末梢性自己寛容誘導機序の解明に基づく自己免疫疾患の発症予知診断法の開発

• 研究課題/領域番号: 20390168
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 病態検査学
• 研究機関: 大阪大学
• 研究代表者: 岩谷 良則 大阪大学, 大学院・医学系研究科, 教授 (60168581)
• 研究分担者: 渡邉 幹夫 大阪大学, 大学院・医学系研究科, 助教 (50294088)
• 研究期間 (年度): 2008 – 2010
• 研究課題ステータス: 完了 (2010年度)
• 配分額: 13,520千円 (直接経費: 10,400千円、間接経費: 3,120千円); 2010年度: 3,900千円 (直接経費: 3,000千円、間接経費: 900千円); 2009年度: 4,160千円 (直接経費: 3,200千円、間接経費: 960千円); 2008年度: 5,460千円 (直接経費: 4,200千円、間接経費: 1,260千円)
• キーワード: 発症予知 / 診断法 / 遺伝子多型 / 一塩基多型 / 自己免疫疾患 / 甲状腺 / 重症度 / 末梢性自己寛容 / 制御性T細胞 / 発生制御因子 / GITR / FOXP3 / 甲状線 / Foxel / GITRL / HHEX

研究概要

自己免疫疾患の病因規定因子である末梢性自己寛容の誘導因子と標的臓器の発生制御因子に着目し、自己免疫性甲状腺疾患の発症増悪予知に有用な遺伝子多型を見出すことを試みた。その結果、GITR、Foxp3、HHHEX、FoxelがAITDの重症度(予後)と関連し、CTLA-4がAITDの発症と関連していること、そして、これらのSNPsがAITDの発症増悪の予知診断法に有用であることを明らかにした。

