| Autor: |
Tamina Rückert, Geoffroy Andrieux, Melanie Boerries, Kathrin Hanke-Müller, Nadine M. Woessner, Stephanie Doetsch, Christoph Schell, Konrad Aumann, Julia Kolter, Annette Schmitt-Graeff, Marcel Schiff, Lukas M. Braun, Eileen Haring, Sandra Kissel, Benjamin A. Siranosian, Ami S. Bhatt, Peter Nordkild, Jan Wehkamp, Benjamin A. H. Jensen, Susana Minguet, Justus Duyster, Robert Zeiser, Natalie Köhler |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Science translational medicine. 14(676) |
| ISSN: |
1946-6242 |
| Popis: |
Acute graft-versus-host disease (aGVHD), which is driven by allogeneic T cells, has a high mortality rate and limited treatment options. Human β-defensin 2 (hBD-2) is an endogenous epithelial cell–derived host-defense peptide. In addition to its antimicrobial effects, hBD-2 has immunomodulatory functions thought to be mediated by CCR2 and CCR6 in myeloid cells. In this study, we analyzed the effect of recombinant hBD-2 on aGVHD development. We found that intestinal β-defensin expression was inadequately induced in response to inflammation in two independent cohorts of patients with aGVHD and in a murine aGVHD model. Treatment of mice with hBD-2 reduced GVHD severity and mortality and modulated the intestinal microbiota composition, resulting in reduced neutrophil infiltration in the ileum. Furthermore, hBD-2 treatment decreased proliferation and proinflammatory cytokine production by allogeneic T cells in vivo while preserving the beneficial graft-versus-leukemia effect. Using transcriptome and kinome profiling, we found that hBD-2 directly dampened primary murine and human allogeneic T cell proliferation, activation, and metabolism in a CCR2- and CCR6-independent manner by reducing proximal T cell receptor signaling. Furthermore, hBD-2 treatment diminished alloreactive T cell infiltration and the expression of genes involved in T cell receptor signaling in the ilea of mice with aGVHD. Together, we found that both human and murine aGVHD were characterized by a lack of intestinal β-defensin induction and that recombinant hBD-2 represents a potential therapeutic strategy to counterbalance endogenous hBD-2 deficiency. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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