4.6 Article

Absence of IL-4, and not suppression of the Th2 response, prevents development of experimental autoimmune Graves' disease

Journal

JOURNAL OF IMMUNOLOGY
Volume 170, Issue 4, Pages 2195-2204

Publisher

AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.170.4.2195

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Funding

  1. NIDDK NIH HHS [DK 47417, DK 44972, DK 57938] Funding Source: Medline

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In autoimmune Graves' disease (GD), autoantibodies bind to the thyrotropin receptor (TSHR) and cause hyperthyroidism. We studied the effects of fins-like tyrosine kinase receptor 3 ligand (Flt3-L) or GM-CSF treatment on the development of experimental autoimmune GD (EAGD) in mice, a slowly progressing Ab-mediated organ-specific autoimmune disease of the thyroid induced by immunization with syngeneic cells expressing TSHR. Flt3-L and GM-CSF treatment resulted in up-regulation of CD8a(+) and CD8a(-) dendritic cells, and skewing of cytokine and immune responses to TSHR in favor of Th1 and Th2, respectively. However, this skewing did not persist until the later stages, and thus failed to affect the course or severity of the disease. To determine whether the total absence of either IL-4 or IFN-gamma could affect the development of EAGD, we immunized wild-type, IFN-gamma(-/-) and IL-4(-/-) BALB/c mice with TSHR. Nearly 100% of the wild-type and IFN-gamma(-/-) mice developed EAGD with optimal TSHR-specific immune responses, while IL-4-/- mice completely resisted disease and showed delayed and suboptimal pathogenic Ab response. These data demonstrated that skewing immune responses to TSHR, using either Flt3-L or GM-CSF, in favor of Th1 or Th2, respectively, may not be sufficient to alter the course of the disease, while the complete absence of IL-4, but not IFN-gamma, can prevent the development of EAGD.

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