Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans

Johana Norona; Petya Apostolova; Dominik Schmidt; Rebekka Ihlemann; Nadine Reischmann; Gregory Taylor; Natalie Köhler; Jocelyn de Heer; Steffen Heeg; Geoffroy Andrieux; Benjamin A. Siranosian; Annette Schmitt-Graeff; Dietmar Pfeifer; Antonella Catalano; Ian J. Frew; Michele Proietti; Bodo Grimbacher; Alla Bulashevska; Ami S. Bhatt; Tilman Brummer; Till Clauditz; Tatjana Zabelina; Nicolaus Kroeger; Bruce R. Blazar; Melanie Boerries; Francis Ayuk; Robert Zeiser

doi:10.1182/blood.2020005957

Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans

Johana Norona, Petya Apostolova, Dominik Schmidt, Rebekka Ihlemann, Nadine Reischmann, Gregory Taylor, Natalie Köhler, Jocelyn de Heer, Steffen Heeg, Geoffroy Andrieux, Benjamin A. Siranosian, Annette Schmitt-Graeff, Dietmar Pfeifer, Antonella Catalano, Ian J. Frew, Michele Proietti, Bodo Grimbacher, Alla Bulashevska, Ami S. Bhatt, Tilman BrummerTill Clauditz, Tatjana Zabelina, Nicolaus Kroeger, Bruce R. Blazar, Melanie Boerries, Francis Ayuk, Robert Zeiser

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Abstract

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). Glucagonlike- 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.

Original language	English (US)
Pages (from-to)	1442-1455
Number of pages	14
Journal	Blood
Volume	136
Issue number	12
DOIs	https://doi.org/10.1182/blood.2020005957
State	Published - Sep 17 2020

Bibliographical note

Funding Information:
Conflict-of-interest disclosure: B.R.B. receives remuneration as an advisor to Kamon Pharmaceuticals, Inc, Five Prime Therapeutics Inc, Regeneron Pharmaceuticals, Magenta Therapeutics, and BlueRock Therapeutics; receives research support from Fate Therapeutics, RXi Pharmaceuticals, Alpine Immune Sciences, Inc, AbbVie Inc, BlueRock Therapeutics, the Leukemia & Lymphoma Society, the Children’s Cancer Research Fund, and the KidsFirst Fund; and is a cofounder of Tmunity. The remaining authors declare no competing financial interests.

Funding Information:
This work was supported by the Deutsche Forschungsgemeinschaft (DFG; Germany): SFB TRR167 (R.Z.), SFB1160 TP B09 (R.Z.), and SFB 850 (Z1 [M.B.]; C6 [R.Z.]); the DFG under Germany’s Excellence Strategy (EXC-2189; project ID: 390939984); and DFG individual grant ZE872/4-1 (R.Z.). This work was also supported by the European Union (proposal number 681012 GvHDCure [ERC consolidator grant; R.Z.]); the Deutsche Krebshilfe (grant 70113473); the Jose-Carreras Leukemia Foundation (grant DJCLS 01R/2019; R.Z.); European Cooperation in Science and Technology (COST) Action 17138 EUROGRAFT, supported by COST; and National Institutes of Health grants R01 HL56067 (National Heart, Lung, and Blood Institute) and R37AI34495 (National Institute of Allergy and Infectious Diseases) (B.R.B.). N. Köhler was supported by the EQUIP-Programme for Medical Scientists, Faculty of Medicine, University of Freiburg and the DKMS Foundation for Giving Life (DKMS-SLS-MHG-2019-02). M.B. was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (coNfirm; FKZ 01ZX1708F) and within the Medical Informatics Funding Scheme (MIRACUM; FKZ 01ZZ1606A-H). B.G. was supported by the DFG (GR1617/14-1/iPAD; SFB1160/2_B5; RESIST–EXC 2155–Project ID 39087428; and CIBSS–EXC-2189–project ID 390939984) and the BMBF (GAIN 01GM1910A).

Publisher Copyright:
© 2020 American Society of Hematology. All rights reserved.

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10.1182/blood.2020005957

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Norona, J., Apostolova, P., Schmidt, D., Ihlemann, R., Reischmann, N., Taylor, G., Köhler, N., de Heer, J., Heeg, S., Andrieux, G., Siranosian, B. A., Schmitt-Graeff, A., Pfeifer, D., Catalano, A., Frew, I. J., Proietti, M., Grimbacher, B., Bulashevska, A., Bhatt, A. S., ... 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, 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 2020, '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, pp. 1442-1455. https://doi.org/10.1182/blood.2020005957

