Selective induction of dendritic cells using granulocyte macrophage-colony stimulating factor, but not fms-like tyrosine kinase receptor 3-ligand, activates thyroglobulin-specific CD4+/CD25+ T cells and suppresses experimental autoimmune thyroiditis.
Fms-like tyrosine kinase receptor 3-ligand (Flt3-L) and GM-CSF cause expansion of different subsets of dendritic cells and skew the immune response toward predominantly Th1 and Th2 type, respectively. In the present study, we investigated their effects on experimental autoimmune thyroiditis in CBA/J mice. Relative to mouse thyroglobulin (mTg) immunized controls, mTg-immunized mice treated with Flt3-L showed more severe thyroiditis characterized by enhanced lymphocytic infiltration of the thyroid, and IFN-gamma and IL-2 production. In contrast, mice treated with GM-CSF, either before or after immunization with mTg, showed suppressed T cell response to mTg and failed to develop thyroiditis. Lymphocytes from these mice, upon activation with mTg in vitro, produced higher levels of IL-4 and IL-10. Additionally, GM-CSF-treated mice showed an increase in the frequency of CD4(+)/CD25(+) T cells, which suppressed the mTg-specific T cell response. Neutralization of IL-10, but not IL-4, or depletion of CD4(+)/CD25(+) cells resulted in increased mTg-specific in vitro T cell proliferation suggesting that IL-10 produced by the Ag-specific CD4(+)/CD25(+) regulatory T cells might be critical for disease suppression. These results indicate that skewing immune response toward Th2, through selective activation of dendritic cells using GM-CSF, may have therapeutic potential in Th1 dominant autoimmune diseases including Hashimoto's thyroiditis.
Vasu
Chenthamarakshan
C
Department of Surgery, University of Illinois, Chicago, IL 60612, USA.
Dogan
Rukiye-Nazan E
RN
Holterman
Mark J
MJ
Prabhakar
Bellur S
BS
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000276:immunology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003713:Dendritic Cells / Q000145:classification / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D016753:Interleukin-10 / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D008808:Mice, Inbred CBA; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D011994:Recombinant Proteins; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013954:Thyroglobulin / Q000276:immunology* / Q000494:pharmacology; D013967:Thyroiditis, Autoimmune / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015854:Up-Regulation / Q000276:immunology
D001323:Autoantibodies; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D006131:Growth Inhibitors; D008565:Membrane Proteins; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; C006606:anti-thyroglobulin; C084881:flt3 ligand protein; D016753:Interleukin-10; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013954:Thyroglobulin; D020794:Receptor Protein-Tyrosine Kinases