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• W4366088085 abstract "Recent clinical trials targeting the OX40-OX40L axis in atopic dermatitis/AD (AMG451, KHK4083, and KY1005) suggest the potential for long-term disease modification. While inflammatory disease models suggest that OX40-OX40L upregulate effector T cell survival and inhibit Foxp3+ Tregs, the mechanism of action remains unelucidated. We assessed OX40 and OX40L expressing cells in skin and blood of AD patients, identifying how they regulate T effectors and Tregs. We evaluated lesional AD samples (n=14) and controls (n=14) using immunohistochemistry/IHC and cultured human keratinocytes in presence of AD-related cytokines (IFN-γ, IL4, IL13, IL17, IL22) to measure TSLP and OX40 expression. We evaluated peripheral blood mononuclear cells/PBMCs from AD patients (n=28) and controls (n=13) by flow cytometry. We performed RNAseq analysis on effector CD4+ Tcells (CD4+CD127+CD25–) and Tregs (CD4+CD25+CD127low) cultured with IL2 or stimulated with anti-CD3/28 in the absence and presence of OX40L from AD patients (n=9) and controls (n=10). IHC showed increased OX40+ and OX40L+ cells, in AD (P<0.001). Keratinocytes cultured with IL-13 significantly upregulated OX40L and TSLP (P<0.001). Flow cytometry characterized cutaneous lymphocyte antigen/CLA + or skin homing CD4+ T cells and CLA+ Tregs as a significant percent of the population expressing OX40 (P<0.0001). CLA+ OX40+ CD4+ Tregs correlated with AD severity/SCORAD (R2=0.311, P<0.05). RNAseq revealed OX40/OX40L interaction maintains the Th2 functionality of circulating effector CD4+ T cells in AD patients but reduces the regulatory capacity of Tregs, as seen with the downregulation of key markers IL10, IL4R, and GZMH (P<0.05). The results indicate skin homing CD4+ T cells and Tregs express OX40 and interact with OX40L in the skin, the axis inhibits Treg’s ability to ameliorate inflammation, and Treg dysfunction correlates with disease severity." @default.
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• W4366088085 date "2023-05-01" @default.
• W4366088085 modified "2023-10-16" @default.
• W4366088085 title "371 The OX40/OX40L axis plays a key role in treg dysfunction in atopic dermatitis" @default.
• W4366088085 doi "https://doi.org/10.1016/j.jid.2023.03.376" @default.
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