Pharmacological modulation of T cell immunity results in long-term remission of autoimmune arthritis.
Proc Natl Acad Sci U S A
; 118(19)2021 05 11.
Article
in En
| MEDLINE
| ID: mdl-33941676
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Arthritis, Experimental
/
Arthritis, Rheumatoid
/
Autoimmune Diseases
/
T-Lymphocytes, Regulatory
/
Th1 Cells
/
Th17 Cells
/
Decitabine
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2021
Document type:
Article
Affiliation country:
Country of publication: