An experimental mouse model of spontaneous generation of HodgkinDisease by introduction of GANP RNA-primase gene

通过引入 GANP RNA 引物酶基因建立自发发生霍奇金病的实验小鼠模型

• 批准号: 15023248
• 负责人: SAKAGUCHI Nobuo
• 金额: $ 10.94万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15023248/
• 关键词: B lymphoma; Oncogenesis; DNA replication; Germinal Center; Affinity of antibody; ホジキン病; DNA修復; 体細胞突然変異; プライマーゼ; ウイルス感線; ウイルス感染

We investigated the molecule that induces lymphomas in mouse. Beta RNA primase GANP was found in germinal center B cells that are rapidly proliferating and maturating upon stimulation with T cell-dependent antigen immunization in vivo. Loss of GANP mice displayed no apparent abnormalities but showed a lack of generation of high-affinity antibody production with reduced somatic hypermutation of immunogolobulin. V-region genes with respect to the antigen stimulation. The mice lacked the high-affinity type mutations. The effect of GANP was further confirmed by the over expression of GANP using transgenic strategy, that clearly indicated the augmented somatic hypermutation rates and the high-affinity type mutations in antigen driven B cells. To prove this further, we studied the affinity of the antibodies by measuring the affinity of the specific antibodies at the monoclonal level. More than 6000 monoclonal antibodies were generated after immunization with nitrophenyl-chicken g-globulin an … More d establishment of the hybridomas secreting anti-NP specific antibodies. GANP-trangenic (GANP-Tg) mice generated the monoclonal antibodies with higher affinity to the hapten NP as KD×109M in comparison with the lower affinities from the wild-type littermate controls. Interestingly, the high affinitymonoclonal antibodies were generated by the V-regions with more somatic hypermutations and using the non-canonical V-region gene in a system of O57BL/6 mice system. These results indicated that GANP is involved in generation of high-affinity B cells upon immunization with antigen by regulating the induction of V-region mutations and/or the repair of the DNA damage during B cell clonal expansion and the selection in germinal center regions.The expression of GANP was detected extremely high in the lymphoma specimens by histochemical analysis with anti-GANP specific and the phosphorylated GANP-specific monoclonal antibodies. Human Hodgkin lymphoma, Read-Sternberg cells displayed the higher expression. The monoclonal antibodies were useful for detection of the malignant cells in the mixed population of the lymphomas often observed in human HD clinical samples. We examined whether the increased expression of GANP could be a causative factor of lymphomas in mice. GANP-Tg generated lymphomas of non-B/non-T cell type as quite similar to the human HD lymphomas spontaneously in aged group. These results indicated that the augmented and abnormal expression of GANP is a causative factor of lymphomas of HD-like lymphomas in mice. We speculated that the additional factors are involved in the generation of lymphomas, presumably associated with the infections with various viruses and the stresses of the immune system in peripheral lymphoid organs. Less

我们研究了诱导小鼠淋巴瘤的分子。在生殖中心B细胞中发现了βRNA培养酶GANP，这些生殖中心B细胞在体内用T细胞依赖性抗原免疫免疫刺激而迅速增殖和成熟。 GANP小鼠的丧失没有明显的异常，但缺乏产生的高亲和力抗体产生，并且免疫糖蛋白的体细胞超女性降低。 V区基因相对于抗原刺激。小鼠缺乏高亲和力的突变。通过使用转基因策略的过度表达GANP的效果得到了进一步证实，这清楚地表明了抗原驱动B细胞中的体细胞超突变率和高亲和力类型突变。为了进一步证明这一点，我们通过测量单克隆水平的特定抗体的亲和力研究了抗体的亲和力。用亚硝基苯基 - 鸡Clobulin进行免疫后，产生了6000种单克隆抗体，并且更多地建立了分泌抗NP特异性抗体的杂交瘤。与野生型窝窝控制器的较低亲和力相比，GANP-TG小鼠与触觉NP具有更高亲和力的单克隆抗体为KD×109m。有趣的是，高亲和力单克抗体是由V-Regions产生的，具有更多的体细胞性高压，并在O57BL/6 MICE系统系统中使用非典型的V-Region基因。这些结果表明，通过调节，通过抗原免疫功养后，GANP参与了高亲和力B细胞的产生单克隆抗体。人霍奇金淋巴瘤，读取的 - - - - - - - - - - 塞伯格细胞表现出较高的表达）。单克隆抗体可用于检测在人HD临床样品中经常观察到的淋巴瘤混合群中的恶性细胞。我们检查了GANP的表达增加是否可能是小鼠淋巴瘤的灾难性因素。 GANP-TG产生的非B/非T细胞类型的淋巴瘤与老年组的人类HD淋巴瘤非常相似。这些结果表明，GANP的增强和异常表达是小鼠HD样淋巴瘤淋巴瘤的严重因素。我们推测，淋巴瘤的产生涉及其他因素，大概与各种病毒感染以及外周淋巴器官中免疫系统的应力有关。较少的

项目成果

The Sac3 homologue shd1 is involved in mitotic progression in mammalian cells

Sac3 同源物 shd1 参与哺乳动物细胞的有丝分裂进程

• 发表时间: 2004
• 期刊: Journal of Biological Chemistry 279
• 作者: Sefat-e-Khuda et al.

IL-6 blocks a discrete early step in lymphopoiesis

• DOI: 10.1182/blood-2005-02-0456
• 发表时间: 2005-08-01
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Maeda, K;Baba, Y;Coggeshall, KM
• 通讯作者: Coggeshall, KM

Kazuhiko Kuwahara, et al.: "Germinal center-associated nuclear protein contributes to affinity maturation of B cell antigen receptor in T cell-dependent responses."Proc.Natl.Acad.Sci.U.S.A.. 27;101(4). 1010-1015 (2004)

Kazuhiko Kuwahara 等人：“生发中心相关核蛋白有助于 T 细胞依赖性反应中 B 细胞抗原受体的亲和力成熟。”Proc.Natl.Acad.Sci.U.S.A.. 27；101(4)。

The Sac3-Homologue Shd1 is Involved in Mitotic Progression in Mammalian Cells.

Sac3 同源物 Shd1 参与哺乳动物细胞的有丝分裂进展。

• 发表时间: 2004
• 期刊: J.Biol.Chem. 279
• 作者: Sefat-e-Khuda;et al.
• 通讯作者: et al.

Early lymphoid progenitors in mouse and man are highly sensitive to glucocorticoids

• DOI: 10.1093/intimm/dxh230
• 发表时间: 2005-05-01
• 期刊: INTERNATIONAL IMMUNOLOGY
• 影响因子: 4.4
• 作者: Igarashi, H;Medina, KL;Kincade, PW
• 通讯作者: Kincade, PW