Studies on the poathogenesis 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。

• 批准号: 14571069
• 负责人: NAGAYAMA Yuji
• 金额: $ 2.56万
• 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: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571069/
• 关键词: Thyroid autoimmunity; TSH receptor; adenovirus; Autoantibody; Graves' disease; サトカイン; サイトカイン

(1)The effect of genetic background on development of Graves' hyperthyroidism : we found that non-MHC genes, but not MHC, play a major role in development of Graves' hyperthyroidism in our mouse model.(2)The effect of environmental factors : Neither environmental. microorganisms nor bacterial/yeast components appear to be involved in the pathogenesis of disease.(3)The effect of Th1/Th2 balance of anti-TSH receptor immune response: Th2-immune deviation at the time of antigen-presentation by co-injection of adenovirus expressing interleukin-4, Schistosoma mansoni infection or administration of a-galactosylceremaide prevent Graves' disease induction. However, anti-TSHR immune response is once activated, Th2-immune polarization has little effect on disease course, indicating this type of immune manipulation may be just preventive, not therapeutic.(4)Analysis of the epitopes on TSH receptor : N-terminus of TSH receptor extracellular domain is the major epitopes, for anti-TSH receptor antibodies recognizing conformational or linear epitopes.(5)The effect of B cell deletion : Existence of normal B cell. population is essential for establishment of anti-TSH receptor memory T lymphocytes.

（1）遗传背景对Graves'甲亢发病的影响：在我们的小鼠模型中，我们发现非MHC基因在Graves'甲亢的发病中起主要作用，而不是MHC基因。（2）环境因素的影响：既不是环境因素。微生物或细菌/酵母成分似乎参与疾病的发病机制。（3）抗TSH受体免疫应答中Th 1/Th 2平衡的影响：联合注射表达IL-4的腺病毒、曼氏血吸虫感染或α-半乳糖基脑酰胺可使抗原呈递时Th 2免疫偏离，从而预防Graves病的发生。然而，一旦抗TSHR免疫应答被激活，Th 2免疫极化对疾病进程的影响不大，表明这种免疫操作可能只是预防性的，而不是治疗性的。（4）TSH受体抗原表位分析：抗TSH受体抗体识别构象或线性抗原表位的主要抗原表位是TSH受体胞外域的N端。（5）B细胞缺失的影响：正常B细胞的存在。群体是建立抗TSH受体记忆T淋巴细胞所必需的。

项目成果

Nagayama Y.: "A major role of non-major histocompatibility complex genes but not for microorganisms in a novel murine model of Graves' hyperthyroidism."Thyroid.. 13(3). 233-238 (2003)

Nagayama Y.：“在格雷夫斯甲状腺功能亢进症的新型小鼠模型中，非主要组织相容性复合体基因发挥着重要作用，但对微生物没有作用。”甲状腺.. 13(3)。

Kakinuma A, Nagayama Y.: "Multiple messenger ribonucleic acid transcripts and revised gene organization of human TSH receptor."Endocrine J.. 49. 175-180 (2002)

Kakinuma A, Nagayama Y.：“多信使核糖核酸转录物和修订的人类 TSH 受体基因组织。”Endocrine J.. 49. 175-180 (2002)

Schwarz-Lauer L, et al.: "The cysteine-rich amino-terminus of. the thyrotropin receptor is the immunodominant linear antibody epitope in mice immunized using naked DNA or adenovirus vectors."Endocrinology.. 144. 1718-1725 (2003)

Schwarz-Lauer L 等人：“促甲状腺素受体富含半胱氨酸的氨基末端是使用裸 DNA 或腺病毒载体免疫的小鼠中的免疫显性线性抗体表位。”内分泌学.. 144. 1718-1725 (2003)

Nagayama Y.: "The Thyroid stimulating hormone receptor. (In Thyroid Eye Disease : Diagnosis and Treatment. (Dutton JJ and Haik BG (ed))"19-27 (2002)

Nagayama Y.：“促甲状腺激素受体。（甲状腺眼病：诊断和治疗。（Dutton JJ 和 Haik BG（编辑））”19-27 (2002)

Guo J.: "Insieht into antibody responses induced by plasmid or adenoviral vectors encoding thyroid peroxidase, a major thyroid autoantigen."Clinical and Experimental Immunology.. 132(3). 408-415 (2003)

郭J.：“研究由编码甲状腺过氧化物酶（一种主要甲状腺自身抗原）的质粒或腺病毒载体诱导的抗体反应。”临床和实验免疫学.. 132（3）。