研究成果

• [雑誌論文] Association of functional polymorphisms in promoter regions of IL5, IL6 and IL13 genes with development and prognosis of autoimmune thyroid diseases. (2011)
  • 著者名/発表者名: Inoue N, Watanabe M, Morita M, Tatusmi K, Hidaka Y, Akamizu T, Iwatani Y.
  • 雑誌名: Clin Exp Immunol. 163(3) ページ: 318-323
• [雑誌論文] mRNA quantification after fluorescence activated cell sorting using locked nucleic acid probes. (2011)
  • 著者名/発表者名: Maruo, R., et al
  • 雑誌名: Molecular Biotechnology 巻: 49(in press)
  • 査読あり
• [雑誌論文] Association of functional polymorphisms in Promoter regions of IL5, IL6 and IL13 genes with development and prognosis of autoimmune thyroid diseases. (2011)
  • 著者名/発表者名: Inoue, N., et al.
  • 雑誌名: Clinical and Experimental Immunology 巻: 163 ページ: 318-323
  • 査読あり
• [雑誌論文] Association of functional polymorphisms related to the transcriptional level of FOXP3 with prognosis of autoimmune thyroid diseases. (2010)
  • 著者名/発表者名: Inoue, N., Watanabe, M., Morita, M., Tomizawa, R., Akamizu, T., Tatsumi, K., Hidaka, Y., Iwatani, Y.
  • 雑誌名: Clin Exp Immunol 162(3) ページ: 402-406
• [雑誌論文] Association of functional polymorphisms related to the transcriptional level of FOXP3 with prognosis of autoimmune thyroid diaeases. (2010)
  • 著者名/発表者名: Inoue, N., et al.
  • 雑誌名: Clinical and Experimental Immunology 巻: 162 ページ: 402-406
  • 査読あり
• [雑誌論文] Messenger RNA quantification after fluorescence-activated cell sorting using in situ hybridization. (2010)
  • 著者名/発表者名: Yamada, H., et al.
  • 雑誌名: Cytometry A 巻: 77 ページ: 1032-1037
  • 査読あり
• [雑誌論文] Increases in urinary creatinine and blood pressure during early pregnancy in pre-eclampsia (2010)
  • 著者名/発表者名: Kuromoto, H., et al.
  • 雑誌名: Annals of Clinical Biochemistry 巻: 47 ページ: 336-342
  • 査読あり
• [雑誌論文] Messenger RNA quantification after fluorescence activated cell sorting using intracellular antigens. (2010)
  • 著者名/発表者名: Yamada, H., et al.
  • 雑誌名: Biochem.Biophys.Res.Commun. 巻: 397 ページ: 425-428
  • 査読あり
• [雑誌論文] Association of -31C/T functional polymorphism in the interleukin-1beta gene with the intractability of Graves' disease and the proportion of Th17 cells. (2009)
  • 著者名/発表者名: Hayashi, F., Watanabe, M., Nanba, T., Inoue, N., Akamizu, T., Iwatani, Y.
  • 雑誌名: Clin Exp Immunol 158(3) ページ: 281-286
• [雑誌論文] Increases of the Th1/Th2 cell ratio in severe Hashimoto's disease and in the proportion of Th17 cells in intractable Graves' disease. (2009)
  • 著者名/発表者名: Nanba, T., Watanabe, M., Inoue, N., Iwatani, Y.
  • 雑誌名: Thyroid 19(5) ページ: 495-501
• [雑誌論文] Involvement of functional polymorphisms in the TNFA gene in the pathogenesis of autoimmune thyroid diseases and production of anti-TSH receptor antibody. (2009)
  • 著者名/発表者名: Inoue, N., Watanabe, M., Nanba, T., Wada, M., Akamizu, T., Iwatani, Y.
  • 雑誌名: Clin Exp Immunol 156(2) ページ: 199-204
• [雑誌論文] Association of -31C/T functional polymorphism in the interleukin-lbeta gene with the intractability of Graves' disease and the proportion of Th17 cells. (2009)
  • 著者名/発表者名: Hayashi, F., et al.
  • 雑誌名: Clinical Experimental Immunology 158 ページ: 281-286
• [雑誌論文] Increases of the Th1/Th2 cell ratio in severe Hashimoto's disease and in the proportion of Th17 cells in intractable Graves' disease. (2009)
  • 著者名/発表者名: Nanba, T., et al.
  • 雑誌名: Thyroid 19 ページ: 495-501
• [雑誌論文] Involvement of functional polymorphisms in the TNFA gene in the pathogenesis of autoimmune thyroid diseases and production of anti-TSH receptor antibody. (2009)
  • 著者名/発表者名: Inoue, N., et al.
  • 雑誌名: Clinical Experimental Immunology 156 ページ: 199-204
• [雑誌論文] Expression of nestin mRNA is a differentiation marker in thyroid tumors. (2009)
  • 著者名/発表者名: Yamada, H., et al.
  • 雑誌名: Cancer Letter 280 ページ: 61-64
• [雑誌論文] Acquired activated protein C resistance is associated with IgG antibodies to protein S in patients with systemic lupus erythematosus. (2009)
  • 著者名/発表者名: Nojima, J., et al.
  • 雑誌名: Thrombosis Research 124 ページ: 127-131
• [雑誌論文] Clinical utility and characteristics of nine anti-HCV antibody screening reagents used in Japan. (2009)
  • 著者名/発表者名: Kita, M., et al.
  • 雑誌名: Clinical Laboratory 55 ページ: 9-22
• [雑誌論文] Early detection of metastasis and relapse of colorectal cancer by recognizing NCA-2 in commercially available CEA assay. (2009)
  • 著者名/発表者名: Hanada, H., et al.
  • 雑誌名: Clinical Chemisty 55 ページ: 1747-1751
• [雑誌論文] Postpartum increase of serum thioredoxin concentrations and the relation to CD8 lymphocytes. (2009)
  • 著者名/発表者名: Kuroda.S., et al.
  • 雑誌名: Annals of Clinical Biochemistry 47 ページ: 62-66
• [雑誌論文] The 869T/C polymorphism in the transforming growth factor-beta1 gene is associated with the severity and intractability of autoimmune thyroid disease. (2008)
