Pharmacological modulation of T cell immunity results in long-term remission of autoimmune arthritis
(2021) In Proceedings of the National Academy of Sciences of the United States of America 118(19).- Abstract
Chronic inflammatory diseases like rheumatoid arthritis are characterized by a deficit in fully functional regulatory T cells. DNA-methylation 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... (More)
Chronic inflammatory diseases like rheumatoid arthritis are characterized by a deficit in fully functional regulatory T cells. DNA-methylation 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 up-regulated 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.
(Less)
- author
- organization
- publishing date
- 2021-05-11
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- autoimmunity, DNA-methylation inhibitor, indoleamine 2,3-dioxygenase, rheumatoid arthritis
- in
- Proceedings of the National Academy of Sciences of the United States of America
- volume
- 118
- issue
- 19
- publisher
- National Academy of Sciences
- external identifiers
-
- pmid:33941676
- scopus:85105318415
- ISSN
- 1091-6490
- DOI
- 10.1073/pnas.2100939118
- language
- English
- LU publication?
- yes
- id
- d8b2c634-7c00-47e3-8013-58d0e2be886b
- date added to LUP
- 2021-05-19 11:30:01
- date last changed
- 2024-06-16 13:51:27
@article{d8b2c634-7c00-47e3-8013-58d0e2be886b,
abstract = {{<p>Chronic inflammatory diseases like rheumatoid arthritis are characterized by a deficit in fully functional regulatory T cells. DNA-methylation 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 up-regulated 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.</p>}},
author = {{Huang, Yi Shu and Tseng, Wen Yi and Clanchy, Felix I.L. and Topping, Louise M. and Ogbechi, Joy and McNamee, Kay and Perocheau, Dany and Chiang, Nien Yi and Ericsson, Peter and Sundstedt, Anette and Xue, Zhong Tian and Salford, Leif G. and Sjögren, Hans Olov and Stone, Trevor W. and Lin, Hsi Hsien and Luo, Shue Fen and Williams, Richard O.}},
issn = {{1091-6490}},
keywords = {{autoimmunity; DNA-methylation inhibitor; indoleamine 2,3-dioxygenase; rheumatoid arthritis}},
language = {{eng}},
month = {{05}},
number = {{19}},
publisher = {{National Academy of Sciences}},
series = {{Proceedings of the National Academy of Sciences of the United States of America}},
title = {{Pharmacological modulation of T cell immunity results in long-term remission of autoimmune arthritis}},
url = {{http://dx.doi.org/10.1073/pnas.2100939118}},
doi = {{10.1073/pnas.2100939118}},
volume = {{118}},
year = {{2021}},
}