Abstract
Aluminum hydroxide (alum) and monophosphoryl-lipid A (MPLA) are conventional adjuvants in vaccines for allergen-specific immunotherapy (AIT). Alum triggers the release of neutrophil extracellular traps (NETs) by neutrophils. NETs contain expelled decondensed chromatin associated with granular material and may act as danger-associated molecular patterns and activate antigen-presenting cells. We investigated whether adjuvant-induced NETs contribute to innate responses to AIT-vaccines. Human neutrophils were incubated with alum, MPLA and adjuvant-containing AIT-vaccine preparations. NETs were verified by time-lapse and confocal fluorescence microscopy and quantitatively assessed by DNA and elastase release and ROS production. In contrast to MPLA, alum represented a potent trigger for NET release. Vaccine formulations containing alum resulted in less NET release than alum alone, whereas the vaccine containing MPLA induced stronger NET responses than MPLA alone. NETs and alum alone and synergistically increased the expression of molecules involved in antigen presentation, i.e., CD80, CD86 and CD83, by peripheral blood monocytes. Monocyte priming with NETs resulted in individually differing IL-1β- and IL-6-responses. Thus, NETs induced by adjuvants in AIT-vaccines can provide autonomous and cooperative effects on early innate responses. The high diversity of individual innate responses to adjuvants and AIT-vaccines may affect their therapeutic efficacy.
Highlights
Allergen-specific immunotherapy (AIT) elicits long-lasting clinical tolerance because it modifies the immune response to allergens [1,2]
Stephen et al found that extravasation and swarming of neutrophils as well as the release of neutrophil extracellular traps (NETs) early after injection of alum into mice was important for its adjuvanticity [15]
NETs are 3-dimensional web-like structures composed of decondensed chromatin and mitochondrial DNA that are complexed with toxic granular material such as myeloperoxidase (MPO), neutrophil elastase (NE) or the cationic cathelicidin peptide LL-37, which can keep microbes from growing and spreading [16,17]
Summary
Allergen-specific immunotherapy (AIT) elicits long-lasting clinical tolerance because it modifies the immune response to allergens [1,2]. Indirect effects via the release of dangerassociated molecular patterns (DAMPs) have been discussed These include urate crystals released from dying cells that activate the nucleotide oligomerization domain (NOD)-like receptor pyrin-domain-containing 3 (NALP3) inflammasome and caspase 1-dependent release of the mature forms of IL-1β and IL-18, which causes local inflammation [6,7,8,9,10,11]. Alum has been shown to promote differentiation by increasing the expression of HLA-class II and co-stimulatory molecules as well as markers of dendritic maturation [22,23,24] Assuming that both NETs and alum are present at the injection site of AIT-vaccines, we sought to investigate their potential cooperative effects on the expression of surface molecules involved in antigen presentation or cytokine release. We assessed the influence of NETs on allergen-uptake, expression of molecules involved in antigen presentation and cytokine production by monocytes
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