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  Bile acids regulate intestinal antigen presentation and reduce graft-versus-host disease without impairing the graft-versus-leukemia effect

Haring, E., Uhl, F. M., Andrieux, G., Proietti, M., Bulashevska, A., Sauer, B., et al. (2020). Bile acids regulate intestinal antigen presentation and reduce graft-versus-host disease without impairing the graft-versus-leukemia effect. Haematologica. doi:10.3324/haematol.2019.242990.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0006-C6DD-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0006-C6DE-1
Genre: Journal Article

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 Creators:
Haring, Eileen1, Author
Uhl, Franziska M.1, Author
Andrieux, Geoffroy1, Author
Proietti, Michele1, Author
Bulashevska, Alla1, Author
Sauer, Barbara1, Author
Braun, Lukas M.1, Author
de Gomez, Enrique Vega1, Author
Esser, Philipp R.1, Author
Martin, Stefan F.1, Author
Pfeifer, Dietmar1, Author
Follo, Marie1, Author
Schmitt-Graeff, Annette1, Author
Büscher, Jörg Martin2, Author              
Duyster, Justus1, Author
Grimbacher, Bodo1, Author
Boerries, Melanie1, Author
Pearce, Erika L.2, Author              
Zeiser, Robert1, Author
Apostolova, Petya1, Author
Affiliations:
1External Organizations, ou_persistent22              
2Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243648              

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Free keywords: stem cell transplantation; graft-versus-host-disease; cell therapy and immunotherapy
 Abstract: Acute graft-versus-host disease causes significant mortality in patients undergoing allogeneic hematopoietic cell transplantation. Immunosuppressive treatment for graft-versus-host disease 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 regulate multiple cellular processes and are in close contact with the intestinal epithelium, a major target of acute graft-versus-host disease. Here, we found that the bile acid pool is reduced following graft-versus-host disease 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 intestinal organoids and cell lines. Systemic prophylactic administration of tauroursodeoxycholic acid, the most potent compound in our in vitro studies, reduced graft-versus-host disease severity in three different murine transplantation 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 tauroursodeoxycholic acid 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 graft-versus-host disease without impairing the graft-versus-leukemia effect. In particular, we provide a scientific rationale for the systematic use of tauroursodeoxycholic acid in patients undergoing allogeneic hematopoietic cell transplantation.

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Language(s): eng - English
 Dates: 2020-07
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.3324/haematol.2019.242990
 Degree: -

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Title: Haematologica
Source Genre: Journal
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Publ. Info: Pavia, Italy : Ferrata Storti Foundation
Pages: - Volume / Issue: - Sequence Number: - Start / End Page: - Identifier: ISSN: 0390-6078
CoNE: https://pure.mpg.de/cone/journals/resource/0390-6078