Pharmacological modulation of T cell immunity results in long-term remission of autoimmune arthritis

Proc Natl Acad Sci U S A. 2021 May 11;118(19):e2100939118. doi: 10.1073/pnas.2100939118.

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 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.

Keywords: DNA-methylation inhibitor; autoimmunity; indoleamine 2,3-dioxygenase; rheumatoid arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / immunology
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / metabolism
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / metabolism
  • Autoimmune Diseases / drug therapy*
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism
  • DNA Demethylation / drug effects
  • Decitabine / pharmacology*
  • Equilibrative Nucleoside Transporter 1 / genetics
  • Equilibrative Nucleoside Transporter 1 / immunology
  • Equilibrative Nucleoside Transporter 1 / metabolism
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Remission Induction
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • Th1 Cells / cytology
  • Th1 Cells / drug effects*
  • Th1 Cells / immunology
  • Th17 Cells / cytology
  • Th17 Cells / drug effects*
  • Th17 Cells / immunology

Substances

  • Equilibrative Nucleoside Transporter 1
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • SLC29A1 protein, mouse
  • Decitabine