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Am J Transplant. 2019 Feb 12. doi: 10.1111/ajt.15305. [Epub ahead of print]

Targeting PI3Kδ Function For Amelioration of Murine Chronic Graft-Versus-Host Disease.

Author information

1
Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.
2
Gilead Sciences, Inc, Foster City, California, USA.
3
Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, and Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
4
Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
5
Department of Pathology, University of Cambridge, Cambridge, UK.
6
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
7
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
8
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
9
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
10
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
11
Stem Cell/Bone Marrow Transplantation Program, Division of Hematologic Malignancy, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
12
Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA.
13
Department of Immunology, QIMR Berghofer Medical Research Institute and School of Medicine, University of Queensland, Brisbane, Australia.
14
Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
15
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
16
Departments of Dermatology and Internal Medicine, Division of Hematology and Oncology, University of California Davis School of Medicine, Sacramento, CA, USA.
17
Georgia Cancer Center and Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, Georgia.
18
UCL Cancer Institute, University College London, London, UK.
19
Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.

Abstract

Chronic graft-versus-host disease 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 -promoting Tfollicular helper cells, resulting in cGVHD. Phosphoinositide-3-kinase-δ, a lipid kinase, is critical for activated T-cell survival, proliferation, differentiation, and metabolism. We demonstrate PI3Kδ activity in donor T-cells that become Tfhs is required for cGVHD in a non-sclerodermatous multi-organ system disease model that includes bronchiolitis obliterans, dependent upon GC B-cells, Tfhs, and counterbalanced by Tfollicular 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 FDA-approved PI3Kδ inhibitors for cGVHD therapy in patients. This article is protected by copyright. All rights reserved.

PMID:
30748099
DOI:
10.1111/ajt.15305

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