PRMT5 Identified as Potential GVHD Treatment Target

Previously, Katiri Snyder and colleagues determined that the enzyme protein arginine methyltransferase 5 (PRMT5) was upregulated in acute graft-versus-host disease (aGVHD) and that PRMT5 inhibition ameliorated T-cell-mediated inflammation without compromising graft-versus-leukemia activity of allogeneic hematopoietic cell transplantation. They further established that prohibitin is a binding partner for PRMT5.

In a subsequent study, the team evaluated the enzymatic mechanism of PRMT5 on prohibitin that leads PRMT5 to mediate T-cell inflammatory responses in aGVHD. Snyder presented the study at the 64th ASH Annual Meeting and Exposition and reported that prohibitin was symmetrically demethylated by PRMT5 in human T cells and that prohibitin inhibitor treatment in a murine modeled impaired differentiation into inflammatory cell subtypes.

Researchers Identify Potential Inflammation-Related Target in aGVHD

In addition, Snyder and researchers found surface expression of prohibitin was increased upon activation in human T cells in vitro. The team also noted that prohibit-expressing splenic T cells generated interferon gamma (IFNγ) and interleukin (IL)-17, inflammatory cytokines from Th17 and T helper cell 1 (Th1) cells.

In the murine model, prohibitin inhibition reduced IL-17 secretion and downregulation of Il17a, Il17f, and Il22 genes. Furthermore, PRMT5-depleted murine T cells showed reduced prohibitin transcription upon activation compared with T-cell controls.

Taken together, the authors concluded their findings “link PRMT5 and [prohibitin], show relevancy of [prohibitin] in Th1- and Th17-mediated inflammation, and suggest a potential role for the PRMT5-[prohibitin] axis in acute GVHD.”

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