Methimazole protects from experimental autoimmune uveitis (EAU) by inhibiting antigen presenting cell function and reducing antigen priming.
Methimazole (methyl-mercapto-imidazole, MMI), a compound used clinically in therapy of Graves' thyroiditis, was found to inhibit development of several autoimmune diseases in animal models. It was suggested on the basis of in vitro data that inhibition is through down-regulation of interferon-gamma (IFN-gamma)-induced expression of major histocompatibility complex class I and class II molecules. Here, we investigate the effect of MMI on experimental autoimmune uveoretinitis (EAU) and study its mechanism(s). Treatment of EAU with MMI administered in drinking water inhibited induction of the disease and associated antigen (Ag)-specific proliferation and cytokine production by draining lymph node cells (LNCs). The treatment was protective only if administered during the first but not during the second week after immunization, suggesting an effect on the induction phase of EAU. It is interesting that MMI inhibited disease in IFN-gamma knockout mice, indicating that the in vivo protective effect is IFN-gamma-independent. Flow cytometric analysis of draining LNCs extracted 5 days after immunization showed that MMI partly to completely reversed the increase in Mac-1(+)/class I(+)/class II(+) cells induced by immunization and reduced the proportion of B7-1 and CD40-positive cells, suggesting a deficit in the Ag-presenting cell (APC) population. APC from untreated mice largely restored antigen-specific proliferation of MMI-treated LNCs. We suggest that MMI inhibits EAU at least in part by preventing the recruitment and/or maturation of APC, resulting in reduced generation of Ag-specific T cells.
Wang
Peng
P
Laboratory of Immunology, NEI/NIH, 10 Center Drive, Bethesda, MD 20892, USA.
Sun
Shu-Hui
SH
Silver
Phyllis B
PB
Chan
Chi-Chao
CC
Agarwal
Rajeev K
RK
Wiggert
Barbara
B
Kohn
Leonard D
LD
Jamieson
Gordon A
GA
Caspi
Rachel R
RR
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D000938:Antigen-Presenting Cells / Q000187:drug effects; D013956:Antithyroid Agents / Q000276:immunology / Q000494:pharmacology*; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000517:prevention & control*; D016207:Cytokines / Q000032:analysis / Q000187:drug effects; D004195:Disease Models, Animal; D005136:Eye Proteins; D005260:Female; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology; D008198:Lymph Nodes / Q000166:cytology; D016177:Macrophage-1 Antigen / Q000032:analysis / Q000187:drug effects; D008713:Methimazole / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012173:Retinitis / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D012177:Retinol-Binding Proteins / Q000008:administration & dosage / Q000276:immunology; D014605:Uveitis / Q000188:drug therapy / Q000276:immunology* / Q000517:prevention & control*; D000099214:Retinol-Binding Proteins, Interstitial
D013956:Antithyroid Agents; D016207:Cytokines; D005136:Eye Proteins; D007371:Interferon-gamma; D016177:Macrophage-1 Antigen; D008713:Methimazole; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial