Gastrin for the treatment of acute graft-versus-host disease of the stomach
Abstract
Abstract Acute graft-versus-host disease (aGVHD) is a major cause of death after allogeneic hematopoietic cell transplantation, and patients with steroid-refractory aGVHD have a dismal prognosis. We have previously shown that the enteroendocrine hormone glucagon-like peptide-2 has tissue regenerative activity in the lower gastrointestinal tract in mice and patients with steroid-refractory aGVHD. Here, we explored the tissue protective effect of the enteroendocrine hormone gastrin for aGVHD of the stomach. We observed that aGVHD caused a loss of gastrin-producing G-cells and parietal cells (PCs) and an increase in pH in the stomach, and allogeneic T cells had infiltrated the stomach wall. Pentagastrin treatment of aGVHD mice rescued the loss of PCs, normalized the pH in the stomach, increased stomach stem cell marker expression and abundance of LGR5+ cells. Gastrin also increased the viability of stomach and small intestine organoids in vitro. Compared with wild-type mice, Gast−/− mice experienced more severe aGVHD in the intestine and liver, which was rescued by pentagastrin treatment. In patients developing aGVHD, low gastrin levels in stomach biopsies were connected to reduced survival. Moreover, gastrin expression in the stomach correlated with aGVHD severity and tissue damage scores in independent patient cohorts. This study delineates the protective role of gastrin in aGVHD of the stomach in mice and patients and provides a rationale for the therapeutic use of pentagastrin in a clinical trial of patients with aGVHD.
Article Details
Authors (26)
Jana Gawron
1Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Marie Czech
1Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Tamina Rückert
1Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Verena Holzmüller
1Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Grigor Andreev
5Department of Pathology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Ann-Cathrin Burk
1Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Alina Hartmann
University Medical Center Freiburg, Freiburg, Germany
Sangya Chatterjee
1Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Geoffroy Andrieux
Franziska E. Marquard
8Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Anna-Sophia Baur
1Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Anna-Verena Stell
1Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Máté Krausz
2Faculty of Biology, University of Freiburg, Freiburg, Germany
Lukas M. Braun
Natascha Osswald
1Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Wolfgang Melchinger
Tobias Wertheimer
Andrea I. Proano-Vasco
2Faculty of Biology, University of Freiburg, Freiburg, Germany
Kristina Maas-Bauer
1Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Annette Schmitt-Graeff
12University of Freiburg, Freiburg, Germany
Melanie Boerries
Natalie Köhler
Francis Ayuk
From the Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Christoph Schell
Michael Quante
Robert Zeiser