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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.

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


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.


Autoimmunity; Cellular immune response; Lupus; T cells

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