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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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 Urheber:
Haring, Eileen1, Autor
Uhl, Franziska M.1, Autor
Andrieux, Geoffroy1, Autor
Proietti, Michele1, Autor
Bulashevska, Alla1, Autor
Sauer, Barbara1, Autor
Braun, Lukas M.1, Autor
de Gomez, Enrique Vega1, Autor
Esser, Philipp R.1, Autor
Martin, Stefan F.1, Autor
Pfeifer, Dietmar1, Autor
Follo, Marie1, Autor
Schmitt-Graeff, Annette1, Autor
Büscher, Jörg Martin2, Autor           
Duyster, Justus1, Autor
Grimbacher, Bodo1, Autor
Boerries, Melanie1, Autor
Pearce, Erika L.2, Autor           
Zeiser, Robert1, Autor
Apostolova, Petya2, Autor
Affiliations:
1External Organizations, ou_persistent22              
2Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243648              

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Schlagwörter: stem cell transplantation; graft-versus-host-disease; cell therapy and immunotherapy
 Zusammenfassung: 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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Sprache(n): eng - English
 Datum: 2020-07
 Publikationsstatus: Online veröffentlicht
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 Ort, Verlag, Ausgabe: -
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 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.3324/haematol.2019.242990
 Art des Abschluß: -

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Titel: Haematologica
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: Pavia, Italy : Ferrata Storti Foundation
Seiten: - Band / Heft: - Artikelnummer: - Start- / Endseite: - Identifikator: ISSN: 0390-6078
CoNE: https://pure.mpg.de/cone/journals/resource/0390-6078