Therapeutic targeting of endoplasmic reticulum stress in acute graft- versus-host disease

Haematologica. 2022 Jul 1;107(7):1538-1554. doi: 10.3324/haematol.2021.278387.


Acute graft-versus-host disease (GvHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), a potentially curative treatment for leukemia. Endoplasmic reticulum (ER) stress occurs when the protein folding capacity of the ER is oversaturated. How ER stress modulates tissue homeostasis in the context of alloimmunity is not well understood. We show that ER stress contributes to intestinal tissue injury during GvHD and can be targeted pharmacologically. We observed high levels of ER stress upon GvHD onset in a murine allo- HCT model and in human biopsies. These levels correlated with GvHD severity, underscoring a novel therapeutic potential. Elevated ER stress resulted in increased cell death of intestinal organoids. In a conditional knockout model, deletion of the ER stress regulator transcription factor Xbp1 in intestinal epithelial cells induced a general ER stress signaling disruption and aggravated GvHD lethality. This phenotype was mediated by changes in the production of antimicrobial peptides and the microbiome composition as well as activation of pro-apoptotic signaling. Inhibition of inositol-requiring enzyme 1α (IRE1α), the most conserved signaling branch in ER stress, reduced GvHD development in mice. IRE1α blockade by the small molecule inhibitor 4m8c improved intestinal cell viability, without impairing hematopoietic regeneration and T-cell activity against tumor cells. Our findings in patient samples and mice indicate that excessive ER stress propagates tissue injury during GvHD. Reducing ER stress could improve the outcome of patients suffering from GvHD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endoplasmic Reticulum Stress
  • Endoribonucleases / genetics
  • Endoribonucleases / therapeutic use
  • Graft vs Host Disease*
  • Hematopoietic Stem Cell Transplantation* / adverse effects
  • Mice
  • Protein Serine-Threonine Kinases


  • Protein Serine-Threonine Kinases
  • Endoribonucleases

Grants and funding

Funding: PA was supported by the Else Kröner-Fresenius-Stiftung (EKFS 2015_A147 to PA), the German Cancer Consortium (DKTK, FR 01-375) and a scholarship from the Berta Ottenstein Program for Clinician Scientists, Faculty of Medicine, Medical Center – University of Freiburg, Germany. RZ is supported by the Deutsche Forschungsgemeinschaft (DFG): SFB1479 (Project ID: 441891347), SFB1160, TRR167 and SFB850, the INTERREG V European regional development fund (European Union) program (Project 3.2 TRIDIAG), the European Union: GVHDCure Proposal n° 681012 ERC consolidator grant, the Deutsche Krebshilfe (grant number 70113473), the Jose-Carreras Leukemia foundation (grant number DJCLS 01R/2019) and the Wilhelm Sander Stiftung (grant 2008.046.4). NK was supported by the German Research Foundation (DFG) under German’s Excellence Strategy (CIBSS - EXC 2189 – Project ID 390939984). MB is supported by the Deutsche Forschungsgemeinschaft (DFG) – SFB 850 subprojects C9 and Z1, SFB1479 (Project ID: 441891347- S1), SFB1160 (Project Z02), SFB1453 (Project S1) and TRR167 (Project Z01), the German Federal Ministry of Education and Research by MIRACUM within the Medical Informatics Funding Scheme (FKZ 01ZZ1801B).