S230: Human beta-defensin 2 treatment modulates the intestinal microbiome and the allogeneic T cell response to limit acute graft-versus-host disease
In: ISSN: 2572-9241, 2022
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Zugriff:
Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy option for patients with hematological malignancies. Acute graft-versus-host disease (GVHD) is primarily driven by allogeneic donor T cells and remains a serious cause of morbidity and mortality post allo-HCT. In particular, acute GVHD of the gastrointestinal tract (GI GVHD) is associated with a high mortality rate and treatment options are limited. Human β-defensin 2 (hBD-2) is an endogenous epithelial cell-derived host-defense peptide, which is induced by inflammatory stimuli and possesses both antimicrobial and immunomodulatory functions. Aims: In this study, we aimed to investigate the expression of beta defensins in human and murine GI GVHD and the therapeutic effect of recombinant hBD-2 on acute GVHD development in mouse models. Methods: To investigate the functional role of hBD-2 post allo-HCT, we employed established murine GVHD and graft-versus-leukemia (GVL) models and analyzed the allogeneic T cell response using transcriptome and kinome profiling. Shotgun metagenomic sequencing was used to examine the effect of hBD-2 on the intestinal microbiome. Furthermore, we studied beta-defensin expression in two independent acute GVHD patient cohorts and in mice with acute GVHD. Results: We found that expression of murine beta-defensin 4 (mBD-4), the murine orthologue for hBD-2, was reduced in the colon and ileum of mice developing acute GVHD. Oral treatment of mice with recombinant hBD-2 post allo-HCT reduced weight loss and acute GVHD severity and mortality. Furthermore, hBD-2 treatment affected the intestinal microbial composition, including a shift towards higher abundance of Bacteroides species in hBD-2 treated compared to vehicle treated mice. The changes in the microbiome resulted in reduced neutrophil infiltration of the ileum during acute GVHD induction in hBD-2 treated mice. Additionally, hBD-2 dampened pro-inflammatory Th1 cytokine production (TNF, IFN-gamma) by allogeneic T cells in vivo, while preserving the ...
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S230: Human beta-defensin 2 treatment modulates the intestinal microbiome and the allogeneic T cell response to limit acute graft-versus-host disease
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Autor/in / Beteiligte Person: | Rückert, Tamina ; Andrieux, Geoffroy ; Boerries, Melanie ; Woessner, Nadine M. ; Minguet, Susana ; Doetsch, Stephanie ; Aumann, Konrad ; Schiff, Marcel ; Braun, Lukas M. ; Haring, Eileen ; Siranosian, Benjamin A. ; Bhatt, Ami S ; Nordkild, Peter ; Wehkamp, Jan ; Jensen, Benjamin A. H. ; Duyster, Justus ; Zeiser, Robert ; Köhler, Natalie |
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Zeitschrift: | ISSN: 2572-9241, 2022 |
Veröffentlichung: | 2022 |
Medientyp: | Audio |
ISSN: | 2572-9241 |
DOI: | 10.1097/01.hs9.0000843812.88278.bd |
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