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)|
|Number of pages||14|
|State||Published - Sep 17 2020|
Bibliographical noteFunding 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.
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).
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