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Bone Marrow Transplantation
Bile acids regulate intestinal antigen presentation and reduce graft-versus-host disease without impairing the graft-versus-leukemia effect
Ferrata Storti Foundation
Haematologica 2021 Volume 106(8):2131-2146
Eileen Haring,1,2* Franziska M. Uhl,1,2* Geoffroy Andrieux,3,4 Michele Proietti,5 Alla Bulashevska,5 Barbara Sauer,1 Lukas M. Braun,1,2
Enrique de Vega Gomez,1 Philipp R. Esser,6 Stefan F. Martin,6 Dietmar Pfeifer,1 Marie Follo,1 Annette Schmitt-Graeff,7 Joerg Buescher,8 Justus Duyster,1
Bodo Grimbacher,5,9,10,11 Melanie Boerries,3,4,12 Erika L. Pearce,8 Robert Zeiser1,4,9 and Petya Apostolova1
1Department of Medicine I, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg; 2Faculty of Biology, Albert-Ludwigs-University, Freiburg; 3Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg; 4German Cancer Consortium (DKTK), partner site Freiburg; and German Cancer Research Center (DKFZ), Heidelberg; 5Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University, Freiburg; 6Allergy Research Group, Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg; 7University of Freiburg; 8Max-Planck Institute of Immunobiology and Epigenetics, Freiburg; 9CIBSS – Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg; 10DZIF – German Center for Infection Research, Satellite Center Freiburg; 11RESIST – Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg and 12Comprehensive Cancer Centre Freiburg (CCCF), University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
ABSTRACT
Acute graft-versus-host disease (GvHD) causes significant mortality in patients undergoing allogeneic hematopoietic cell transplanta- tion. Immunosuppressive treatment for GvHD can impair the beneficial graft-versus-leukemia effect and facilitate malignancy relapse. Therefore, novel approaches that protect and regenerate injured tissues without impeding the donor immune system are needed. Bile acids reg- ulate multiple cellular processes and are in close contact with the intes- tinal epithelium, a major target of acute GvHD. Here, we found that the bile acid pool is reduced following GvHD induction in a preclinical model. We evaluated the efficacy of bile acids to protect the intestinal epithelium without reducing anti-tumor immunity. We observed that application of bile acids decreased cytokine-induced cell death in intes- tinal organoids and cell lines. Systemic prophylactic administration of tauroursodeoxycholic acid (TUDCA), the most potent compound in our in vitro studies, reduced GvHD severity in three different murine trans- plantation models. This effect was mediated by decreased activity of the antigen presentation machinery and subsequent prevention of apoptosis of the intestinal epithelium. Moreover, bile acid administration did not alter the bacterial composition in the intestine suggesting that its effects are cell-specific and independent of the microbiome. Treatment of human and murine leukemic cell lines with TUDCA did not interfere with the expression of antigen presentation-related molecules. Systemic T-cell expansion and especially their cytotoxic capacity against leukemic cells remained intact. This study establishes a role for bile acids in the prevention of acute GvHD without impairing the graft-versus-leukemia effect. In particular, we provide a scientific rationale for the systematic use of TUDCA in patients undergoing allogeneic hematopoietic cell transplantation.
*EH and FMU contributed equally as co-first authors.
Correspondence:
PETYA APOSTOLOVA
petya.apostolova@uniklinik-freiburg.de
Received: November 15, 2019. Accepted: July 7, 2020. Pre-published: July 16, 2020.
https://doi.org/10.3324/haematol.2019.242990
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