title: Prolonged TSH receptor A subunit immunization of female mice leads to a long-term model of Graves' disease, tachycardia, and cardiac hypertrophy.
abstract: A transient model for human Graves' disease was successfully established in mice using up to 3 immunizations with recombinant adenovirus expressing the extracellular A-subunit of the human TSH receptor (TSHR) (Ad-TSHR). We studied extension of adenovirally induced TSHR A-subunit immunization in mice by using a novel protocol of long-term 3- and 4-weekly injections. Generation of TSHR binding stimulatory antibodies (capacity to stimulate cAMP activity in TSHR-expressing test cells), goiter, and histological thyroid alterations were maintained for at least 9 months in all Ad-TSHR-immunized mice. In response to injection of 10(10) plaque-forming units of Ad-TSHR, also elevated mean serum T4 levels were observed throughout the study. Moreover, cardiac organ involvement (tachycardia and hypertrophy) were consistently observed in these mice. Higher doses of Ad-TSHR (10(11) plaque-forming units) did not produce consistent elevation of T4 and were not associated with a clear increase in heart rate vs controls, probably because these high doses provoked an immune response-induced tachycardia on their own. In summary, a long-term model of Graves' disease induced by a relatively simple protocol of continuing monthly immunizations should allow to investigate long-term disease mechanisms and may possibly obviate the need for more complicated disease models. Moreover, the clinical outcome predictor of tachycardia and cardiac involvement was reliably detected in the model.
authors.affiliation: AdvanceCOR (Procorde) (H.-P.H., S.G., Z.L., J.F., A.R., S.Z., G.M., M.U.), 82152 Martinsried, Germany; and Rudolf Virchow Centre (M.J.L.), University of Würzburg, 97078 Würzburg, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Holthoff
authors.forename: Sylvia
authors.initials: S
authors.lastname: Goebel
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Li
authors.forename: Julia
authors.initials: J
authors.lastname: Faßbender
authors.forename: Andreas
authors.initials: A
authors.lastname: Reimann
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeibig
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lohse
authors.forename: Götz
authors.initials: G
authors.lastname: Münch
authors.forename: Martin
authors.initials: M
authors.lastname: Ungerer
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001323:Autoantibodies; D006332:Cardiomegaly / Q000209:etiology* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006111:Graves Disease / Q000209:etiology* / Q000276:immunology; D007114:Immunization; D051379:Mice; D011989:Receptors, Thyrotropin / Q000276:immunology*; D013610:Tachycardia / Q000209:etiology* / Q000276:immunology; D013974:Thyroxine / Q000097:blood
chemical_list: D001323:Autoantibodies; D011989:Receptors, Thyrotropin; D013974:Thyroxine