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Departments of
*
Pharmacology 1 and
Internal Medicine 1, Nagasaki University School of Medicine, and
Health Research Center, Nagasaki University, Nagasaki, Japan; and
Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Tokyo, Japan
In this work we report a novel method to efficiently induce a
murine model of Graves’ hyperthyroidism. Inbred mice of different
strains were immunized by i.m. injection with adenovirus expressing
thyrotropin receptor (TSHR) or 
-galactosidase (1 x
1011 particles/mouse, three times at 3-wk intervals) and
followed up to 8 wk after the third immunization. Fifty-five percent of
female and 33% of male BALB/c (H-2d) and 25% of female
C57BL/6 (H-2b) mice developed Graves’-like hyperthyroidism
with elevated serum thyroxine (T4) levels and positive
anti-TSHR autoantibodies with thyroid-stimulating Ig (TSI) and
TSH-binding inhibiting Ig (TBII) activities. In contrast, none of
female CBA/J (H-2k), DBA/1J (H-2q), or SJL/J
(H-2s) mice developed Graves’ hyperthyroidism or
anti-TSHR autoantibodies except SJL/J, which showed strong TBII
activities. There was a significant positive correlation between TSI
values and T4 levels, but the correlations between
T4 and TBII and between TSI and TBII were very weak. TSI
activities in sera from hyperthyroid mice measured with some chimeric
TSH/lutropin receptors suggested that their epitope(s) on TSHR appeared
similar to those in patients with Graves’ disease. The thyroid glands
from hyperthyroid mice displayed diffuse enlargement with hypertrophy
and hypercellularity of follicular epithelia with occasional protrusion
into the follicular lumen, characteristics of Graves’ hyperthyroidism.
Decreased amounts of colloid were also observed. However, there was no
inflammatory cell infiltration. Furthermore, extraocular muscles from
hyperthyroid mice were normal. Thus, the highly efficient means that we
now report to induce Graves’ hyperthyroidism in mice will be very
useful for studying the pathogenesis of autoimmunity in Graves’
disease.
This article has been cited by other articles:
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O. Saitoh, N. Abiru, M. Nakahara, and Y. Nagayama CD8+CD122+ T Cells, a Newly Identified Regulatory T Subset, Negatively Regulate Graves' Hyperthyroidism in a Murine Model Endocrinology, December 1, 2007; 148(12): 6040 - 6046. [Abstract] [Full Text] [PDF]
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S. M. McLachlan, Y. Nagayama, P. N. Pichurin, Y. Mizutori, C.-R. Chen, A. Misharin, H. A. Aliesky, and B. Rapoport The Link between Graves' Disease and Hashimoto's Thyroiditis: A Role for Regulatory T Cells Endocrinology, December 1, 2007; 148(12): 5724 - 5733. [Abstract] [Full Text] [PDF]
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T. Kaneda, A. Honda, A. Hakozaki, T. Fuse, A. Muto, and T. Yoshida An Improved Graves' Disease Model Established by Using in Vivo Electroporation Exhibited Long-Term Immunity to Hyperthyroidism in BALB/c Mice Endocrinology, May 1, 2007; 148(5): 2335 - 2344. [Abstract] [Full Text] [PDF]
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 S.-C. Ho, S.-S. Goh, I. H C Kee, P. K H Chow, C.-P. Yeo, and D. H C Khoo Effects of genetic immunization of Swiss outbred mice with human thyroid stimulating hormone receptor cDNA plasmids harboring gain-of-function mutations J. Mol. Endocrinol., February 1, 2007; 38(2): 277 - 288. [Abstract] [Full Text] [PDF]
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C.-R. Chen, G. D. Chazenbalk, K. A. Wawrowsky, S. M. McLachlan, and B. Rapoport Evidence that Human Thyroid Cells Express Uncleaved, Single-Chain Thyrotropin Receptors on Their Surface Endocrinology, June 1, 2006; 147(6): 3107 - 3113. [Abstract] [Full Text] [PDF]
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H. A. Aliesky, P. N. Pichurin, C.-R. Chen, R. W. Williams, B. Rapoport, and S. M. McLachlan Probing the Genetic Basis for Thyrotropin Receptor Antibodies and Hyperthyroidism in Immunized CXB Recombinant Inbred Mice Endocrinology, June 1, 2006; 147(6): 2789 - 2800. [Abstract] [Full Text] [PDF]
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O. Saitoh and Y. Nagayama Regulation of Graves' Hyperthyroidism with Naturally Occurring CD4+CD25+ Regulatory T Cells in a Mouse Model Endocrinology, May 1, 2006; 147(5): 2417 - 2422. [Abstract] [Full Text] [PDF]
