Targeting PI3Kδ function for amelioration of murine chronic graft-versus-host disease.

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Paz, Katelyn 
Flynn, Ryan 
Du, Jing 
Tannheimer, Stacey 
Johnson, Amy J 

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.

basic (laboratory) research/science, graft-versus-host disease (GVHD), immunobiology, immunosuppressant - other, Animals, B-Lymphocytes, Bone Marrow Transplantation, Bronchiolitis Obliterans, Chronic Disease, Class I Phosphatidylinositol 3-Kinases, Disease Models, Animal, Graft vs Host Disease, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Phosphoinositide-3 Kinase Inhibitors, Scleroderma, Localized, T-Lymphocytes, Helper-Inducer
Journal Title
Am J Transplant
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Elsevier BV
Medical Research Council (MR/M012328/1)