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

Research Project

Project/Area Number 14571069
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Endocrinology
Research InstitutionNagasaki University

Principal Investigator

NAGAYAMA Yuji  Nagasaki University, Graduate School of Biomedical Sciences Atomic Bomb Disease Institute Department of Medical Gene Technology, Professor, 大学院・医歯薬学総合研究科, 教授 (30274632)

Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2002: ¥2,300,000 (Direct Cost: ¥2,300,000)
KeywordsThyroid autoimmunity / TSH receptor / adenovirus / Autoantibody / Graves' disease / サトカイン / サイトカイン
Research Abstract

(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.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (63 results)

All Other

All Publications (63 results)

  • [Publications] 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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagayama Y.: "Prevention of autoantibodv-mediated Graves'-like hyperthyroidism in mice with IL-4,a Th2 cytokine."Journal of Immunology.. 170(7). 3522-3527 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Schwartz-Laurer L.L.: "The cycteine-rich amino-terminus of the thyrotropin receptor is the Immunodominant linear antibody epitope in mice immunized using naked DNA or adenovirus vectors."Endocrinology.. 144(5). 1718-1725 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Chen C.-R.: "The thyrotropin receptor autoantigen in Graves' disease"Journal of Clinical Investigation.. 111(2). 1897-1904 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagayama Y.: "Enhanced antitumor effect of combined replicative and non-replicative adenovirus expressing interleukin-12."Gene Therapy.. 10(16). 1400-1403 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagayama Y.: "Novel murine models of thyroid autoimmunity."Current opinion in Endocrinology & Diabetes.. 10. 364-370 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Abiru N.: "In vivo expression of B:923 peptide/I-A^<g7> complex may abrogate the inhibition of diabetes induced by RGD-fiber-mutant adenovirus in NOD mice."Annals of New York Academy of Science.. 1005. 218-221 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Pichurin P.: "Thyrotropin receptor-specific memory T cell responses require normal B cells in a raurine model of Graves' disease."Clinical and Experimental Immunology.. 134(3). 396-402 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Saeki A.: "Diverse efficacy of vaccination therapy using the α-fetoprotein gene against hepatocellular carcinoma."International Jouranl of Oncology.. 13(1). 111-1116 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tanaka K.: "Thyroid cancer immuno-therapy with retroviral and adenoviral vectors expressing GMCSF and IL-12 in a rat model."Clinical Endocrinology.. 59(6). 734-742 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Chen C.-R.: "Low dose immunization with adenovirus expressing the TSH receptor A-subunit deviates the antibody responses towards that of autoantibodoies in human Graves' disease."Endocrinology.. 145(1). 228-233 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tamada Y, et al.: "p48 overexpression enhances interferon-mediated expression and activity of double-stranded RNA-dependent protein kinase (PKR) in human hepatoma cells."J Hepatol.. 37. 493-499 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Schwarz-Lauer LL, et al.: "Evidence for a simplified view of autoantibody interactions with the TSH receptor."Thyroid.. 12. 115-120 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagayama Y, et al.: "A novel murine model of Graves' hyperthyroidism with intramuscular injection of adenovirus expressing thyrotropin receptor."J Immunol.. 168. 2789-2794 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kakinuma A, Nagayama Y.: "Multiple messenger ribonucleic acid transcripts and revised gene organization of human TSH receptor."Endocrine J.. 49. 175-180 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] S.Kuroda H, et al.: "Distinctive gene expression of receptor-type tyrosine kinase families during rat hepatocarcinogenesis."Int J Nol Med.. 9. 473-480 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kawamata Y, et al.: "Receptor-independent augmentation of adenovirus-mediated gene transfer with chitosan in vitro."Biomaterials.. 23. 4573-4579 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ando T, et al.: "A monoclonal thyroid-stimulating antibody."J Clin Invest.. 110. 1667-1674 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ito M, et al.: "Expression of receptor-type tyrosine kinase, Ax1, and its ligand, Gas6, in pediatric thyroid carcinomas around Chernobyl."Thyroid.. 12. 971-975 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yanagi K, et al.: "Immuno-gene therapy with adenoviruses expressing fins-like tyrosine kinase ligand and CD40 ligand for mouse hepatoma cells in vivo."Int J Oncol.. 22. 345-351 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kita-Furuyama M, et al.: "Dendritic cells infected with adenovirus expressing the thyrotropin receptor induce Graves' hyperthyroidism in BALB/c mice."Clin Exp Immunol.. 131. 234-240 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagayama Y, et al.: "A major role for non-major histocompatibility complex genes but not for microorganisms in a novel murine model of Graves' hyperthyroidism."Thyroid.. 13. 233-238 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagayama Y, et al.: "Prevention of autoantibody-mediated Graves'-like hyperthyroidism in mice by IL-4, a Th2 cytokine."J Immunol.. 170. 3522-3527 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Guo J, et al.: "Insight into antibody responses induced by plasmid or adenoviral vectors encoding thyroid peroxidase, a major thyroid autoantigen."Clin Exp Immunol.. 132. 408-415 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Chen C-R, et al.: "The thyrotropin receptor autoantigen in Graves' disease is the culprit as well as the victim."J Clin Invest.. 111. 1897-1904 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagayama Y, et al.: "Enhanced antitumor effect of combined replicative adenovirus and non-replicative adenovirus expressing interleukin-12 in an immunocompetent mouse model."Gene. 10. 1400-1403 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagayama Y.: "Novel murine models of thyroid autoimmunity."Current Opinion in Endocrinology & Diabetes.. 10. 364-370 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] AbiruN, et al.: "In vivo expression of B:923 peptide/I-A^<97> complexmay abrogate the inhibition of diabetes induced by RGD-fiber-mutant adenovirus in NOD mice."Ann NY Acad Sci.. 1005. 218-221 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Pichurin P, et al.: "Thyrotropin receptor-specific memory T cell responses require normal B cells in a murine model of Graves' disease."Clin Exp Immunol.. 134. 396-402 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Saeki A, et al.: "Diverse efficacy of vaccination therapy using the a-fetoprotein gene against hepatocellular carcinoma."Int J Oncol.. 13. 111-116 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tanaka K, et al.: "Thyroid cancer immunotherapy with retroviral and adenoviral vectors expressing granulocyte-macrophage colony stimulating factor and interleukin-12 in a rat model."Clin Endocrinol.. 59. 734-742 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Chen C-R, et al.: "Low dose immunization with adenovirus expressing the TSH receptor A-subunit deviates the antibody response towards that of autoantibodies in human Graves' disease."Endocrinology.. 145. 228-233 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagayama Y.: "The Thyroid stimulating hormone receptor. (In Thyroid Eye Disease : Diagnosis and Treatment. (Dutton JJ and Haik BG (ed))"19-27 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 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)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nagayama Y.: "Prevention of autoantibody-mediated Graves'-like hyperthyroidism in mice with IL-4, a Th2 cytokine"Journal of Immunology. 170(7). 3522-3527 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Schwartz-Laurer L.L.: "The cycteine-rich amino-terminus of the thyrotropin receptor is the Immunodominant linear antibody epitope in mice immunized using naked DNA or adenovirus vectors"Endocrinology. 144(5). 1718-1725 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Guo J.: "Insight 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)

