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- W4313356593 abstract "Abstract Oral antigen administration results in systemic hyporesponsiveness to a subsequent challenge with the fed antigen (oral tolerance) and has been shown to inhibit autoimmune disease in multiple animal models. However, transfer of this strategy to the clinics has not yet been achieved. Our aim is to better understand mechanisms implicated in the generation of Th3 cells and oral tolerance in order to enhance oral tolerance induction for a use in the clinics. Low dose oral tolerance depends on the presence of Th3 type Tregs, characterized by surface expression of latent TGF-beta (LAP and TGF-beta) and its adapter protein GARP (LRRC32). We established an in vitro system to induce Th3 like cells that express LAP and GARP on their surface. In vitro induced CD4+LAP+ T cells suppress proliferation of naïve T cells and production of IL-17A by Th17 cells. RT- PCR showed that membrane bound TGF-beta correlated with mRNA transcription levels of GARP but not TGF-beta, suggesting that the availability of GARP directly limits the expression of membrane bound TGF-beta. We used this in vitro system to screen for molecules that modulate generation of Th3 like cells and identified IL-6 as a potent inhibitor of membrane TGF-beta. IL-6 inhibited transcription of GARP in a STAT3 dependent manner. To test the therapeutic potential of targeting IL-6R signaling additionally to oral tolerance induction we assessed the DTH (delayed-type hypersensitivity) response in wild-type or CD4CreIL6Rafl/fl mice after feeding with ovalbumin for 5 consecutive days. Importantly, oral tolerance was significantly improved in mice that lack IL-6R signaling in CD4+ T cells. This demonstrates that blocking of IL-6R signaling is a promising approach to enhance oral tolerance induction." @default.
- W4313356593 created "2023-01-06" @default.
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- W4313356593 date "2016-05-01" @default.
- W4313356593 modified "2023-10-16" @default.
- W4313356593 title "IL-6R signaling inhibits generation of Th3 cells and is a promising therapeutic target for enhancing oral tolerance induction" @default.
- W4313356593 doi "https://doi.org/10.4049/jimmunol.196.supp.139.5" @default.
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