Targeting NAD immunometabolism limits severe graft-versus-host disease and has potent antileukemic activity.

Acrylamides / pharmacology Animals Antineoplastic Agents / pharmacology Apoptosis Cell Proliferation Cytokines / antagonists & inhibitors Energy Metabolism Female Graft vs Host Disease / immunology Humans Immunologic Memory / drug effects Leukemia / drug therapy Male Mice Mice, Inbred BALB C Mice, Inbred C57BL NAD / metabolism Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors Piperidines / pharmacology T-Lymphocytes, Regulatory / drug effects Tumor Cells, Cultured Xenograft Model Antitumor Assays

Journal

Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895

Informations de publication

Date de publication:
07 2020
Historique:
received: 02 06 2019
accepted: 14 01 2020
revised: 06 12 2019
pubmed: 25 1 2020
medline: 28 10 2020
entrez: 25 1 2020
Statut: ppublish

Résumé

Acute graft-versus-host disease (aGVHD) and tumor relapse remain major complications after allogeneic hematopoietic stem cell transplantation. Alloreactive T cells and cancer cells share a similar metabolic phenotype to meet the bioenergetic demands necessary for cellular proliferation and effector functions. Nicotinamide adenine dinucleotide (NAD) is an essential co-factor in energy metabolism and is constantly replenished by nicotinamide phosphoribosyl-transferase (Nampt), the rate-limiting enzyme in the NAD salvage pathway. Here we show, that Nampt blockage strongly ameliorates aGVHD and limits leukemic expansion. Nampt was highly elevated in serum of patients with gastrointestinal GVHD and was particularly abundant in human and mouse intestinal T cells. Therapeutic application of the Nampt small-molecule inhibitor, Fk866, strongly attenuated experimental GVHD and caused NAD depletion in T-cell subsets, which displayed differential susceptibility to NAD shortage. Fk866 robustly inhibited expansion of alloreactive but not memory T cells and promoted FoxP3-mediated lineage stability in regulatory T cells. Furthermore, Fk866 strongly reduced the tumor burden in mouse leukemia and graft-versus-leukemia models. Ex vivo studies using lymphocytes from GVHD patients demonstrated potent antiproliferative properties of Fk866, suggesting potential clinical utility. Thus, targeting NAD immunometabolism represents a novel approach to selectively inhibit alloreactive T cells during aGVHD with additional antileukemic efficacy.

Identifiants

DOI: 10.1038/s41375-020-0709-0 PMID: 31974433
pubmed: 31974433
doi: 10.1038/s41375-020-0709-0
pii: 10.1038/s41375-020-0709-0
doi:

Substances chimiques

Acrylamides 0
Antineoplastic Agents 0
Cytokines 0
N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide 0
Piperidines 0
NAD 0U46U6E8UK
Nicotinamide Phosphoribosyltransferase EC 2.4.2.12
nicotinamide phosphoribosyltransferase, human EC 2.4.2.12

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1885-1897

Références

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Auteurs

Romana R Gerner (RR)

Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Innsbruck, Austria. romana.gerner@i-med.ac.at.
Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria. romana.gerner@i-med.ac.at.
Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California San Diego, 92037, La Jolla, CA, USA. romana.gerner@i-med.ac.at.
ORCID: 0000-0003-2377-6509

Sophie Macheiner (S)

Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Innsbruck, Austria.
Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria.

Simon Reider (S)

Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria.

Kerstin Siegmund (K)

Department for Pharmacology and Genetics, Medical University Innsbruck, Innsbruck, Austria.

Felix Grabherr (F)

Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Innsbruck, Austria.

Lisa Mayr (L)

Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Innsbruck, Austria.

Bernhard Texler (B)

Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria.

Patrizia Moser (P)

Department of Pathology, Medical University Innsbruck, Innsbruck, Austria.

Maria Effenberger (M)

Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Innsbruck, Austria.

Hubert Schwaighofer (H)

Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Innsbruck, Austria.

Alexander R Moschen (AR)

Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Innsbruck, Austria.
Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria.

Brigitte Kircher (B)

Department of Internal Medicine V, Hematology & Oncology, Medical University Innsbruck, Innsbruck, Austria.

Herbert Oberacher (H)

Institute of Legal Medicine and Core Facility Metabolomics, Medical University Innsbruck, Innsbruck, Austria.

Robert Zeiser (R)

Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.

Herbert Tilg (H)

Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Innsbruck, Austria.

David Nachbaur (D)

Department of Internal Medicine V, Hematology & Oncology, Medical University Innsbruck, Innsbruck, Austria. david.nachbaur@i-med.ac.at.

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Classifications MeSH

questionsmedicales.fr › Composés chimiques organiques › Acides carboxyliques › Acides acycliques › Acrylates › Acrylamides › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Eucaryotes › Animaux › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Apoptose › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Métabolisme › Métabolisme énergétique › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Maladies du système immunitaire › Maladie du greffon contre l'hôte › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Phénomènes du système immunitaire › Immunité › Immunité acquise › Mémoire immunologique › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Leucémies › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée BALB C › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Ribonucléotides › Nucléotides adényliques › NAD › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Glycosyltransferase › Pentosyltransferases › Nicotinamide phosphoribosyltransferase › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pipéridines › Targeting NAD immunometabolism limits severe...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes T › Sous-populations de lymphocytes T › Lymphocytes T régulateurs › Targeting NAD immunometabolism limits severe...
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