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.

Paneth cell dysfunction in radiation injury and radio-mitigation by human α-defensin 5

“…Therefore, it does not rule out the potential role of altered ileal microbiota composition in the mechanism of barrier dysfunction in irradiated mice. A recent study showed that another antimicrobial peptide, human β-defensin-2, modulated intestinal microbiota composition and attenuated neutrophil infiltration in a graft-versus-host disease model, suggesting a potential direct effect of this peptide on the intestinal mucosa ( 75 ). The antibacterial effect of HD5 is attributed to the creation of pores on the bacterial plasma membrane.…”

Human α-Defensin 51–9 and Human β-Defensin 2 Improve Metabolic Parameters and Gut Barrier Function in Mice Fed a Western-Style Diet

“…In vitro, hBD-2 has been found to reduce proinflammatory cytokines, such as interleukin 1-β (IL1-β) and TNF-α (TNF) in LPS-treated human peripheral blood mononuclear cells (PBMCs) [ 38 ]. Furthermore, oral administration of hBD-2 reduced both alcohol-induced liver injury and graft-versus-host disease, in numerous mouse strains, by improving barrier function and thereby modulating host–microbe interactions and immunoreactivity [ 40 , 41 ].…”

Mechanisms and regulation of defensins in host defense

“… 262 In addition, a recent study reported that hBD2 ameliorates acute graft–versus–host disease (aGvHD) through regulating the gut microbiome to limit ileal neutrophil infiltration and restrain T-cell receptor signaling. 263 Tamima and colleagues found that induction of hBD2 is impaired in cases of aGVHD in both humans and mice. However, when hBD2 was administered, the severity and mortality of aGVHD were reduced.…”