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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, A-K; ... Blazar, BR; + view all (2019) Targeting PI3Kδ function for amelioration of murine chronic graft‐versus‐host disease. American Journal of Transplantation , 19 (6) pp. 1820-1830. 10.1111/ajt.15305. Green open access

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Abstract

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.

Type: Article
Title: Targeting PI3Kδ function for amelioration of murine chronic graft‐versus‐host disease
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/ajt.15305
Publisher version: https://doi.org/10.1111/ajt.15305
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: basic (laboratory) research/science, graft‐versus‐host disease (GVHD), immunobiology, immunosuppressant ‐ other
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10068844
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