Experimental Autoimmune Thyroiditis (EAT) is characterized by eventual destruction of thyroid by infiltrating lymphocytes resulting in hypothyroidism. CD4+ T cells that produce IFN-gamma, TNF-alpha and IL-12 are critical for the pathogenesis. In a recent study, we showed that relative to thyroglobulin (mTg) immunized controls, mice treated with Flt3-L developed a more severe EAT characterized by massive thyroid lymphocytic infiltration, and IL-2 and IFN-gamma production. In contrast, GM-CSF treated mice failed to develop EAT, and showed a significant increase in CD4+CD25+ regulatory T cells (Tregs). Activation of lymphocytes from these mice with mTg in vitro yielded higher levels of IL-4 and IL-10. Neutralization of IL-10, but not IL-4, and depletion of Tregs from these cultures restored mTg specific T cell proliferation, and IL-2 and IFN-gamma production. Further, adoptive transfer of Tregs to mTg immunized mice suppressed EAT while, inoculation of anti-IL-10 receptor Ab reversed GM-CSF induced suppression resulting in EAT. These results showed that suppression of EAT was mediated by Tregs most likely through enhanced production of IL-10. Based on these results we hypothesize that """"""""selective activation of CD8a- dendritic cells using GM-CSF can activate CD4+CD25+ regulatory T cells and skew ongoing anti-thyroglobulin immune responses in favor of Th2 type, with consequent suppressive effects on the development and/or, progression of experimental autoimmune thyroiditis."""""""" In Aim-1, efficacy of GM-CSF to confer long-term antigen specific protection upon re-exposure to mTg will be tested.
In Aim -2, we will test the ability of CD8a- and CD8a+ DCs to undergo maturation, capture and present the antigen, and produce cytokines, and determine the mTg specific T cell phenotype and cytokine profiles. Both DCs and T cells will be tested for their ability suppress in vitro and in vivo mTg specific responses in WT and IL-10-/- mice.
In Aim -3, we will test the effects of GM-CSF, DCs and Tregs on the expression of MHC and B7 molecules, ARC function, and sensitivity to Fas induced apoptosis of thyrocytes from WT and SCID mice. These studies will provide significant insights into the mode of action of GM-CSF in suppressing EAT. ? ?
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