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title = "Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans",

abstract = "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). Glucagonlike- 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.",

author = "Johana Norona and Petya Apostolova and Dominik Schmidt and Rebekka Ihlemann and Nadine Reischmann and Gregory Taylor and Natalie K{\"o}hler and {de Heer}, Jocelyn and Steffen Heeg and Geoffroy Andrieux and Siranosian, {Benjamin A.} and Annette Schmitt-Graeff and Dietmar Pfeifer and Antonella Catalano and Frew, {Ian J.} and Michele Proietti and Bodo Grimbacher and Alla Bulashevska and Bhatt, {Ami S.} and Tilman Brummer and Till Clauditz and Tatjana Zabelina and Nicolaus Kroeger and Blazar, {Bruce R.} and Melanie Boerries and Francis Ayuk and Robert Zeiser",

note = "Funding Information: Conflict-of-interest disclosure: B.R.B. receives remuneration as an advisor to Kamon Pharmaceuticals, Inc, Five Prime Therapeutics Inc, Regeneron Pharmaceuticals, Magenta Therapeutics, and BlueRock Therapeutics; receives research support from Fate Therapeutics, RXi Pharmaceuticals, Alpine Immune Sciences, Inc, AbbVie Inc, BlueRock Therapeutics, the Leukemia & Lymphoma Society, the Children{\textquoteright}s Cancer Research Fund, and the KidsFirst Fund; and is a cofounder of Tmunity. The remaining authors declare no competing financial interests. Funding Information: This work was supported by the Deutsche Forschungsgemeinschaft (DFG; Germany): SFB TRR167 (R.Z.), SFB1160 TP B09 (R.Z.), and SFB 850 (Z1 [M.B.]; C6 [R.Z.]); the DFG under Germany{\textquoteright}s Excellence Strategy (EXC-2189; project ID: 390939984); and DFG individual grant ZE872/4-1 (R.Z.). This work was also supported by the European Union (proposal number 681012 GvHDCure [ERC consolidator grant; R.Z.]); the Deutsche Krebshilfe (grant 70113473); the Jose-Carreras Leukemia Foundation (grant DJCLS 01R/2019; R.Z.); European Cooperation in Science and Technology (COST) Action 17138 EUROGRAFT, supported by COST; and National Institutes of Health grants R01 HL56067 (National Heart, Lung, and Blood Institute) and R37AI34495 (National Institute of Allergy and Infectious Diseases) (B.R.B.). N. K{\"o}hler was supported by the EQUIP-Programme for Medical Scientists, Faculty of Medicine, University of Freiburg and the DKMS Foundation for Giving Life (DKMS-SLS-MHG-2019-02). M.B. was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (coNfirm; FKZ 01ZX1708F) and within the Medical Informatics Funding Scheme (MIRACUM; FKZ 01ZZ1606A-H). B.G. was supported by the DFG (GR1617/14-1/iPAD; SFB1160/2_B5; RESIST–EXC 2155–Project ID 39087428; and CIBSS–EXC-2189–project ID 390939984) and the BMBF (GAIN 01GM1910A). Publisher Copyright: {\textcopyright} 2020 American Society of Hematology. All rights reserved.",

year = "2020",

month = sep,

day = "17",

doi = "10.1182/blood.2020005957",

language = "English (US)",

volume = "136",

pages = "1442--1455",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "12",

}

TY - JOUR

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 J.

AU - Proietti, Michele

AU - Grimbacher, Bodo

AU - Bulashevska, Alla

AU - Bhatt, Ami S.

AU - Brummer, Tilman

AU - Clauditz, Till

AU - Zabelina, Tatjana

AU - Kroeger, Nicolaus

AU - Blazar, Bruce R.

AU - Boerries, Melanie

AU - Ayuk, Francis

AU - Zeiser, Robert

N1 - Funding Information: Conflict-of-interest disclosure: B.R.B. receives remuneration as an advisor to Kamon Pharmaceuticals, Inc, Five Prime Therapeutics Inc, Regeneron Pharmaceuticals, Magenta Therapeutics, and BlueRock Therapeutics; receives research support from Fate Therapeutics, RXi Pharmaceuticals, Alpine Immune Sciences, Inc, AbbVie Inc, BlueRock Therapeutics, the Leukemia & Lymphoma Society, the Children’s Cancer Research Fund, and the KidsFirst Fund; and is a cofounder of Tmunity. The remaining authors declare no competing financial interests. Funding Information: This work was supported by the Deutsche Forschungsgemeinschaft (DFG; Germany): SFB TRR167 (R.Z.), SFB1160 TP B09 (R.Z.), and SFB 850 (Z1 [M.B.]; C6 [R.Z.]); the DFG under Germany’s Excellence Strategy (EXC-2189; project ID: 390939984); and DFG individual grant ZE872/4-1 (R.Z.). This work was also supported by the European Union (proposal number 681012 GvHDCure [ERC consolidator grant; R.Z.]); the Deutsche Krebshilfe (grant 70113473); the Jose-Carreras Leukemia Foundation (grant DJCLS 01R/2019; R.Z.); European Cooperation in Science and Technology (COST) Action 17138 EUROGRAFT, supported by COST; and National Institutes of Health grants R01 HL56067 (National Heart, Lung, and Blood Institute) and R37AI34495 (National Institute of Allergy and Infectious Diseases) (B.R.B.). N. Köhler was supported by the EQUIP-Programme for Medical Scientists, Faculty of Medicine, University of Freiburg and the DKMS Foundation for Giving Life (DKMS-SLS-MHG-2019-02). M.B. was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (coNfirm; FKZ 01ZX1708F) and within the Medical Informatics Funding Scheme (MIRACUM; FKZ 01ZZ1606A-H). B.G. was supported by the DFG (GR1617/14-1/iPAD; SFB1160/2_B5; RESIST–EXC 2155–Project ID 39087428; and CIBSS–EXC-2189–project ID 390939984) and the BMBF (GAIN 01GM1910A). Publisher Copyright: © 2020 American Society of Hematology. All rights reserved.

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). Glucagonlike- 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). Glucagonlike- 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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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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