| Autor: |
Rückert, Tamina, Andrieux, Geoffroy, Boerries, Melanie, Hanke-Müller, Kathrin, Woessner, Nadine M., Doetsch, Stephanie, Schell, Christoph, Aumann, Konrad, Kolter, Julia, Schmitt-Graeff, Annette, Schiff, Marcel, Braun, Lukas M., Haring, Eileen, Kissel, Sandra, Siranosian, Benjamin A., Bhatt, Ami S., Nordkild, Peter, Wehkamp, Jan, Jensen, Benjamin A. H., Minguet, Susana |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 12/21/2022, Vol. 14 Issue 676, p1-16, 16p |
| Abstrakt: |
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. Defending against GVHD: Defending against GVHDAcute graft-versus-host disease (aGVHD) occurring after allogeneic hematopoietic stem cell transplantation is a major cause of mortality for patients. Treatment options for aGVHD are limited, and additional therapeutics are urgently needed. Here, Rückert et al. identified human β-defensin-2 (hBD-2), a host-defense peptide, as a candidate treatment for aGVHD. The authors found that, in mice that received stem cell transplantation, oral hBD-2 treatment modulated the intestinal microbiome, reduced neutrophil infiltration into the ileum, and controlled alloreactive T cell responses, all while leaving the graft-versus-leukemia effect intact. These findings highlight the potential for hBD-2 as a therapeutic option for aGVHD.—CM [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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