Precision DNA demethylation ameliorates disease in lupus-prone mice

JCI Insight. 2018 Aug 23;3(16):e120880. doi: 10.1172/jci.insight.120880.

Abstract

Defective DNA methylation in T cells leads to a series of T cell abnormalities in lupus; however, the full effect of T cell lineage-specific DNA methylation on disease expression has not been explored. Here, we show that 5-azacytidine, a DNA methyltransferase inhibitor, targeted to either CD4 or CD8 T cells in mice with established disease using a nanolipogel delivery system dramatically ameliorates lupus-related pathology through distinct mechanisms. In vivo targeted delivery of 5-azacytidine into CD4 T cells favors the expansion and function of Foxp3+ Tregs, whereas targeted delivery to CD8 T cells enhances the cytotoxicity and restrains the expansion of pathogenic TCR-αβ+CD4-CD8- double-negative T cells. Our results signify the importance of cell-specific inhibition of DNA methylation in the treatment of established lupus.

Keywords: Autoimmunity; Cellular immune response; Lupus; T cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Azacitidine / administration & dosage*
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • DNA Methylation / drug effects*
  • DNA Methylation / immunology
  • DNA Modification Methylases / antagonists & inhibitors
  • Disease Models, Animal
  • Epigenesis, Genetic / drug effects
  • Epigenesis, Genetic / immunology
  • Female
  • Humans
  • Immunoconjugates / chemistry
  • Lupus Erythematosus, Systemic / drug therapy*
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology
  • Mice
  • Mice, Transgenic
  • Nanoconjugates / chemistry*
  • Treatment Outcome

Substances

  • Immunoconjugates
  • Nanoconjugates
  • DNA Modification Methylases
  • Azacitidine