Baba Masanori, Okamoto Mika, Hamasaki Takayuki, Horai Sawako, Wang Xin, Ito Yuji, Suda Yasuo, Arima Naomichi
Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan.
J Virol. 2008 Apr;82(8):3843-52. doi: 10.1128/JVI.02013-07. Epub 2008 Feb 6.
Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL). In Japan, the number of HTLV-1 carriers is estimated to be 1.2 million and more than 700 cases of ATL have been diagnosed every year. Considering the poor prognosis and lack of curative therapy of ATL, it seems mandatory to establish an effective strategy for the treatment of ATL. In this study, we attempted to identify the cell surface molecules that will become suitable targets of antibodies for anti-ATL therapy. The expression levels of approximately 40,000 host genes of three human T-cell lines carrying HTLV-1 genomes were analyzed by oligonucleotide microarray and compared with the expression levels of the genes in an HTLV-1-negative T-cell line. The HTLV-1-carrying T-cell lines used for experiments had totally different expression patterns of viral genome. Among the genes evaluated, the expression levels of 108 genes were found to be enhanced more than 10-fold in all of the T-cell lines examined and 11 of the 108 genes were considered to generate the proteins expressed on the cell surface. In particular, the CD70 gene was upregulated more than 1,000-fold and the enhanced expression of the CD70 molecule was confirmed by laser flow cytometry for various HTLV-1-carrying T-cell lines and primary CD4(+) T cells isolated from acute-type ATL patients. Such expression was not observed for primary CD4(+) T cells isolated from healthy donors. Since CD70 expression is strictly restricted in normal tissues, such as highly activated T and B cells, CD70 appears to be a potential target for effective antibody therapy against ATL.
人类嗜T淋巴细胞病毒1型（HTLV-1）是成人T细胞白血病（ATL）的病原体。在日本，HTLV-1携带者估计有120万，每年有超过700例ATL被诊断出来。考虑到ATL预后不良且缺乏治愈性疗法，制定有效的ATL治疗策略似乎是必要的。在本研究中，我们试图鉴定出可成为抗ATL治疗抗体合适靶点的细胞表面分子。通过寡核苷酸微阵列分析了携带HTLV-1基因组的三个人类T细胞系中约40000个宿主基因的表达水平，并与HTLV-1阴性T细胞系中基因的表达水平进行比较。用于实验的携带HTLV-1的T细胞系具有完全不同的病毒基因组表达模式。在所评估的基因中，发现108个基因的表达水平在所有检测的T细胞系中均增强了10倍以上，其中108个基因中的11个被认为可产生在细胞表面表达的蛋白质。特别是，CD70基因上调了1000倍以上，通过激光流式细胞术证实了各种携带HTLV-1的T细胞系和从急性型ATL患者分离的原代CD4(+) T细胞中CD70分子的表达增强。从健康供体分离的原代CD4(+) T细胞未观察到这种表达。由于CD70表达在正常组织中如高度活化的T和B细胞中受到严格限制，CD70似乎是针对ATL进行有效抗体治疗的潜在靶点。