    • Related Report
      2003 Annual Research Report
  • [Publications] Chen C.-R.: "The thyrotropin receptor autoantigen in Graves' disease"Journal of Clinical Investigation. 111(2). 1897-1904 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nagayama Y.: "Enhanced antitumor effect of combined replicative and non-replicative adenovirus expressing interleukin-12"Gene Therapy. 10(16). 1400-1403 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nagayama Y.: "Novel murine models of thyroid autoimmunity"Current opinion in Endocrinology & Diabetes. 10. 364-370 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Abiru N.: "In vivo expression of B:923 peptide/I-A^<g7> complex may abrogate the inhibition of diabetes induced by RGD-fiber-mutant adenovirus in NOD mice"Annals of New York Academy of Science. 1005. 218-221 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Pichurin P.: "Thyrotropin receptor-specific memory T cell responses require normal B cells in a murine model of Graves' disease"Clinical and Experimental Immunology. 134(3). 396-402 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Saeki A.: "Diverse efficacy of vaccination therapy using the α-fetoprotein gene against hepatocellular carcinoma"International Journal of Oncology. 13(1). 111-116 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tanaka K.: "Thyroid cancer immuno-therapy with retroviral and adenoviral vectors expressing GMCSF and IL-12 in a rat model"Clinical Endocrinology. 59(6). 734-742 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Chen C.-R.: "Low dose immunization with adenovirus expressing the TSH receptor A-subunit deviates the antibody responses towards that of autoantibodies in human Graves' disease"Endocrinology. 145(1). 228-233 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tamada Y.: "p48 overexpression enhances interferon-mediated expression and activity of double-stranded RNA-dependent protein kinase (PKR) in human hepatoma cells"Journal of Hepatology. 37(4). 493-499 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Schwarz-Lauer L.L.: "Evidence for a simplified view of autoantibody interactions with the TSH receptor"Thyroid. 12(2). 115-120 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagayama Y.: "A novel murine model of Graves' hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor"Journal of Immunology. 168(6). 2789-2794 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kakinuma A.: "Multiple messenger ribonucleic acid transcripts and revised gene organization of human TSH receptor"Endocrine Journal. 49(2). 175-180 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kuroda H.: "Distinctive gene expression of receptor-type tyrosine kinase families during rat hepatocarcinogenesis"International Journal of Molecular Medicine. 9(5). 473-480 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kawamata Y.: "Receptor-independent augmentation of adenovirus-mediated gene transfer with chitosan in vitro"Biomaterials. 23(23). 4573-4579 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ando T.: "A monoclonal thyroid-stimulating antibody"Journal of Clinical Investigation. 110(11). 1667-1674 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ito M.: "Expression of receptor-type tyrosine kinase, Axl, and its ligand, Gas6, in pediatric thyroid carcinomas around Chernobyl"Thyroid. 12(11). 971-975 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yanagi K.: "Immuno-gene therapy with adenoviruses expressing fms-like tyrosine kinase 3 ligand and CD40 ligand for mouse hepatoma cells in vivo"International Journal of Oncology. 22(2). 345-351 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kita-Furuyama M.: "Dendritic cells infected with adenovirus expressing the thyrotropin receptor induce Graves' hyperthyroidism in BALB/c mice"Clinical and Experimental Immunology. 131(2). 234-240 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagayama Y.: "A major role for non-MHC genes, but not for microorganisms, in a novel murine model of Graves' hyperthyroidism"Thyroid. (In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagayama Y.: "Enhanced antitumor effect of combined replicative adenovirus and non-replicative adenovirus expressing interlerkin-12 in an immunocompetent mouse model"Gene Therapy. (In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Schwarz-Lauer L.L.: "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. (In press). (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagayama Y.: "Prevention of autoantibody-mediated Graves'-like hyperthyroidism in mice by IL-4, a Th2 cytokine"Journal of Immunology. (In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagayama Y.: "Thyroid Eye Disease : Diagnosis and Treatment"Marcel Dekker. 9 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagayama Y.: "The encyclopedia of Endocrinology and Endocrine Diseases"Academic Press (In press). (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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