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Studies on the pathogenesis of Graves' disease and new treatment using our recently established mouse model.

使用我们最近建立的小鼠模型研究格雷夫斯病的发病机制和新的治疗方法。

基本信息

批准号：
17590965
负责人：
NAGAYAMA Yuji
金额：
$ 2.18万
依托单位：
Nagasaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590965/
关键词：
thyroid autoimmunity thyrotropin receptor regulatory T cells autoantibody Graves' disease adenovirus

项目摘要

1. Suppression of disease development by CD4^+CD25^+ regulatory T cells (Treg) : Depletion of Treg by anti-CD25 antibody induced Graves' hyperthyroidism in 30 % of resistant C57BL/6 mice, and increased serum T_4 levels by 200 % in susceptible BALB/c mice. This effect was attributed to decreased stimulatory antibody titers and increased blocking antibody titers. Furthermore, in transfer experiments to naive wt mice, splenocytes from Graves' mice induced little anti-TSHR antibody, but CD25-depleted splenocytes did low but significant levels of antibody.2. Suppression of disease development by regulatory cytokines : adenovirus expressing IL-10 or TGF-beta (both are regulatory cytokines) were constructed, and administered to mice together with adenovirus coding the TSHR (Ad-TSHR). Only Ad-IL-10 significantly inhibited hyperthyroidism.3. Suppression of disease development by apoptosis-inducing Fas ligand (FasL) : Adenovirus expressing FasL was constructed, and infected into dendritic cells (DCs) derived from bone-marrow cells by using GMCSF and IL-4 together with Ad-TSHR. These DCs inhibited anti-TSHR immune response and development of Graves' disease induced by intramuscular injection of Ad-TSHR.4. TSHR-specific T cell lines are now being established by the TSHR protein and three : peptides which induced IFNgamma release in recall assay. Abilities of individual clones to produce cytokine(s) and to induce hyperthyroidism as well as amino acid sequences of T cell receptors will be studied.

1. CD4^+CD25^+调节性T细胞（Treg）抑制疾病发展：抗CD25抗体消耗Treg诱导30%的耐药C57BL/6小鼠Graves甲亢，易感BALB/c小鼠血清T_4水平增加200%。这种效应归因于刺激抗体滴度降低和阻断抗体滴度增加。此外，在移植到幼年wt小鼠的实验中，来自Graves小鼠的脾细胞很少产生抗tshr抗体，但cd25缺失的脾细胞产生低但显著水平的抗体2。通过调节细胞因子抑制疾病发展：构建了表达IL-10或tgf - β（两者都是调节细胞因子）的腺病毒，并与编码TSHR的腺病毒（Ad-TSHR）一起施用于小鼠。只有Ad-IL-10能显著抑制甲亢。凋亡诱导Fas配体（FasL）抑制疾病发展：构建表达FasL的腺病毒，利用GMCSF、IL-4和Ad-TSHR感染来源于骨髓的树突状细胞（DCs）。这些dc可抑制肌内注射ad - tshr诱导的抗tshr免疫反应和Graves病的发展。目前正在建立TSHR特异性T细胞系，其中TSHR蛋白和三种肽在召回试验中诱导IFNgamma释放。个体克隆产生细胞因子和诱导甲状腺机能亢进的能力以及T细胞受体的氨基酸序列将被研究。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Adenovirus-mediated gene delivery of interleukin-10, but not transforming growth factor beta, ameliorates Graves' hyperthyroidism in BALB/c mice.

腺病毒介导的白细胞介素 10（但不转化生长因子 β）基因传递可改善 BALB/c 小鼠的格雷夫斯甲状腺功能亢进症。

DOI：
发表时间：
2005
期刊：
Clin Exp Immunol. 141(3)
影响因子：
0
作者：
Saitoh O;Mizutori Y;Takamura N;Kita A;Kuwahara H;Yamasaki H;Nagayama Y.
通讯作者：
Nagayama Y.

BRAFV600E promotes invasiveness of thyroid cancer cells through NF-kB activation

BRAFV600E通过NF-kB激活促进甲状腺癌细胞的侵袭

DOI：
发表时间：
2006
期刊：
Endocrinol 147
影响因子：
0
作者：
I.Palona;et al.
通讯作者：
et al.

Animal model of Graves' disease.

格雷夫斯病的动物模型。

DOI：
发表时间：
2005
期刊：
Acta Med Nagasaki. 50(2)
影响因子：
0
作者：
Hayashi T;Nakao K;Nagayama Y;Saitoh O;Ichikawa T;Ishikawa H;Hamasaki K;Eguchi K;Ishii N.;柴田洋孝;柴田洋孝;Nagayama Y.
通讯作者：
Nagayama Y.

Adenovirus coding the thyrotropin receptor A subunit improves the efficacy of dendritic cell-based mouse model of Graves' hyperthyroidism.

编码促甲状腺素受体 A 亚基的腺病毒可提高基于树突状细胞的格雷夫斯甲状腺功能亢进症小鼠模型的疗效。