Autophagy prevents graft failure during murine graft-versus-host disease.

Autor:	Lineburg KE; Department of Infection and Inflammation, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.; School of Medicine, The University of Queensland, Brisbane, Australia., Leveque-El Mouttie L; Department of Infection and Inflammation, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.; School of Medicine, The University of Queensland, Brisbane, Australia., Hunter CR; Department of Infection and Inflammation, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia., Le Texier L; Department of Infection and Inflammation, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia., McGirr C; Stem Cell Biology Group, Mater Research Institute, The University of Queensland, Brisbane, Australia., Teal B; Department of Infection and Inflammation, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia., Blazar BR; Pediatric Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, University of Minnesota, Minneapolis, MN.; Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Lane SW; Department of Infection and Inflammation, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.; Department of Haematology, Royal Brisbane and Women's Hospital, Brisbane, Australia., Hill GR; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Research Center, Seattle, WA.; Department of Medicine, University of Washington, Seattle, WA., Lévesque JP; Stem Cell Biology Group, Mater Research Institute, The University of Queensland, Brisbane, Australia., MacDonald KPA; Department of Infection and Inflammation, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2024 Apr 23; Vol. 8 (8), pp. 2032-2043.
DOI:	10.1182/bloodadvances.2023010972
Abstrakt:	Abstract: Autophagy is an intracellular survival process that has established roles in the long-term survival and function of hematopoietic stem cells (HSC). We investigated the contribution of autophagy to HSC fitness during allogeneic transplantation and graft-versus-host disease (GVHD). We demonstrate in vitro that both tumor necrosis factor and IL-1β, major components of GVHD cytokine storm, synergistically promote autophagy in both HSC and their more mature hematopoietic progenitor cells (HPC). In vivo we demonstrate that autophagy is increased in donor HSC and HPC during GVHD. Competitive transplant experiments demonstrated that autophagy-deficient cells display reduced capacity to reconstitute the hematopoietic system compared to wild-type counterparts. In a major histocompatibility complex-mismatched model of GVHD and associated cytokine dysregulation, we demonstrate that autophagy-deficient HSC and progenitors fail to establish durable hematopoiesis, leading to primary graft failure and universal transplant related mortality. Using several different models, we confirm that autophagy activity is increased in early progenitor and HSC populations in the presence of T-cell-derived inflammatory cytokines and that these HSC populations require autophagy to survive. Thus, autophagy serves as a key survival mechanism in HSC and progenitor populations after allogeneic stem cell transplant and may represent a therapeutic target to prevent graft failure during GVHD. (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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