Human β-defensin 2 ameliorates acute GVHD by limiting ileal neutrophil infiltration and restraining T cell receptor signaling

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Human β-defensin 2 ameliorates acute GVHD by limiting ileal neutrophil infiltration and restraining T cell receptor signaling. / 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; Duyster, Justus; Zeiser, Robert; Köhler, Natalie.

In: Science Translational Medicine, Vol. 14, No. 676, eabp9675, 2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Rückert, T, Andrieux, G, Boerries, M, Hanke-Müller, K, Woessner, NM, Doetsch, S, Schell, C, Aumann, K, Kolter, J, Schmitt-Graeff, A, Schiff, M, Braun, LM, Haring, E, Kissel, S, Siranosian, BA, Bhatt, AS, Nordkild, P, Wehkamp, J, Jensen, BAH, Minguet, S, Duyster, J, Zeiser, R & Köhler, N 2022, 'Human β-defensin 2 ameliorates acute GVHD by limiting ileal neutrophil infiltration and restraining T cell receptor signaling', Science Translational Medicine, vol. 14, no. 676, eabp9675. https://doi.org/10.1126/scitranslmed.abp9675

APA

Rückert, T., Andrieux, G., Boerries, M., Hanke-Müller, K., Woessner, N. M., Doetsch, S., Schell, C., Aumann, K., Kolter, J., Schmitt-Graeff, A., Schiff, M., Braun, L. M., Haring, E., Kissel, S., Siranosian, B. A., Bhatt, A. S., Nordkild, P., Wehkamp, J., Jensen, B. A. H., ... Köhler, N. (2022). Human β-defensin 2 ameliorates acute GVHD by limiting ileal neutrophil infiltration and restraining T cell receptor signaling. Science Translational Medicine, 14(676), [eabp9675]. https://doi.org/10.1126/scitranslmed.abp9675

Vancouver

Rückert T, Andrieux G, Boerries M, Hanke-Müller K, Woessner NM, Doetsch S et al. Human β-defensin 2 ameliorates acute GVHD by limiting ileal neutrophil infiltration and restraining T cell receptor signaling. Science Translational Medicine. 2022;14(676). eabp9675. https://doi.org/10.1126/scitranslmed.abp9675

Author

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 ; Duyster, Justus ; Zeiser, Robert ; Köhler, Natalie. / Human β-defensin 2 ameliorates acute GVHD by limiting ileal neutrophil infiltration and restraining T cell receptor signaling. In: Science Translational Medicine. 2022 ; Vol. 14, No. 676.

Bibtex

@article{76734cdf67254b19a08748e4723463fd,
title = "Human β-defensin 2 ameliorates acute GVHD by limiting ileal neutrophil infiltration and restraining T cell receptor signaling",
abstract = "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.",
author = "Tamina R{\"u}ckert and Geoffroy Andrieux and Melanie Boerries and Kathrin Hanke-M{\"u}ller and Woessner, {Nadine M.} and Stephanie Doetsch and Christoph Schell and Konrad Aumann and Julia Kolter and Annette Schmitt-Graeff and Marcel Schiff and Braun, {Lukas M.} and Eileen Haring and Sandra Kissel and Siranosian, {Benjamin A.} and Bhatt, {Ami S.} and Peter Nordkild and Jan Wehkamp and Jensen, {Benjamin A.H.} and Susana Minguet and Justus Duyster and Robert Zeiser and Natalie K{\"o}hler",
year = "2022",
doi = "10.1126/scitranslmed.abp9675",
language = "English",
volume = "14",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "american association for the advancement of science",
number = "676",

}

RIS

TY - JOUR

T1 - Human β-defensin 2 ameliorates acute GVHD by limiting ileal neutrophil infiltration and restraining T cell receptor signaling

AU - Rückert, Tamina

AU - Andrieux, Geoffroy

AU - Boerries, Melanie

AU - Hanke-Müller, Kathrin

AU - Woessner, Nadine M.

AU - Doetsch, Stephanie

AU - Schell, Christoph

AU - Aumann, Konrad

AU - Kolter, Julia

AU - Schmitt-Graeff, Annette

AU - Schiff, Marcel

AU - Braun, Lukas M.

AU - Haring, Eileen

AU - Kissel, Sandra

AU - Siranosian, Benjamin A.

AU - Bhatt, Ami S.

AU - Nordkild, Peter

AU - Wehkamp, Jan

AU - Jensen, Benjamin A.H.

AU - Minguet, Susana

AU - Duyster, Justus

AU - Zeiser, Robert

AU - Köhler, Natalie

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

U2 - 10.1126/scitranslmed.abp9675

DO - 10.1126/scitranslmed.abp9675

M3 - Journal article

C2 - 36542690

AN - SCOPUS:85144598071

VL - 14

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 676

M1 - eabp9675

ER -

ID: 332603936