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

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。1.SCID小鼠模型我们建立了一种改进的ATL严重联合免疫缺陷(SCID)小鼠模型。用HTLV-I感染细胞株TL-OM1、MT-1、MT-2和HUT-102接种5周龄自然杀伤(NK)细胞已被清除的SCID小鼠。注射后40d未见TL-OM1细胞植入，MT-1细胞几乎无成瘤现象。相比之下，MT-2和HUT-102细胞接种小鼠可引起较高的死亡率、100%的肉眼成瘤率和肿瘤细胞在各器官的浸润率，这些均可在接种期间联合应用DHMEQ而减少。此外，DHMEQ治疗的小鼠肿瘤有很高的凋亡率。这些结果表明，二氢美其清在体内诱导HTLV-I转化细胞的凋亡，从而抑制肿瘤的形成和器官侵袭…。HTLV-I基因Tax基因产物HTLV-I编码的小鼠Tax基因产物可能与该病毒引起的疾病的发生有关。我们建立了一系列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携带Tax基因的新型转基因小鼠。LCK-近端Tax小鼠的几个品系出现皮炎，然而我们没有证明Tax在这些皮损中的表达。在成熟胸腺细胞和外周T淋巴细胞中表达LCK远端启动子调控的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。组织学检查显示弥漫性大细胞淋巴瘤累及脾、淋巴结、肝脏、胸腺、骨髓、肾脏、肺、脑膜和皮肤。血涂片显示存在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+。这是首次报道了TAX转基因表达模型导致成熟T细胞淋巴瘤的发生。较少

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