WATANABE Toshiki Tokyo University, The Institute of Medical Science, Professor, 医科学研究所, 教授 (30182934)
URANO Toru Kumamoto University, Institute of Resource Development and Analysis, Professor, 生命資源研究・支援センター, 教授 (90101899)
山口 一成 熊本大学, 医学部附属病院, 講師 (20128325)
|Budget Amount *help
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
We established small-animal models that is appropriate to assess therapeutic agents for adult T-cell leukemia (ATL).
1.SCID mice model
We 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
ration, thereby enhancing survival.
2.HTLV-I Tax transgenic mice
Tax 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