期刊
ISCIENCE
卷 24, 期 12, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.isci.2021.103509
关键词
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资金
- Walter and Eliza Hall Institute of Medical Research Indigenous Fund
- H&L Hecht Trust, Perpetual Trustees [A11/00131]
- Reid Charitable Trusts
- National Health and Medical Research Council of Australia [1113577, 1176553, 1137739, 1154325]
- Victorian State Government
- Mathison Centenary Fellowship, University of Melbourne
- Walter and Eliza Hall Institute of Medical Research
- National Health and Medical Research Council of Australia [1176553] Funding Source: NHMRC
The study revealed immunomodulatory effects of HCQ in CD4 T-cells and antigen-presenting cells, suggesting its potential repurposing for diseases like celiac disease.
Although hydroxychloroquine (HCQ) has long been used to treat autoimmune diseases, its mechanism of action remains poorly understood. In CD4 T-cells, we found that a clinically relevant concentration of HCQ inhibited the mitochondrial antioxidant system triggered by TCR crosslinking, leading to increasedmitochon-drial superoxide, impaired activation-induced autophagic flux, and reduced proliferation of CD4 T-cells. In antigen-presenting cells, HCQ also reduced constitutive activation of the endo-lysosomal protease legumain and toll-like receptor 9, thereby reducing cytokine production, but it had little apparent impact on constitutive antigen processing and peptide presentation. HCQ's effects did not require endo-lysosomal pH change, nor impaired autophagosome-lysosome fusion. We explored the clinical relevance of these findings in patients with celiac disease-a prototypic CD4 T-cell-mediated disease-and found that HCQ limit sex vivo antigen-specific T cell responses. We report a T-cell-intrinsic immunomodulatory effect from HCQ and suggest potential re-purposing of HCQ for celiac disease.
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