Glucagon like peptide-2 for Intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans
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Glucagon like peptide-2 for Intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans. / Norona, Johana; Apostolova, Petya; Schmidt, Dominik; Ihlemann, Rebekka; Reischmann, Nadine; Taylor, Gregory; Köhler, Natalie; de Heer, Jocelyn; Heeg, Steffen; Andrieux, Geoffroy; Siranosian, Benjamin A; Schmitt-Graeff, Annette; Pfeifer, Dietmar; Catalano, Antonella; Frew, Ian; Proietti, Michele; Grimbacher, Bodo; Bulashevska, Alla; Bhatt, Ami S; Brummer, Tilman; Clauditz, Till Sebastian; Zabelina, Tatjana; Kroeger, Nicolaus; Blazar, Bruce R; Boerries, Melanie; Ayuk, Francis; Zeiser, Robert.
In: BLOOD, Vol. 136, No. 12, 17.09.2020, p. 1442-1455.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Glucagon like peptide-2 for Intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans
AU - Norona, Johana
AU - Apostolova, Petya
AU - Schmidt, Dominik
AU - Ihlemann, Rebekka
AU - Reischmann, Nadine
AU - Taylor, Gregory
AU - Köhler, Natalie
AU - de Heer, Jocelyn
AU - Heeg, Steffen
AU - Andrieux, Geoffroy
AU - Siranosian, Benjamin A
AU - Schmitt-Graeff, Annette
AU - Pfeifer, Dietmar
AU - Catalano, Antonella
AU - Frew, Ian
AU - Proietti, Michele
AU - Grimbacher, Bodo
AU - Bulashevska, Alla
AU - Bhatt, Ami S
AU - Brummer, Tilman
AU - Clauditz, Till Sebastian
AU - Zabelina, Tatjana
AU - Kroeger, Nicolaus
AU - Blazar, Bruce R
AU - Boerries, Melanie
AU - Ayuk, Francis
AU - Zeiser, Robert
N1 - Copyright © 2020 American Society of Hematology.
PY - 2020/9/17
Y1 - 2020/9/17
N2 - Acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). Although currently used GVHD treatment regimens target the donor immune system, we explored here an approach that aims at protecting and regenerating Paneth cells (PCs) and intestinal stem cells (ISCs). Glucagon-like-peptide-2 (GLP-2) is an enteroendocrine tissue hormone produced by intestinal L cells. We observed that acute GVHD reduced intestinal GLP-2 levels in mice and patients developing GVHD. Treatment with the GLP-2 agonist, teduglutide, reduced de novo acute GVHD and steroid-refractory GVHD, without compromising graft-versus-leukemia (GVL) effects in multiple mouse models. Mechanistically GLP-2 substitution promoted regeneration of PCs and ISCs, which enhanced production of antimicrobial peptides and caused microbiome changes. GLP-2 expanded intestinal organoids and reduced expression of apoptosis-related genes. Low numbers of L cells in intestinal biopsies and high serum levels of GLP-2 were associated with a higher incidence of nonrelapse mortality in patients undergoing allo-HCT. Our findings indicate that L cells are a target of GVHD and that GLP-2-based treatment of acute GVHD restores intestinal homeostasis via an increase of ISCs and PCs without impairing GVL effects. Teduglutide could become a novel combination partner for immunosuppressive GVHD therapy to be tested in clinical trials.
AB - Acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). Although currently used GVHD treatment regimens target the donor immune system, we explored here an approach that aims at protecting and regenerating Paneth cells (PCs) and intestinal stem cells (ISCs). Glucagon-like-peptide-2 (GLP-2) is an enteroendocrine tissue hormone produced by intestinal L cells. We observed that acute GVHD reduced intestinal GLP-2 levels in mice and patients developing GVHD. Treatment with the GLP-2 agonist, teduglutide, reduced de novo acute GVHD and steroid-refractory GVHD, without compromising graft-versus-leukemia (GVL) effects in multiple mouse models. Mechanistically GLP-2 substitution promoted regeneration of PCs and ISCs, which enhanced production of antimicrobial peptides and caused microbiome changes. GLP-2 expanded intestinal organoids and reduced expression of apoptosis-related genes. Low numbers of L cells in intestinal biopsies and high serum levels of GLP-2 were associated with a higher incidence of nonrelapse mortality in patients undergoing allo-HCT. Our findings indicate that L cells are a target of GVHD and that GLP-2-based treatment of acute GVHD restores intestinal homeostasis via an increase of ISCs and PCs without impairing GVL effects. Teduglutide could become a novel combination partner for immunosuppressive GVHD therapy to be tested in clinical trials.
U2 - 10.1182/blood.2020005957
DO - 10.1182/blood.2020005957
M3 - SCORING: Journal article
C2 - 32542357
VL - 136
SP - 1442
EP - 1455
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 12
ER -