RRC ID 2039
Author Nagayama Y, Mizuguchi H, Hayakawa T, Niwa M, McLachlan SM, Rapoport B.
Title Prevention of autoantibody-mediated Graves'-like hyperthyroidism in mice with IL-4, a Th2 cytokine.
Journal J Immunol
Abstract Graves' hyperthyroidism has long been considered to be a Th2-type autoimmune disease because it is directly mediated by autoantibodies against the thyrotropin receptor (TSHR). However, several lines of evidence have recently challenged this concept. The present study evaluated the Th1/Th2 paradigm in Graves' disease using a recently established murine model involving injection of adenovirus expressing the TSHR (AdCMVTSHR). Coinjection with adenovirus expressing IL-4 (AdRGDCMVIL-4) decreased the ratio of Th1/Th2-type anti-TSHR Ab subclasses (IgG2a/IgG1) and suppressed the production of IFN-gamma by splenocytes in response to TSHR Ag. Importantly, immune deviation toward Th2 was accompanied by significant inhibition of thyroid-stimulating Ab production and reduction in hyperthyroidism. However, in a therapeutic setting, injection of AdRGDCMVIL-4 alone or in combination with AdCMVTSHR into hyperthyroid mice had no beneficial effect. In contrast, coinjection of adenoviruses expressing IL-12 and the TSHR promoted the differentiation of Th1-type anti-TSHR immune responses as demonstrated by augmented Ag-specific IFN-gamma secretion from splenocytes without changing disease incidence. Coinjection of adenoviral vectors expressing IL-4 or IL-12 had no effect on the titers of anti-TSHR Abs determined by ELISA or thyroid-stimulating hormone-binding inhibiting Ig assays, suggesting that Ab quality, not quantity, is responsible for disease induction. Our observations demonstrate the critical role of Th1 immune responses in a murine model of Graves' hyperthyroidism. These data may raise a cautionary note for therapeutic strategies aimed at reversing Th2-mediated autoimmune responses in Graves' disease in humans.
Volume 170(7)
Pages 3522-7
Published 2003-4-1
DOI 10.4049/jimmunol.170.7.3522
PMID 12646613
MeSH Adenoviridae / genetics Adenoviridae / immunology Animals Autoantibodies / physiology* COS Cells Disease Models, Animal* Epitopes, T-Lymphocyte / immunology Female Genetic Vectors Graves Disease / immunology* Graves Disease / prevention & control* Humans Immunoglobulins, Thyroid-Stimulating / administration & dosage Immunoglobulins, Thyroid-Stimulating / biosynthesis Immunoglobulins, Thyroid-Stimulating / genetics Injections, Intramuscular Interleukin-12 / biosynthesis Interleukin-12 / genetics Interleukin-4 / administration & dosage Interleukin-4 / biosynthesis Interleukin-4 / genetics Interleukin-4 / therapeutic use* Mice Mice, Inbred BALB C Receptors, Thyrotropin / administration & dosage Receptors, Thyrotropin / biosynthesis Receptors, Thyrotropin / genetics Receptors, Thyrotropin / immunology Th1 Cells / immunology Th1 Cells / metabolism Th2 Cells / immunology* Th2 Cells / metabolism*
IF 4.886
Times Cited 75
DNA material pBluescript KS+mIL4 (RDB01473)