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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.

Publication ,  Journal Article
Norona, J; Apostolova, P; Schmidt, D; Ihlemann, R; Reischmann, N; Taylor, G; Köhler, N; de Heer, J; Heeg, S; Andrieux, G; Siranosian, BA ...
Published in: Blood
September 17, 2020

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.

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

September 17, 2020

Volume

136

Issue

12

Start / End Page

1442 / 1455

Location

United States

Related Subject Headings

  • Transplantation, Homologous
  • Stem Cells
  • Peptides
  • Paneth Cells
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
  • Male
  • Intestines
  • Immunology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Norona, J., Apostolova, P., Schmidt, D., Ihlemann, R., Reischmann, N., Taylor, G., … Zeiser, R. (2020). Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans. Blood, 136(12), 1442–1455. https://doi.org/10.1182/blood.2020005957
Norona, Johana, Petya Apostolova, Dominik Schmidt, Rebekka Ihlemann, Nadine Reischmann, Gregory Taylor, Natalie Köhler, et al. “Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans.Blood 136, no. 12 (September 17, 2020): 1442–55. https://doi.org/10.1182/blood.2020005957.
Norona J, Apostolova P, Schmidt D, Ihlemann R, Reischmann N, Taylor G, et al. Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans. Blood. 2020 Sep 17;136(12):1442–55.
Norona, Johana, et al. “Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans.Blood, vol. 136, no. 12, Sept. 2020, pp. 1442–55. Pubmed, doi:10.1182/blood.2020005957.
Norona J, Apostolova P, Schmidt D, Ihlemann R, Reischmann N, Taylor G, Köhler N, de Heer J, Heeg S, Andrieux G, Siranosian BA, Schmitt-Graeff A, Pfeifer D, Catalano A, Frew IJ, Proietti M, Grimbacher B, Bulashevska A, Bhatt AS, Brummer T, Clauditz T, Zabelina T, Kroeger N, Blazar BR, Boerries M, Ayuk F, Zeiser R. Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans. Blood. 2020 Sep 17;136(12):1442–1455.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

September 17, 2020

Volume

136

Issue

12

Start / End Page

1442 / 1455

Location

United States

Related Subject Headings

  • Transplantation, Homologous
  • Stem Cells
  • Peptides
  • Paneth Cells
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
  • Male
  • Intestines
  • Immunology