Blood smears showed the presence of large and abnormal leukemic cells. The malignant phenotype observed in the transgenic mice was CD4+ or CD8+. This is the first report that transgenic model of Tax expression resulted in the development of mature T-cell lymphoma. Less

我们建立了适合于评估成人t细胞白血病（ATL）治疗药物的小动物模型。我们建立了一种改良的ATL严重联合免疫缺陷（SCID）小鼠模型。将自然杀伤（NK）细胞活性被消除的5周龄SCID小鼠腹腔接种htlv -i感染的细胞系TL-Om1、MT-1、MT-2和HUT-102。注射后40 d未见TL-Om1细胞移植，MT-1细胞无肿瘤发生。相比之下，MT-2和HUT-102细胞接种小鼠，死亡率高，大体肿瘤形成频率100%，肿瘤细胞浸润各器官，接种DHMEQ时，这些都减少了。此外，用DHMEQ处理的小鼠肿瘤具有较高的凋亡频率。这些结果表明，DHMEQ在体内诱导htlv - 1转化细胞凋亡，从而抑制肿瘤形成和器官浸润，从而提高生存率。HTLV-I基因编码的Tax基因产物可能与该病毒引起的疾病的发生有关。我们在小鼠淋巴细胞特异性蛋白酪氨酸激酶（p56lck）近端或远端启动子的控制下，建立了一系列携带tax基因的新型转基因小鼠。几系lck -近端Tax小鼠表现出皮炎，但我们没有在这些病变中证明Tax的表达。在成熟胸腺细胞和外周T淋巴细胞中表达由Lck远端启动子控制的Tax的小鼠发生T细胞淋巴瘤和白血病。小鼠表现出明显的脾肿大、肝肿大和淋巴结病变。组织学检查显示弥漫性大细胞淋巴瘤累及脾脏、淋巴结、肝脏、胸腺、骨髓、肾脏、肺、脑膜和皮肤。血涂片显示有大而异常的白血病细胞。在转基因小鼠中观察到的恶性表型为CD4+或CD8+。这是首次报道转基因Tax表达模型导致成熟t细胞淋巴瘤的发展。少