TY - JOUR
T1 - Inhibition of inositol kinase B controls acute and chronic graft-versus-host disease
AU - Thangavelu, Govindarajan
AU - Du, Jing
AU - Paz, Katelyn G.
AU - Loschi, Michael
AU - Zaiken, Michael C.
AU - Flynn, Ryan
AU - Taylor, Patricia A.
AU - Kirchmeier, Andrew Kemal
AU - Panoskaltsis-Mortari, Angela
AU - Luznik, Leo
AU - MacDonald, Kelli P.
AU - Hill, Geoffrey R.
AU - Maillard, Ivan
AU - Munn, David H.
AU - Serody, Jonathan S.
AU - Murphy, William J.
AU - Miklos, David
AU - Cutler, Corey S.
AU - Koreth, John
AU - Antin, Joseph H.
AU - Soiffer, Robert J.
AU - Ritz, Jerome
AU - Dahlberg, Carol
AU - Miller, Andrew T.
AU - Blazar, Bruce R.
N1 - Publisher Copyright:
© 2020 by The American Society of Hematology.
PY - 2020
Y1 - 2020
N2 - T-cell activation releases inositol 1,4,5-trisphosphate (IP3), inducing cytoplasmic calcium (Ca21) influx. In turn, inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) phosphorylates IP3 to negatively regulate and thereby tightly control Ca21 fluxes that are essential for mature T-cell activation and differentiation and protection from cell death. Itpkb pathway inhibition increases intracellular Ca21, induces apoptosis of activated T cells, and can control T-cell–mediated autoimmunity. In this study, we employed genetic and pharmacological approaches to inhibit Itpkb signaling as a means of controlling graft-versus-host disease (GVHD). Murine-induced, Itpkb-deleted (Itpkb2/2) T cells attenuated acute GVHD in 2 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 2 acute myeloid leukemia lines (MLL-AF9-eGFP and C1498-luciferase). Compared with FK506, GNF362 more selectively deleted donor alloreactive vs nominal antigen-responsive T cells. Consistent with these data and as compared with FK506, GNF362 had favorable acute GVHD and GVL properties against MLL-AF9-eGFP cells. In chronic GVHD preclinical models that have a pathophysiology distinct from acute GVHD, Itpkb2/2 donor T cells reduced active chronic GVHD in a multiorgan system model of bronchiolitis obliterans (BO), driven by germinal center reactions and resulting in target organ fibrosis. GNF362 treatment reduced active chronic GVHD in both BO and scleroderma models. Thus, intact Itpkb signaling is essential to drive acute GVHD pathogenesis and sustain active chronic GVHD, pointing toward a novel clinical application to prevent acute or treat chronic GVHD.
AB - T-cell activation releases inositol 1,4,5-trisphosphate (IP3), inducing cytoplasmic calcium (Ca21) influx. In turn, inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) phosphorylates IP3 to negatively regulate and thereby tightly control Ca21 fluxes that are essential for mature T-cell activation and differentiation and protection from cell death. Itpkb pathway inhibition increases intracellular Ca21, induces apoptosis of activated T cells, and can control T-cell–mediated autoimmunity. In this study, we employed genetic and pharmacological approaches to inhibit Itpkb signaling as a means of controlling graft-versus-host disease (GVHD). Murine-induced, Itpkb-deleted (Itpkb2/2) T cells attenuated acute GVHD in 2 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 2 acute myeloid leukemia lines (MLL-AF9-eGFP and C1498-luciferase). Compared with FK506, GNF362 more selectively deleted donor alloreactive vs nominal antigen-responsive T cells. Consistent with these data and as compared with FK506, GNF362 had favorable acute GVHD and GVL properties against MLL-AF9-eGFP cells. In chronic GVHD preclinical models that have a pathophysiology distinct from acute GVHD, Itpkb2/2 donor T cells reduced active chronic GVHD in a multiorgan system model of bronchiolitis obliterans (BO), driven by germinal center reactions and resulting in target organ fibrosis. GNF362 treatment reduced active chronic GVHD in both BO and scleroderma models. Thus, intact Itpkb signaling is essential to drive acute GVHD pathogenesis and sustain active chronic GVHD, pointing toward a novel clinical application to prevent acute or treat chronic GVHD.
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U2 - 10.1182/blood.2019000032
DO - 10.1182/blood.2019000032
M3 - Article
C2 - 31697815
AN - SCOPUS:85077477653
SN - 0006-4971
VL - 135
SP - 28
EP - 40
JO - Blood
JF - Blood
IS - 1
ER -