Inositol kinase Itpkb is a novel therapeutic target for chronic graft versus host disease (cGVHD)

Abstract

Abstract Chronic graft versus host disease (cGVHD) is a common and life-threatening complication of allogeneic hematopoietic stem cell transplantation. cGVHD is mediated by donor T cells recognizing and attacking host tissues followed by activation of effector cells such as B cells to product pathogenic autoantibodies and macrophages to mediate fibrotic responses. Safer and more effective therapies are needed for cGVHD treatment. Inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) is a Ca2+ dependent kinase downstream of lymphocyte receptor signaling that regulates T and B cell homeostasis and function by controlling the intracellular Ca2+ level, thus regulating apoptotic responses. Genetic deletion of Itpkb results in apoptosis. GNF362, a LMW Itpkb inhibitor blocks T cell driven autoimmunity. In this study, we explore the role of Itpkb in cGVHD pathogenesis and hypothesize that cGVHD can be prevented by disrupting the Itpkb signaling pathway. We test the hypothesis in two preclinical cGVHD models with distinct clinical manifestations and pathophysiology, including a multi-organ system cGVHD mouse model that is characterized by bronchiolitis obliterans (BO) driven by spontaneous germinal center reactions and antibody deposition, and a scleroderma model that is characterized by macrophage infiltration and skin fibrosis. This study demonstrates that depleting Itpkb in donor T cells, but not in donor bone marrow blocked cGVHD lung disease and germinal center reaction in the BO model. In addition, pharmaceutical inhibition of Itpkb with GNF362 significantly reduced cGVHD manifestations in both models. These data identify Itpkb as an essential mediator of cGVHD pathogenesis and suggest Itpkb inhibition as a novel approach to treat cGVHD.