Acute Graft-Versus-Host Disease (aGVHD) is a T cell mediated immunological disorder and the leading cause of non-relapse mortality in patients who receive allogeneic hematopoietic cell transplants. Based on recent observations that PRMT5 and arginine methylation is upregulated in activated memory T cells, we hypothesized that PRMT5 is involved in the pathogenesis of aGVHD. Here, we show that PRMT5 expression and enzymatic activity is upregulated in activated T cells in vitro and in T cells from mice developing aGVHD after allogeneic transplant. PRMT5 expression is also upregulated in T cells of patients who developed aGVHD after allogeneic hematopoietic cell transplant compared to those who did not develop aGVHD.PRMT5 inhibition using a selective small-molecule inhibitor (C220) significantly reduces mouse and human allogeneic T cell proliferation and inflammatory IFN-γ and IL-17 cytokine production. Administration of PRMT5 small-molecule inhibitors significantly improves survival, reducing disease incidence and clinical severity in mouse models of aGVHD without adversely affecting engraftment. Importantly, we show that PRMT5 inhibition retains the beneficial graft versus leukemia (GVL) effect by maintaining cytotoxic CD8 T cell responses. Mechanistically, we show that PRMT5 inhibition potently reduces STAT-1 phosphorylation as well as transcription of pro-inflammatory genes including Interferon Stimulated Genes (ISG) and IL-17. Additionally, PRMT5 inhibition deregulates cell-cycle in activated T cells and disrupts signaling by impacting ERK1/2 phosphorylation. Thus, we have identified PRMT5 as a regulator of T cell responses and as a therapeutic target in aGVHD.
Katiri Snyder, Nina C. Zitzer, Yandi Gao, Hannah K. Choe, Natalie E. Sell, Lotus Neidemire-Colley, Anora Ignaci, Charuta Kale, Raymond D. Devine, Maria G. Abad, Maciej Pietrzak, Min Wang, Hong Lin, Yang W. Zhang, Gregory K. Behbehani, Jane E. Jackman, Ramiro Garzon, Kris Vaddi, Robert A. Baiocchi, Parvathi Ranganathan