title: The HSP90 inhibitor, 17AAG, protects the intestinal stem cell niche and inhibits graft versus host disease development.
abstract: Graft versus host disease (GvHD), which is the primary complication of allogeneic bone marrow transplantation, can alter the intestinal barrier targeted by activated donor T-cells. Chemical inhibition of the stress protein HSP90 was demonstrated in vitro to inhibit T-cell activation and to modulate endoplasmic reticulum (ER) stress to which intestinal cells are highly susceptible. Since the HSP90 inhibitor 17-allylamino-demethoxygeldanamycin (17AAG) is developed in clinics, we explored here its ability to control intestinal acute GvHD in vivo in two mouse GvHD models (C57BL/6BALB/c and FVB/NLgr5-eGFP), ex vivo in intestine organoids and in vitro in intestinal epithelial cultures. We show that 17AAG decreases GvHD-associated mortality without impairing graft versus leukemia effect. While 17AAG effect in T-cell activation is just moderate at the dose used in vivo, we observe a striking intestinal integrity protection. At the intestine level, the drug promotes the splicing of the transcription factor X-box binding protein 1 (XBP1), which is a key component of the ER stress. This effect is associated with a decrease in intestinal damage and an increase in Lgr5(+) stem cells, Paneth cells and defensins production. The importance of XBP1 splicing control is further confirmed in cultured cells and organoids of primary intestinal epithelium where XBP1 is either shRNA depleted or inhibited with toyocamycin. In conclusion, 17AAG has a protective effect on the epithelial intestinal barrier in mouse models of acute GvHD. This compound deserves to be tested in the therapeutic control of acute GvHD.
authors.affiliation: INSERM UMR 866, « Equipe labellisée» Ligue National contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.
authors.forename: A-L
authors.initials: AL
authors.lastname: Joly
authors.affiliation: INSERM UMR 866, « Equipe labellisée» Ligue National contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.
authors.forename: A
authors.initials: A
authors.lastname: Deepti
authors.affiliation: INSERM UMR 866, « Equipe labellisée» Ligue National contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.|CHU, Dijon, France.
authors.forename: A
authors.initials: A
authors.lastname: Seignez
authors.affiliation: INSERM UMR 866, « Equipe labellisée» Ligue National contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.
authors.forename: A
authors.initials: A
authors.lastname: Goloudina
authors.affiliation: INSERM UMR 866, « Equipe labellisée» Ligue National contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.
authors.forename: S
authors.initials: S
authors.lastname: Hebrard
authors.affiliation: INSERM UMR 866, « Equipe labellisée» Ligue National contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.
authors.forename: E
authors.initials: E
authors.lastname: Schmitt
authors.affiliation: INSERM UMR 866, « Equipe labellisée» Ligue National contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.
authors.forename: S
authors.initials: S
authors.lastname: Richaud
authors.affiliation: INSERM UMR 866, « Equipe labellisée» Ligue National contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.
authors.forename: E
authors.initials: E
authors.lastname: Fourmaux
authors.affiliation: INSERM UMR 866, « Equipe labellisée» Ligue National contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.
authors.forename: A
authors.initials: A
authors.lastname: Hammann
authors.affiliation: INSERM, UMR S938, Centre de Recherche Saint-Antoine, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Collura
authors.affiliation: INSERM, UMR S938, Centre de Recherche Saint-Antoine, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Svrcek
authors.affiliation: INSERM UMR 866, « Equipe labellisée» Ligue National contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.
authors.forename: G
authors.initials: G
authors.lastname: Jego
authors.affiliation: INSERM U748, Institut de Virologie, Strasbourg, France.|Institut Hospitalo-Universitaire de Strasbourg, Strasbourg, France.
authors.forename: E
authors.initials: E
authors.lastname: Robinet
authors.affiliation: INSERM UMR1009, Institut Gustave Roussy, Villejuif, France.|Université Paris-Sud 11, Villejuif, France.
authors.forename: E
authors.initials: E
authors.lastname: Solary
authors.affiliation: INSERM UMR 866, « Equipe labellisée» Ligue National contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.
authors.forename: O
authors.initials: O
authors.lastname: Demidov
authors.affiliation: INSERM UMR 866, « Equipe labellisée» Ligue National contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.
authors.forename: E
authors.initials: E
authors.lastname: Kohli
authors.affiliation: INSERM UMR 866, « Equipe labellisée» Ligue National contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.|Anticancer Centre George François Leclerc, Dijon, France.
authors.forename: C
authors.initials: C
authors.lastname: Garrido
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D019610:Cytoprotection / Q000187:drug effects*; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D007422:Intestines / Q000187:drug effects / Q000473:pathology*; D047029:Lactams, Macrocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D012326:RNA Splicing / Q000187:drug effects; D055153:Stem Cell Niche / Q000187:drug effects*; D000071717:X-Box Binding Protein 1 / Q000235:genetics
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C112765:tanespimycin