title: Critical Differences between Induced and Spontaneous Mouse Models of Graves' Disease with Implications for Antigen-Specific Immunotherapy in Humans.
abstract: Graves' hyperthyroidism, a common autoimmune disease caused by pathogenic autoantibodies to the thyrotropin (TSH) receptor (TSHR), can be treated but not cured. This single autoantigenic target makes Graves' disease a prime candidate for Ag-specific immunotherapy. Previously, in an induced mouse model, injecting TSHR A-subunit protein attenuated hyperthyroidism by diverting pathogenic TSHR Abs to a nonfunctional variety. In this study, we explored the possibility of a similar diversion in a mouse model that spontaneously develops pathogenic TSHR autoantibodies, NOD.H2h4mice with the human (h) TSHR (hTSHR) A-subunit transgene expressed in the thyroid and (shown in this article) the thymus. We hypothesized that such diversion would occur after injection of "inactive" hTSHR A-subunit protein recognized only by nonpathogenic (not pathogenic) TSHR Abs. Surprisingly, rather than attenuating the pre-existing pathogenic TSHR level, in TSHR/NOD.H2h4mice inactive hTSHR Ag injected without adjuvant enhanced the levels of pathogenic TSH-binding inhibition and thyroid-stimulating Abs, as well as nonpathogenic Abs detected by ELISA. This effect was TSHR specific because spontaneously occurring autoantibodies to thyroglobulin and thyroid peroxidase were unaffected. As controls, nontransgenic NOD.H2h4mice similarly injected with inactive hTSHR A-subunit protein unexpectedly developed TSHR Abs, but only of the nonpathogenic variety detected by ELISA. Our observations highlight critical differences between induced and spontaneous mouse models of Graves' disease with implications for potential immunotherapy in humans. In hTSHR/NOD.H2h4mice with ongoing disease, injecting inactive hTSHR A-subunit protein fails to divert the autoantibody response to a nonpathogenic form. Indeed, such therapy is likely to enhance pathogenic Ab production and exacerbate Graves' disease in humans.
authors.affiliation: Thyroid Autoimmune Disease Unit, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, CA 90048; and.
authors.forename: Basil
authors.initials: B
authors.lastname: Rapoport
authors.affiliation: Thyroid Autoimmune Disease Unit, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, CA 90048; and.
authors.forename: Bianca
authors.initials: B
authors.lastname: Banuelos
authors.affiliation: Thyroid Autoimmune Disease Unit, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, CA 90048; and.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Aliesky
authors.affiliation: Department of Autoimmunology and Biomarkers, Statens Serum Institut, DK-2300 Copenhagen S, Denmark.
authors.forename: Nicole
authors.identifier: 0000-0003-1548-2009
authors.initials: N
authors.lastname: Hartwig Trier
authors.affiliation: Thyroid Autoimmune Disease Unit, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, CA 90048; and mclachlans@cshs.org.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: McLachlan
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D015292:Glycoprotein Hormones, alpha Subunit / Q000276:immunology / Q000378:metabolism; D006111:Graves Disease / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D006801:Humans; D007167:Immunotherapy / Q000379:methods* / Q000639:trends; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism*; D013961:Thyroid Gland / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D015292:Glycoprotein Hormones, alpha Subunit; D011989:Receptors, Thyrotropin