Thangavelu, Govindarajan, Du, Jing, Paz, Katelyn, Loschi, Michael, Flynn, Ryan, Taylor, Patricia, Kirchmeier, Andrew, Zaiken, Micheal, Panoskaltsis-Mortari, Angela, Luznik, Leo, MacDonald, Kelli, Hill, Geoffrey, Maillard, Ivan, Munn, David, Serody, Jonathan, Murphy, William, Miklos, David, Cutler, Corey, Koreth, John, Antin, Joseph, Soiffer, Robert, Ritz, Jerome, Dahlberg-Bohl, Carol, Miller, Andrew and Blazar, Bruce (2019) Inhibition of Inositol kinase B controls acute and chronic graft-versus-host disease. Blood. ISSN 15280020

Abstract

T-cell activation releases inositol 1,4,5-trisphosphate (IP3), inducing cytoplasmic calcium (Ca2+) influx. In turn, inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) phosphorylates IP3 to negatively regulate and thereby tightly control Ca2+ fluxes that are essential for mature T-cell activation, differentiation and protection from cell death. Itpkb pathway inhibition increases intracellular Ca2+, induces apoptosis of activated T-cells, and can control T-cell mediated autoimmunity. Here, we employed genetic and pharmacological approaches to inhibit Itpkb signaling as a means of controlling graft-versus-host disease (GVHD). Murine induced Itpkb deleted (Itpkb-/-) T-cells had attenuated acute GVHD in two models without eliminating A20-luciferase B-cell lymphoma graft-versus-leukemia (GVL). A highly potent, selective inhibitor, GNF362, ameliorated acute GVHD without impairing GVL against two acute myeloid leukemia lines (MLL-AF9-eGFP; C1498-luciferase). Compared to FK506, GNF362 more selectively deleted donor alloreactive versus nominal antigen responsive T-cells. Consistent with these data and as compared to FK506, GNF362 had favorable acute GVHD and GVL properties against MLL-AF9-eGFP cells. In chronic GVHD preclinical models that have a distinct pathophysiology from acute GVHD, Itpkb-/- donor T-cells reduced active chronic GVHD in a multi-organ system model with bronchiolitis obliterans (BO) driven by germinal center reactions, resulting in target organ fibrosis. GNF362 treatment reduced active chronic GVHD in both BO and scleroderma models. Thus, intact Itpkb signaling is required to drive acute GVHD pathogenesis and sustain active chronic GVHD, pointing toward a novel clinical application to prevent acute or treat chronic GVHD.

Item Type:	Article
Date Deposited:	03 Dec 2019 00:45
Last Modified:	03 Dec 2019 00:45
URI:	https://oak.novartis.com/id/eprint/38848