Prevention of Autoantibody-Mediated Graves’-Like Hyperthyroidism in Mice with IL-4, a Th2 Cytokine

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-γ 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-γ 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.

Schistosoma mansoni and α-Galactosylceramide: Prophylactic Effect of Th1 Immune Suppression in a Mouse Model of Graves’ Hyperthyroidism

“…Similar data have been obtained in our recent study (3), showing prevention of Graves' hyperthyroidism by transient expression of IL-4 by adenovirus at the time of Ag presentation. Thus, suppression of the Ag-specific Th1 immune response appears to be crucial to prevent the development of a pathogenic anti-TSHR immune response, but may not be able to revert a fully activated anti-TSHR immune response.…”

“…Furthermore, we have also shown that transient coexpression of TSHR and IL-4 by adenovirus induces Th2 deviation of the anti-TSHR immune response and suppresses disease induction. In contrast, coinjection of adenovirus coding IL-12 deviates the anti-TSHR immune response to Th1 without affecting disease incidence (3). Thus, Th2 polarization may be beneficial for the control of Graves' disease.…”

“…For instance, in our mouse model involving repeated i.m. injection of adenovirus coding the TSHR (Ad-TSHR) (2), the TSHR Abs induced are of both IgG1 and IgG2a subclasses, and splenocytes produce the Th1 cytokine IFN-␥ in response to in vitro stimulation with TSHR Ag (3). Similarly, Prabhakar et al (4) have found both IgG1 and IgG2a of TSHR Abs and Ag-specific splenocyte secretion of IFN-␥ and the Th2 cytokine IL-4 after injecting M12 B lymphoma cells expressing the TSHR.…”

The clinical and physiological spectrum of interferon-alpha induced thyroiditis: Toward a new classification

“…One clue to this puzzle comes from recent studies by Rapoport and colleagues suggesting that the initiation of GD is likely to be Th1 mediated. 101 In patients with subclinical AITD, it is possible that IFN␣ exacerbates or triggers clinical disease. Indeed, results from our recent study suggest IFN␣ accelerates thy- roiditis in a thyroiditis-prone mouse model, the NODH2h4 mouse.…”

Changes in expression of T-helper (Th) 1- and Th2-associated chemokine receptors on peripheral blood lymphocytes and plasma concentrations of their ligands, interferon-inducible protein-10 and thymus and activation-regulated chemokine, after antithyroid drug administration in hyperthyroid patients with Graves’ disease

“…Graves' disease has long been thought to be an autoantibody-mediated, Th2-dominant autoimmune disease. However, using a model in which mice were injected with adenovirus expressing TSH receptor, Nagayama et al demonstrated that an immune shift toward Th2 was accompanied by a decrease rather than an expected increase in production of thyroid stimulating antibody, which also suggested that predominant Th1 immune responses to TSH receptor are associated with induction of Graves' disease (7). More importantly, human TSH receptor stimulating antibodies (TSAbs) are predominantly immuno-globulin G (IgG)1, a Th1 type subclass in humans (8).…”