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

我们建立了适用于评估成人T细胞白血病（ATL）治疗药物的小动物模型。1. SCID小鼠模型我们开发了一种改良的严重联合免疫缺陷（SCID）小鼠ATL模型。将其中自然杀伤（NK）细胞活性已被消除的五周龄SCID小鼠腹膜内接种HTLV-1感染的细胞系TL-Om 1、MT-1、MT-2和HUT-102。注射后40天未检测到TL-Om 1细胞的植入和MT-1细胞的少量成瘤。相比之下，用MT-2和HUT-102细胞接种小鼠引起高死亡率、100%的大体肿瘤形成频率和各种器官的肿瘤细胞浸润，所有这些都通过在接种期间共施用DHMEQ而减少。此外，来自用DHMEQ处理的小鼠的肿瘤具有高的细胞凋亡频率。这些结果表明，DHMEQ在体内诱导HTLV-I转化细胞的凋亡，从而抑制肿瘤形成和器官浸润。 关于我们 HTLV-I Tax转基因小鼠HTLV-I编码的Tax基因产物可能与该病毒引起的疾病的发展有关。我们建立了一系列新的转基因小鼠携带的小鼠淋巴细胞特异性蛋白酪氨酸激酶（p56 lck）的近端或远端启动子控制下的tax基因。几种LCK-近端-Tax小鼠表现出皮炎，但是我们没有证明Tax在这些病变中的表达。在成熟胸腺细胞和外周血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。小鼠出现明显的脾肿大、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、胸腺、骨髓、肾、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CD 4+或CD 8+。这是首次报道Tax基因表达的转基因模型导致成熟T细胞淋巴瘤的发展。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