Format

Send to

Choose Destination
Blood. 2019 Nov 7;134(19):1670-1682. doi: 10.1182/blood.2019001950.

Danger-associated extracellular ATP counters MDSC therapeutic efficacy in acute GVHD.

Author information

1
Division of Blood and Marrow Transplantation, Department of Pediatrics.
2
Center for Immunology.
3
Department of Laboratory Medicine and Pathology.
4
Department of Medicine, University of Minnesota, Minneapolis, MN.
5
Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
6
Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland.
7
Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan.
8
Lineberger Comprehensive Cancer Center.
9
Inflammatory Diseases Institute.
10
Department of Genetics.
11
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC.
12
Department of Dermatology.
13
Department of Internal Medicine, School of Medicine, University of California Davis, Sacramento, CA.
14
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
15
Department of Bone Marrow Transplantation, Royal Brisbane and Women's Hospital, Brisbane, Australia.
16
Department of Infectious Diseases.
17
Department of Immunology, St Jude Children's Research Hospital, Memphis, TN.
18
Dipartimento di Afferenza Medicina, Verona University, Verona, Italy.
19
Cancer Center, Department of Pediatrics, Georgia Regent's University, Augusta, GA.
20
Department of Hematology and Oncology, Freiburg University Medical Center, Albert Ludwigs University, Freiburg, Germany; and.
21
BIOSS Centre for Biological Signaling Studies, Freiburg, Germany.

Abstract

Myeloid-derived suppressor cells (MDSCs) can subdue inflammation. In mice with acute graft-versus-host disease (GVHD), donor MDSC infusion enhances survival that is only partial and transient because of MDSC inflammasome activation early posttransfer, resulting in differentiation and loss of suppressor function. Here we demonstrate that conditioning regimen-induced adenosine triphosphate (ATP) release is a primary driver of MDSC dysfunction through ATP receptor (P2x7R) engagement and NLR pyrin family domain 3 (NLRP3) inflammasome activation. P2x7R or NLRP3 knockout (KO) donor MDSCs provided significantly higher survival than wild-type (WT) MDSCs. Although in vivo pharmacologic targeting of NLRP3 or P2x7R promoted recipient survival, indicating in vivo biologic effects, no synergistic survival advantage was seen when combined with MDSCs. Because activated inflammasomes release mature interleukin-1β (IL-1β), we expected that IL-1β KO donor MDSCs would be superior in subverting GVHD, but such MDSCs proved inferior relative to WT. IL-1β release and IL-1 receptor expression was required for optimal MDSC function, and exogenous IL-1β added to suppression assays that included MDSCs increased suppressor potency. These data indicate that prolonged systemic NLRP3 inflammasome inhibition and decreased IL-1β could diminish survival in GVHD. However, loss of inflammasome activation and IL-1β release restricted to MDSCs rather than systemic inhibition allowed non-MDSC IL-1β signaling, improving survival. Extracellular ATP catalysis with peritransplant apyrase administered into the peritoneum, the ATP release site, synergized with WT MDSCs, as did regulatory T-cell infusion, which we showed reduced but did not eliminate MDSC inflammasome activation, as assessed with a novel inflammasome reporter strain. These findings will inform future clinical using MDSCs to decrease alloresponses in inflammatory environments.

PMID:
31533918
DOI:
10.1182/blood.2019001950

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center