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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI058190-01A3
Application #
7037820
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Esch, Thomas R
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
1
Fiscal Year
2006
Total Cost
$383,023
Indirect Cost
Name
University of Illinois at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Bhattacharya, Palash; Thiruppathi, Muthusamy; Elshabrawy, Hatem A et al. (2015) GM-CSF: An immune modulatory cytokine that can suppress autoimmunity. Cytokine 75:261-71
Thiruppathi, Muthusamy; Sheng, Jian Rong; Li, Liangcheng et al. (2014) Recombinant IgG2a Fc (M045) multimers effectively suppress experimental autoimmune myasthenia gravis. J Autoimmun 52:64-73
Gopisetty, Anupama; Bhattacharya, Palash; Haddad, Christine et al. (2013) OX40L/Jagged1 cosignaling by GM-CSF-induced bone marrow-derived dendritic cells is required for the expansion of functional regulatory T cells. J Immunol 190:5516-25
Thiruppathi, Muthusamy; Rowin, Julie; Ganesh, Balaji et al. (2012) Impaired regulatory function in circulating CD4(+)CD25(high)CD127(low/-) T cells in patients with myasthenia gravis. Clin Immunol 145:209-23
Thiruppathi, Muthusamy; Rowin, Julie; Li Jiang, Qin et al. (2012) Functional defect in regulatory T cells in myasthenia gravis. Ann N Y Acad Sci 1274:68-76
Rowin, Julie; Thiruppathi, Muthusamy; Arhebamen, Ebinehita et al. (2012) Granulocyte macrophage colony-stimulating factor treatment of a patient in myasthenic crisis: effects on regulatory T cells. Muscle Nerve 46:449-53
Sheng, Jian Rong; Muthusamy, Thiruppathi; Prabhakar, Bellur S et al. (2011) GM-CSF-induced regulatory T cells selectively inhibit anti-acetylcholine receptor-specific immune responses in experimental myasthenia gravis. J Neuroimmunol 240-241:65-73
Ganesh, Balaji B; Bhattacharya, Palash; Gopisetty, Anupama et al. (2011) IL-1ýý promotes TGF-ýý1 and IL-2 dependent Foxp3 expression in regulatory T cells. PLoS One 6:e21949
Bhattacharya, Palash; Gopisetty, Anupama; Ganesh, Balaji B et al. (2011) GM-CSF-induced, bone-marrow-derived dendritic cells can expand natural Tregs and induce adaptive Tregs by different mechanisms. J Leukoc Biol 89:235-49
Ganesh, Balaji B; Bhattacharya, Palash; Gopisetty, Anupama et al. (2011) Role of cytokines in the pathogenesis and suppression of thyroid autoimmunity. J Interferon Cytokine Res 31:721-31

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