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 J. A. Gilbert, A. G. Gianoukakis, S. Salehi, J. Moorhead, P. V. Rao, M. Z. Khan, A. M. McGregor, T. J. Smith, and J. P. Banga Monoclonal pathogenic antibodies to the thyroid-stimulating hormone receptor in Graves' disease with potent thyroid-stimulating activity but differential blocking activity activate multiple signaling pathways. J. Immunol., April 15, 2006; 176(8): 5084 - 5092. [Abstract] [Full Text] [PDF]
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K. J. Land, P. Gudapati, M. H. Kaplan, and G. S. Seetharamaiah Differential Requirement of Signal Transducer and Activator of Transcription-4 (Stat4) and Stat6 in a Thyrotropin Receptor-289-Adenovirus-Induced Model of Graves' Hyperthyroidism Endocrinology, January 1, 2006; 147(1): 111 - 119. [Abstract] [Full Text] [PDF]
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P. N. Pichurin, C.-R. Chen, G. D. Chazenbalk, H. Aliesky, N. Pham, B. Rapoport, and S. M. McLachlan Targeted Expression of the Human Thyrotropin Receptor A-Subunit to the Mouse Thyroid: Insight into Overcoming the Lack of Response to A-Subunit Adenovirus Immunization J. Immunol., January 1, 2006; 176(1): 668 - 676. [Abstract] [Full Text] [PDF]
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J. Guo, S. M. McLachlan, P. N. Pichurin, C.-R. Chen, N. Pham, H. A. Aliesky, C. S. David, and B. Rapoport Relationship between Thyroid Peroxidase T Cell Epitope Restriction and Antibody Recognition of the Autoantibody Immunodominant Region in Human Leukocyte Antigen DR3 Transgenic Mice Endocrinology, November 1, 2005; 146(11): 4961 - 4967. [Abstract] [Full Text] [PDF]
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 S. M. McLachlan, Y. Nagayama, and B. Rapoport Insight into Graves' Hyperthyroidism from Animal Models Endocr. Rev., October 1, 2005; 26(6): 800 - 832. [Abstract] [Full Text] [PDF]
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E. M. Jacobson, E. Concepcion, T. Oashi, and Y. Tomer A Graves' Disease-Associated Kozak Sequence Single-Nucleotide Polymorphism Enhances the Efficiency of CD40 Gene Translation: A Case for Translational Pathophysiology Endocrinology, June 1, 2005; 146(6): 2684 - 2691. [Abstract] [Full Text] [PDF]
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G. Baker, G. Mazziotti, C. von Ruhland, and M. Ludgate Reevaluating Thyrotropin Receptor-Induced Mouse Models of Graves' Disease and Ophthalmopathy Endocrinology, February 1, 2005; 146(2): 835 - 844. [Abstract] [Full Text] [PDF]
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S. M. McLachlan, H. Braley-Mullen, C.-R. Chen, H. Aliesky, P. N. Pichurin, and B. Rapoport Dissociation between Iodide-Induced Thyroiditis and Antibody-Mediated Hyperthyroidism in NOD.H-2h4 Mice Endocrinology, January 1, 2005; 146(1): 294 - 300. [Abstract] [Full Text] [PDF]
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 S. Costagliola, M. Bonomi, N. G. Morgenthaler, J. Van Durme, V. Panneels, S. Refetoff, and G. Vassart Delineation of the Discontinuous-Conformational Epitope of a Monoclonal Antibody Displaying Full in Vitro and in Vivo Thyrotropin Activity Mol. Endocrinol., December 1, 2004; 18(12): 3020 - 3034. [Abstract] [Full Text] [PDF]
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P. N. Pichurin, G. D. Chazenbalk, H. Aliesky, O. Pichurina, B. Rapoport, and S. M. McLachlan "Hijacking" the Thyrotropin Receptor: A Chimeric Receptor-Lysosome Associated Membrane Protein Enhances Deoxyribonucleic Acid Vaccination and Induces Graves' Hyperthyroidism Endocrinology, December 1, 2004; 145(12): 5504 - 5514. [Abstract] [Full Text] [PDF]
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C.-R. Chen, H. Aliesky, P. N. Pichurin, Y. Nagayama, S. M. McLachlan, and B. Rapoport Susceptibility Rather than Resistance to Hyperthyroidism Is Dominant in a Thyrotropin Receptor Adenovirus-Induced Animal Model of Graves' Disease as Revealed by BALB/c-C57BL/6 Hybrid Mice Endocrinology, November 1, 2004; 145(11): 4927 - 4933. [Abstract] [Full Text] [PDF]
