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.
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Change history
02 June 2016
This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue
Abbreviations
- 17AAG:
-
17-allylamino-demethoxygeldanamycin
- ER:
-
endoplasmic reticulum
- GvHD:
-
graft versus host disease
- GvL:
-
graft versus leukemia
- HSP:
-
heat shock protein
- IEC:
-
intestinal epithelial cell
- ISC:
-
intestinal stem cell
- UPR:
-
unfolded protein response
- XBP1:
-
X-box binding protein 1
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Acknowledgements
We thank J Haiech (University of Strasbourg), P Saas and B Gaugler (INSERM U1098, Besançon, France), for helpful discussions. We thank P Saas, H Clevers (Hubrecht Institute, The Netherlands) and A Jevnikar (Ontario, CA) for providing A20-luc cells, Lgr5-eGFP mice and IEC 4-1, respectively, and A Bouchot and JF Merlin (INSERM U866, Dijon, France) for excellent technical assistance. This work was supported by grants from the Institut National du Cancer, Agence Nationale de la Recherche, Ligue Nationale Contre le Cancer (‘Labeled teams’ to CG and ES), the Association pour la Recherche sur le Cancer (labeled team to CG and OD), and FEDER. CG team belongs to the LabEx LipSTIC and GR-Ex. ALJ has a doctoral fellowship from La Ligue Nationale Contre le Cancer and AD by the ‘Conseil Régional de Bourgogne’.
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Joly, AL., Deepti, A., Seignez, A. et al. The HSP90 inhibitor, 17AAG, protects the intestinal stem cell niche and inhibits graft versus host disease development. Oncogene 35, 2842–2851 (2016). https://doi.org/10.1038/onc.2015.242
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DOI: https://doi.org/10.1038/onc.2015.242