Amelioration of progressive autoimmune encephalomyelitis by epigenetic regulation involves selective repression of mature neutrophils during the preclinical phase.

We have recently demonstrated that treatment of NOD mice with the epigenetic drug Trichostatin A (TSA) ameliorated myelin peptide induced progressive experimental autoimmune encephalomyelitis (P-EAE). Protection was accompanied by induction of antigen-specific T-cell tolerance in the periphery and reduced influx of T cells into the spinal cord. In this investigation, we examined whether the epigenetic drug could impact the innate immune system as well. Whereas the mature (MHC class II) CD11bLy-6G neutrophils expanded substantially in the peripheral lymphoid compartment during the preclinical phase, the MHC class II, CD11bLy-6C mature monocytes increased modestly throughout the disease course. Amelioration of the clinical disease by TSA treatment was accompanied by diminished abundance of CD11bLy-6G activated neutrophils in secondary lymphoid organs and their influx into the spinal cord without affecting monocytes. Interestingly, the co-inhibitory ligand CD274 (PD-L1) but not CD275 (ICOS-L), CD39 or CD11c dendritic cells were decreased in the peripheral lymphoid compartment of drug treated mice. Thus, in addition to myelin-specific T cell tolerance induction observed previously, selective repression of mature neutrophils and PD-L1 cells is critically involved in the epigenetic regulation of P-EAE.