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T. Ando, R. Latif, S. Daniel, K. Eguchi, and T. F. Davies Dissecting Linear and Conformational Epitopes on the Native Thyrotropin Receptor Endocrinology, November 1, 2004; 145(11): 5185 - 5193. [Abstract] [Full Text] [PDF]
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Y. Nagayama, S. M. McLachlan, B. Rapoport, and K. Oishi Graves' Hyperthyroidism and the Hygiene Hypothesis in a Mouse Model Endocrinology, November 1, 2004; 145(11): 5075 - 5079. [Abstract] [Full Text] [PDF]
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K. J. Land, J. S. Moll, M. H. Kaplan, and G. S. Seetharamaiah Signal Transducer and Activator of Transcription (Stat)-6-Dependent, But Not Stat4-Dependent, Immunity Is Required for the Development of Autoimmunity in Graves' Hyperthyroidism Endocrinology, August 1, 2004; 145(8): 3724 - 3730. [Abstract] [Full Text] [PDF]
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J. Guo, P. N. Pichurin, J. C. Morris, B. Rapoport, and S. M. McLachlan "Naked" Deoxyribonucleic Acid Vaccination Induces Recognition of Diverse Thyroid Peroxidase T Cell Epitopes Endocrinology, August 1, 2004; 145(8): 3671 - 3678. [Abstract] [Full Text] [PDF]
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Y. Nagayama, K. Watanabe, M. Niwa, S. M. McLachlan, and B. Rapoport Schistosoma mansoni and {alpha}-Galactosylceramide: Prophylactic Effect of Th1 Immune Suppression in a Mouse Model of Graves' Hyperthyroidism J. Immunol., August 1, 2004; 173(3): 2167 - 2173. [Abstract] [Full Text] [PDF]
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T. Muehlberg, J. A. Gilbert, P. V. Rao, A. M. McGregor, and J. P. Banga Dynamics of Thyroid-Stimulating and -Blocking Antibodies to the Thyrotropin Receptor in a Murine Model of Graves' Disease Endocrinology, April 1, 2004; 145(4): 1539 - 1545. [Abstract] [Full Text] [PDF]
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P. N. Pichurin, O. Pichurina, R. C. Marians, C.-R. Chen, Terry. F. Davies, B. Rapoport, and S. M. McLachlan Thyrotropin Receptor Knockout Mice: Studies on Immunological Tolerance to a Major Thyroid Autoantigen Endocrinology, March 1, 2004; 145(3): 1294 - 1301. [Abstract] [Full Text] [PDF]
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C.-R. Chen, P. Pichurin, G. D. Chazenbalk, H. Aliesky, Y. Nagayama, S. M. McLachlan, and B. Rapoport Low-Dose Immunization with Adenovirus Expressing the Thyroid-Stimulating Hormone Receptor A-Subunit Deviates the Antibody Response toward That of Autoantibodies in Human Graves' Disease Endocrinology, January 1, 2004; 145(1): 228 - 233. [Abstract] [Full Text] [PDF]
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B. S. Prabhakar, R. S. Bahn, and T. J. Smith Current Perspective on the Pathogenesis of Graves' Disease and Ophthalmopathy Endocr. Rev., December 1, 2003; 24(6): 802 - 835. [Abstract] [Full Text] [PDF]
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L. Schwarz-Lauer, P. N. Pichurin, C.-R. Chen, Y. Nagayama, C. Paras, J. C. Morris, B. Rapoport, and S. M. McLachlan The Cysteine-Rich Amino Terminus of the Thyrotropin Receptor Is the Immunodominant Linear Antibody Epitope in Mice Immunized Using Naked Deoxyribonucleic Acid or Adenovirus Vectors Endocrinology, May 1, 2003; 144(5): 1718 - 1725. [Abstract] [Full Text] [PDF]
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Y. Nagayama, H. Mizuguchi, T. Hayakawa, M. Niwa, S. M. McLachlan, and B. Rapoport Prevention of Autoantibody-Mediated Graves'-Like Hyperthyroidism in Mice with IL-4, a Th2 Cytokine J. Immunol., April 1, 2003; 170(7): 3522 - 3527. [Abstract] [Full Text] [PDF]
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T. Ando, M. Imaizumi, P. Graves, P. Unger, and T. F. Davies Induction of Thyroid-Stimulating Hormone Receptor Autoimmunity in Hamsters Endocrinology, February 1, 2003; 144(2): 671 - 680. [Abstract] [Full Text] [PDF]
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P. V. Rao, P. F. Watson, A. P. Weetman, G. Carayanniotis, and J. P. Banga Contrasting Activities of Thyrotropin Receptor Antibodies in Experimental Models of Graves' Disease Induced by Injection of Transfected Fibroblasts or Deoxyribonucleic Acid Vaccination Endocrinology, January 1, 2003; 144(1): 260 - 266. [Abstract] [Full Text] [PDF]
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