Targeting PI3Kδ function for amelioration of murine chronic graft-versus-host disease.
Paz K, Flynn R, Du J, Tannheimer S, Johnson AJ, Dong S, Stark AK, Okkenhaug K, Panoskaltsis-Mortari A, Sage PT, Sharpe AH, Luznik L, Ritz J, Soiffer RJ, Cutler CS, Koreth J, Antin JH, Miklos DB, MacDonald KP, Hill GR, Maillard I, Serody JS, Murphy WJ, Munn DH, Feser C, Zaiken M, Vanhaesebroeck B, Turka LA, Byrd JC, Blazar BR
Am J Transplant in press 02/12/2019
Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality following allotransplant. Activated donor effector T cells can differentiate into pathogenic T helper (Th)-17 cells and germinal center (GC)-promoting T follicular helper (Tfh) cells, resulting in cGVHD. Phosphoinositide-3-kinase-δ (PI3Kδ), a lipid kinase, is critical for activated T cell survival, proliferation, differentiation, and metabolism. We demonstrate PI3Kδ activity in donor T cells that become Tfh cells is required for cGVHD in a nonsclerodermatous multiorgan system disease model that includes bronchiolitis obliterans (BO), dependent upon GC B cells, Tfhs, and counterbalanced by T follicular regulatory cells, each requiring PI3Kδ signaling for function and survival. Although B cells rely on PI3Kδ pathway signaling and GC formation is disrupted resulting in a substantial decrease in Ig production, PI3Kδ kinase-dead mutant donor bone marrow-derived GC B cells still supported BO cGVHD generation. A PI3Kδ-specific inhibitor, compound GS-649443, that has superior potency to idelalisib while maintaining selectivity, reduced cGVHD in mice with active disease. In a Th1-dependent and Th17-associated scleroderma model, GS-649443 effectively treated mice with active cGVHD. These data provide a foundation for clinical trials of US Food and Drug Administration (FDA)-approved PI3Kδ inhibitors for cGVHD therapy in patients.Full Text