  • 著者名/発表者名: Yamada H, Watanabe M, Nanba T, Akamizu T, Iwatani Y
  • 雑誌名: Clin Exp Immunol 151 ページ: 379-382
• [雑誌論文] The-590CC Genotype in the IL4 Gene as a Strong Predictive Factor for the Development of Hypothyroidism in Hashimoto Disease. (2008)
  • 著者名/発表者名: Nanba T, Watanabe M, Akamizu T, Iwatani Y
  • 雑誌名: Clin Chem 54(3) ページ: 621-623
• [雑誌論文] Decrease of intrathyroidal CD161+ Valpha24+Vbeta11+ NKT cells in Graves' disease. (2008)
  • 著者名/発表者名: Watanabe M, Nakamura Y, Matsuzuka F, Takamura Y, Miyauchi A, Iwatani Y
  • 雑誌名: Endocrine J 55 ページ: 199-203
• [雑誌論文] The 869T/C polymorphism in the transforming growth factor-betal gene is associated with the severity and intractability ofautoimmune thyroid disease. (2008)
  • 著者名/発表者名: Yamada H, et al
  • 雑誌名: Clinical Experimental Immunology 151 ページ: 379-382
  • 査読あり
• [雑誌論文] The -590CC genotype in the IL4 gene as a strong predictivefactor for the development of hypothyroidism in Hashimoto Disease. (2008)
  • 著者名/発表者名: Nanba T, et al
  • 雑誌名: Clinical Chemistry 54 ページ: 621-3
  • 査読あり
• [雑誌論文] Tissue factor expression on monocytes induced by anti-phospholipid antibodies as a strong risk factor forthromboembolic complications in SLE patients. (2008)
  • 著者名/発表者名: Noj ima J, et al
  • 雑誌名: Biochem Biophys Res Commun 365 ページ: 195-200
  • 査読あり
• [雑誌論文] Decrease of intrathyroidal CD161+Valpha24+Vbetall+NKT cellsin Graves' disease. (2008)
  • 著者名/発表者名: Watanabe M, et al
  • 雑誌名: Endocrine Journal 55 ページ: 199-203
  • 査読あり
• [雑誌論文] Arteriosclerosis obliterans associated with antti-cardiolipinantibody /{beta}2-glycoprotein I antibodies as a strong riskfactor for ischaemic heart disease in patients with systemiclupus erythematosus. (2008)
  • 著者名/発表者名: Noi ima J, et al
  • 雑誌名: Rheumatology (Oxford) 47 ページ: 684-9
  • 査読あり
• [雑誌論文] Association of functional GITR gene polymorphisms related to expression of GITR molecules with prognosis of autoimmune thyroid disease.
  • 著者名/発表者名: Tomizawa R, Watanabe M, Inoue N, Takemura N, Hidaka Y, Akamizu T, Hayakawa K, Iwatani Y.
  • 雑誌名: Clin.Exp.Immunolo. in press
• [学会発表] (Discussed Poster) Association of functional polymorphisms related to the transcriptional level of FOXP3 gene with prognosis of autoimmune thyroid diseases. (2010)
  • 著者名/発表者名: Watanabe, M., Inoue, N., Morita, M., Tomizawa, R., Akamizu, T., Tatsumi, K., Hidaka, Y., Iwatani, Y.
  • 学会等名: 14th International Thyroid Congress (ITC)
  • 発表場所: Paris
  • 年月日: 2010-09-12
• [学会発表] Association of functional polymorphisms related to the transcriptional level of FOXP3 gene with prognosis of autoimmune thyroid diseases. (2010)
  • 著者名/発表者名: Watanabe, M., et al.
  • 学会等名: 14th International Thyroid Congress
  • 発表場所: Paris, France
  • 年月日: 2010-09-12
• [学会発表] Increases of the Th1/Th2 cell ratio in severe Hashimoto's disease and in the proportion of Th17 cells in intractable Graves' disease. (2010)
  • 著者名/発表者名: Watanabe, M., Nanba, T., Inoue, N., Iwatani, Y.
  • 学会等名: 14th International Congress of Endocrinology (ICE)
  • 発表場所: Kyoto
  • 年月日: 2010-03-30
• [学会発表] Involvement of the functional polymorphisms in TNFA gene in the pathogenesis of autoimmune thyroid diseases and the production of anti-TSH receptor antibody. (2009)
  • 著者名/発表者名: Inoue, N., Watanabe, M., Nanba, T., Akamizu, T., Iwatani, Y.
  • 学会等名: 9th Congress of the Asia and Oceania Thyroid Association (AOTA)
  • 発表場所: Nagoya
  • 年月日: 2009-11-02
• [学会発表] Association of the -31C/T functional polymorphism in the interleukin-1β gene with the intractability of Graves' disease and the proportion of Th17 cells. (2009)
  • 著者名/発表者名: Watanabe, M., Hayashi, F., Nanba, T., Inoue, N., Akamizu, T., Iwatani, Y.
  • 学会等名: 80th Annual Meeting of the American Thyroid Association
  • 発表場所: Palm Beach
  • 年月日: 2009-09-26
• [学会発表] Association of the -31C/T functional polymorphism in the interleukin-lbeta gene with the intractability of Graves' disease and the proportion of Th17 cells. (2009)
  • 著者名/発表者名: Watanabe, M., et al.
  • 学会等名: The 80^<th> Annual Meeting of the American Thyroid Association
  • 発表場所: Palm Beach, FL, USA
  • 年月日: 2009-09-26
• [学会発表] Patients of Hashimoto's disease with-590CC genotype in the IL4 gene would develop hypothyroidism. (2008)
  • 著者名/発表者名: Watanabe M, Namba T, Akamizu T, Iwatani Y
  • 学会等名: The 79th Annual Meeting of the American Thyroid Association
  • 発表場所: Chicago, IL
  • 年月日: 2008-10-03
• [学会発表] Patients of Hashimoto' s disease with -590CC genotype in the IL4 gene would develop hypothyroidism. (2008)
  • 著者名/発表者名: Watanabe M, et al
  • 学会等名: The 79^<th> Annual Meeting of the American Thyroid Association
  • 発表場所: Chicago, IL, USA
  • 年月日: 2008-10-03
• [図書] 臨床検査学実習書シリーズ遺伝子検査学実習書 (2010)
  • 著者名/発表者名: 岩谷良則編
  • 出版者: 医歯薬出版株式会社