title: A novel murine model of Graves' hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor.
abstract: 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 beta-galactosidase (1 x 10(11) 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-2(d)) and 25% of female C57BL/6 (H-2(b)) mice developed Graves'-like hyperthyroidism with elevated serum thyroxine (T(4)) 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-2(k)), DBA/1J (H-2(q)), or SJL/J (H-2(s)) 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 T(4) levels, but the correlations between T(4) 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.
authors.affiliation: Department of Pharmacology 1, Nagasaki University School of Medicine, Tokyo, Japan. nagayama@net.nagasaki-u.ac.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nagayama
authors.forename: Masako
authors.initials: M
authors.lastname: Kita-Furuyama
authors.forename: Takao
authors.initials: T
authors.lastname: Ando
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakao
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizuguchi
authors.forename: Takao
authors.initials: T
authors.lastname: Hayakawa
authors.forename: Katsumi
authors.initials: K
authors.lastname: Eguchi
authors.forename: Masami
authors.initials: M
authors.lastname: Niwa
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006111:Graves Disease / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000821:virology; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D010957:Plasmids / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology; D011989:Receptors, Thyrotropin / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics*; D013961:Thyroid Gland / Q000473:pathology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology
chemical_list: D011989:Receptors, Thyrotropin; D019444:Vaccines, DNA; D014765:Viral Vaccines