- Paz, Katelyn;
- Flynn, Ryan;
- Du, Jing;
- Tannheimer, Stacey;
- Johnson, Amy J;
- Dong, Shuai;
- Stark, Anne-Katrien;
- Okkenhaug, Klaus;
- Panoskaltsis-Mortari, Angela;
- Sage, Peter T;
- Sharpe, Arlene H;
- Luznik, Leo;
- Ritz, Jerome;
- Soiffer, Robert J;
- Cutler, Corey S;
- Koreth, John;
- Antin, Joseph H;
- Miklos, David B;
- MacDonald, Kelli P;
- Hill, Geoffrey R;
- Maillard, Ivan;
- Serody, Jonathan S;
- Murphy, William J;
- Munn, David H;
- Feser, Colby;
- Zaiken, Michael;
- Vanhaesebroeck, Bart;
- Turka, Laurence A;
- Byrd, John C;
- Blazar, Bruce R
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.