Adjuvants and Vaccines Used in Allergen-Specific Immunotherapy Induce Neutrophil Extracellular Traps

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.

An Autophagy Modulator Peptide Prevents Lung Function Decrease and Corrects Established Inflammation in Murine Models of Airway Allergy

“…Contrarily to the OVA-induced model, the HDM-induced allergic model does not require aluminum hydroxide as an adjuvant and more closely resembles the heterogeneous nature of human allergic asthma. It is effectively well documented that alum, a conventional adjuvant that is approved for human vaccination for decades, can trigger the release of NETs by neutrophils [ 50 , 51 ], a feature that could obscure or even alter the effect of P140 peptide. The chronic HDM model is not only a more natural model that is closer to human pathophysiology, but is also free of this potential bias.…”

Innate immune stimulation by monophosphoryl lipid A prevents chronic social defeat stress-induced anxiety-like behaviors in mice

“…An interval of 10 days between MPL injection and stress exposure abolished the preventive effect of MPL on CSDS-induced anxiety-like behaviors, which was rescued with consolidated immunization by a second MPL injection 10 days after the first MPL injection or 4 × MPL injections 1 day before stress exposure. As MPL is used as a vaccine adjuvant in clinic [ 35 , 36 ] and shows little toxicities compared to its parent molecule LPS [ 52 ], our findings may provide a promising alternative for the development of MPL as novel drugs for the prevention of anxiety-associated behaviors.…”

“…In the present study, we selected MPL, a compound that possesses fewer undesirable actions and a significant therapeutic window compared to LPS [ 25 , 26 ], to study the preventive effect of innate immune pre-stimulation on chronic stress-induced anxiety-like behaviors. MPL is commercialized as a vaccine adjuvant [ 35 , 36 ] and can induce neuroprotective effects. Pre-administration of animals with a low dose of MPL has been demonstrated to protect the neurons against ischemic stimuli [ 37 ] and reduce seizure severity induced by traumatic brain injury or pilocarpine by reducing the over-production of pro-inflammatory cytokines in the brain [ 38 , 39 ].…”

CpG-ODN Signaling via Dendritic Cells-Expressing MyD88, but Not IL-10, Inhibits Allergic Sensitization

“…Data represent the mean ± SEM. We have previously demonstrated that sensitization to allergens, with a TLR4 or TLR9 agonist, prevents the development of Th2 lung inflammation without shifting the lung inflammation towards a Th1/Th17 pattern [1][2][3]. Classically, CpG-ODN signals through the MyD88 pathway [4], but at high CpG-ODN doses, the TRIF pathway could be involved [5].…”

“…The ovalbumin (OVA) allergen and the aluminum hydroxide gel (alum) adjuvant have been extensively used to induce Th2-cell-dominated immune responses in the lung [ 1 ]. In contrast, Toll-like receptor (TLR) agonists have been used as adjuvants to downmodulate the Th2-dominated immune response [ 1 , 2 ]. Among the TLR agonists used experimentally, a TLR4 agonist composed of monophosphoryl lipid A (MPLA), and a TLR9 agonist, composed of oligodeoxynucleotides (ODN) containing CpG motifs (CpG-ODN), have been extensively used in clinical trials [ 3 , 4 , 5 ] and a formulation with CpG-ODN has been approved for human use [ 6 ].…”