RRC ID |
2039
|
著者 |
Nagayama Y, Mizuguchi H, Hayakawa T, Niwa M, McLachlan SM, Rapoport B.
|
タイトル |
Prevention of autoantibody-mediated Graves'-like hyperthyroidism in mice with IL-4, a Th2 cytokine.
|
ジャーナル |
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.
|
巻・号 |
170(7)
|
ページ |
3522-7
|
公開日 |
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
|
引用数 |
75
|
WOS 分野
|
IMMUNOLOGY
|
リソース情報 |
遺伝子材料 |
pBluescript KS+mIL4 (RDB01473) |