Huang, YS;
Tseng, WY;
Clanchy, FIL;
Topping, LM;
Ogbechi, J;
McNamee, K;
Perocheau, D;
... Williams, RO; + view all
(2021)
Pharmacological modulation of T cell immunity results in long-term remission of autoimmune arthritis.
Proceedings of the National Academy of Sciences of the United States of America
, 118
(19)
, Article e2100939118. 10.1073/pnas.2100939118.
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Abstract
Chronic inflammatory diseases like rheumatoid arthritis are characterized by a deficit in fully functional regulatory T cells. DNAmethylation inhibitors have previously been shown to promote regulatory T cell responses and, in the present study, we evaluated their potential to ameliorate chronic and acute animal models of rheumatoid arthritis. Of the drugs tested, decitabine was the most effective, producing a sustained therapeutic effect that was dependent on indoleamine 2,3-dioxygenase (IDO) and was associated with expansion of induced regulatory T cells, particularly at the site of disease activity. Treatment with decitabine also caused apoptosis of Th1 and Th17 cells in active arthritis in a highly selective manner. The molecular basis for this selectivity was shown to be ENT1, a nucleoside transporter, which facilitates intracellular entry of the drug and is upregulated on effector T cells during active arthritis. It was further shown that short-term treatment with decitabine resulted in the generation of a population of regulatory T cells that were able to suppress arthritis upon adoptive transfer. In summary, a therapeutic approach using an approved drug is described that treats active inflammatory disease effectively and generates robust regulatory T cells with the IDO-dependent capacity to maintain remission.
| Type: | Article |
|---|---|
| Title: | Pharmacological modulation of T cell immunity results in long-term remission of autoimmune arthritis |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1073/pnas.2100939118 |
| Publisher version: | http://dx.doi.org/10.1073/pnas.2100939118 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, autoimmunity, DNA-methylation inhibitor, rheumatoid arthritis, indoleamine 2, 3-dioxygenase, RHEUMATOID-ARTHRITIS, UPSTREAM ENHANCER, FOXP3, METHYLATION, EXPRESSION, INDUCTION, INTERLEUKIN-2, EXPANSION, CTLA-4, BETA |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10196654 |
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