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

Precision DNA demethylation ameliorates disease in lupus-prone mice.

Author information

1
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Biomedical Engineering.
3
Department of Immunobiology, and.
4
Department of Chemical and Environmental Engineering, Yale University School of Medicine, New Haven, Connecticut, USA.

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

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