Inhibition of 15-PGDH Protects Mice from Immune-Mediated Bone Marrow Failure

Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved..

Aplastic anemia (AA) is a human immune-mediated bone marrow failure syndrome that is treated by stem cell transplantation for patients who have a matched related donor and by immunosuppressive therapy (IST) for those who do not. Responses to IST are variable, with patients still at risk for prolonged neutropenia, transfusion dependence, immune suppression, and severe opportunistic infections. Therefore, additional therapies are needed to accelerate hematologic recovery in patients receiving front-line IST. We have shown that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) with the small molecule SW033291 (PGDHi) increases bone marrow (BM) prostaglandin E2 levels, expands hematopoietic stem cell (HSC) numbers, and accelerates hematologic reconstitution following murine BM transplantation. We now report that in a murine model of immune-mediated BM failure, PGDHi therapy mitigated cytopenias, increased BM HSC and progenitor cell numbers, and significantly extended survival compared with vehicle-treated mice. PGDHi protection was not immune-mediated, as serum IFN-γ levels and BM CD8+ T lymphocyte frequencies were not impacted. Moreover, dual administration of PGDHi plus low-dose IST enhanced total white blood cell, neutrophil, and platelet recovery, achieving responses similar to those seen with maximal-dose IST with lower toxicity. Taken together, these data demonstrate that PGDHi can complement IST to accelerate hematologic recovery and reduce morbidity in severe AA.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:26

Enthalten in:

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation - 26(2020), 8 vom: 01. Aug., Seite 1552-1556

Sprache:

Englisch

Beteiligte Personen:

Smith, Julianne N P [VerfasserIn]
Otegbeye, Folashade [VerfasserIn]
Jogasuria, Alvin P [VerfasserIn]
Christo, Kelsey F [VerfasserIn]
Antczak, Monika I [VerfasserIn]
Ready, Joseph M [VerfasserIn]
Gerson, Stanton L [VerfasserIn]
Markowitz, Sanford D [VerfasserIn]
Desai, Amar B [VerfasserIn]

Links:

Volltext

Themen:

15-hydroxyprostaglandin dehydrogenase
EC 1.1.1.-
EC 1.1.1.141
Hydroxyprostaglandin Dehydrogenases
Journal Article
Research Support, N.I.H., Extramural

Anmerkungen:

Date Completed 23.06.2021

Date Revised 31.05.2022

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.bbmt.2020.04.010

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM310048532