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Diisononyl phthalate (DINP) is commonly used as a plasticizer in industrial and consumer product applications. Several studies have suggested a possible link between exposure to DINP and the development of allergic asthma, and the synergistic effect of DINP combined with Ovalbumin (OVA) is a possible way to promote an immune response. These findings are still speculative, since there is insufficient evidence to assess the ability of DINP to influence "allergic asthma pathology". This study was designed to determine any effects of OVA/DINP exposure on airway reactivity, particularly when combined with allergen exposure. Experiments to determine these effects were conducted after 15 days of combined exposure and a subsequent challenge with aerosolized ovalbumin for one week. Airway hyper-responsiveness (lung function), lung tissue pathology, cytokines and oxidative stress biomarkers were investigated. We showed that oral exposure to OVA/DINP could induce airway hyper-responsiveness (AHR), and aggravate airway wall remodeling, and that this deterioration was concomitant with increased immunoglobulin-E and Th2 cytokines secretion. The data also demonstrated that DINP could promote oxidative damage in the lung. In summary, this study showed that DINP has an adjuvant effect on allergic asthma affecting lung function, lung histopathology, immune molecules and causes oxidative damage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Activating innate immunity by an adjuvant is required in vaccine development. The study aims to investigate adjuvant effects of aqueous extracts of Artemisia rupestris L. (AEAR) in vivo and in vitro. ICR mice were subcutaneously administered with antigen and AEAR at various doses to evaluate their immune responses of antibodies, dendritic cells (DCs), regulatory T cells (Treg), splenic lymphocyte, and cytokine. The evaluation results showed that AEAR could largely increase titers of antigen-specific antibodies (IgG, IgG 1 , and IgG 2a ) and T cell proliferation. AEAR also increased expression of IFN-γ in CD8 + T cells as well as IL-4 and INF-γ expression in CD4 + T cells. Expression levels of MHC-II, CD40, CD80, and CD86 on DCs were significantly elevated, whereas the Treg frequency was significantly decreased. AEAR (200μg) showed remarkable adjuvant activity. Furthermore, AEAR enhanced MHC-II, CD40, CD80, and CD86 expression as well as the yields of TNF-α and IL-12 on DCs through toll-like receptor4 (TLR4) in vitro. Those results indicated that AEAR could serve as an efficacious immune stimulator for vaccines because it significantly enhanced specific immune responses by promoting DCs maturation and reduced Treg through TLR4 signaling pathway., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Silica nanoparticles (SNPs) can easily enter in respiratory system via inhalation because of their low molecular weight and ease of dispersion. Toxicity and adverse effects of SNPs vary according to the physical characteristics of the particle., Methods: To evaluate the toxic and adjuvant effects of 3 types of SNPs in the airway system, six-week-old female BALB/c mice were intranasally administered 3 types of SNPs (spherical [S-SNP], mesoporous [M-SNP], and polyethylene glycol-conjugated [P-SNP]) alone or SNPs/ovalbumin (OVA), three times weekly for 2 weeks. Airway hyper-responsiveness (AHR), bronchoalveolar lavage fluid (BALF), cytokine levels, and histology of the lungs were analyzed., Results: The S-SNPs/OVA group and M-SNPs/OVA group showed significant AHR, compared to the control group. Among all SNP-treated groups, the group administered SNPs/OVA showed greater inflammatory cell infiltration in BALF, extensive pathological changes, and higher cytokine levels (IL-5, IL-13, IL-1β, and IFN-γ) than those administered SNPs alone or saline/OVA., Conclusion: Exposure to SNPs alone and SNPs/OVA induced toxicity in the respiratory system. SNPs alone showed significant toxic effects on the airway system. Meanwhile, SNPs/OVA exerted adjuvant effects to OVA of inducing allergic airway inflammation. In particular, M-SNPs showed the most severe airway inflammation in both direct toxicity and adjuvant effect assays. P-SNPs induced less inflammation than the other types of SNPs in both models.

Subvisible particles in a therapeutic protein product may act as adjuvants to promote unwanted immune responses against the protein. Silicone oil is used as a lubricant in prefilled syringes, and microdroplets of silicone oil are often detected in protein formulations expelled from prefilled syringes. In order to test the adjuvant potency of silicone oil microdroplets, antibody responses in mice to subcutaneous injections of formulations of ovalbumin (OVA) that contained silicone oil microdroplets were measured. These responses were compared against responses to oil-free OVA formulations and to OVA formulations that contained microparticulate aluminum hydroxide ("alum"), the common vaccine adjuvant. When administered with high concentrations of silicone oil microdroplets, OVA formulations elicited strong anti-OVA IgG1 and IgG2a antibody responses. These responses were equivalent to those observed when alum microparticles were added to OVA formulations, suggesting that silicone oil can act as a potent adjuvant. However, when OVA formulations were prepared with lower levels of silicone oil that had been obtained directly from commercial siliconized syringes, the anti-OVA antibody response was not enhanced significantly compared with responses against OVA alone., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Di-(2-ethylhexyl) phthalate (DEHP) has been considered as a widespread environmental persistent organic pollutant and its potential concern on human health is raised by previous studies. In particular, children are more likely to be exposed to DEHP through gastrointestinal route and consequently are more susceptible to DEHP hazards. Some reports have uncovered a positive association between DEHP exposure and an increased prevalence of allergic diseases in infants and juveniles. Allergy is a hypersensitive reaction rooted in imbalanced humoral immunity. T follicular helper cell (Tfh), an important CD4(+) Th cell subset, until recently has been identified as a key player in humoral immune response by modifying B cells functions. Tfh cells are therefore perceived as the therapeutic target of immune disorders. In the present study, focusing on the newly confirmed Tfh cells, we examined the effects of DEHP on humoral immunity and investigated the underlying mechanisms. Using ovalbumin (OVA) sensitization weanling mice model under the condition of gastrointestinal exposure to DEHP, we found that DEHP acted as an immunoadjuvant to augment OVA-specific IgE and IgG1 production, amplified germinal center formation in lymphoid nodule, as well as stimulated the expansion of CD4(+)CXCR5(+)ICOS(+)/CD4(+)CXCR5(+)PD-1(+) Tfh cells and CD19(+)CD138(+)GL7(+) plasma cells. Based on the results of immune adoptive transfusion, DEHP-related anaphylactic response was ascribed to Tfh cells hyperfunction directly. We further proved that DEHP gavage together with OVA sensitization adjuvantly promoted the synthesis of cytokines IL-21 and IL-4 and the expression of transcription factors Bcl-6 and c-Maf in Tfh cells. In conclusion, our study demonstrates that DEHP has adjuvant toxic effects on Tfh cells by synthesizing an excess of cytokines IL-21 and IL-4 via over-expression of transcription factors Bcl-6 and c-Maf, leading to an increasing secretion of allergy-related IgE and IgG1., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Particulate matter (PM) is an important risk factor for asthma. Generation of oxidative stress by PM is a major mechanism of its health effects. Transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) mediates antioxidant and phase II enzymes and is essential in protecting against oxidative stress and lung inflammation. We have previously shown that ambient ultrafine particles (UFP) could exert a potent adjuvant effect on allergic sensitization to ovalbumin (OVA) in mice. We hypothesized that Nrf2 deficiency in dendritic cells (DC) could enhance the adjuvant potential of UFP on allergic sensitization. We show that the adjuvant effect of intranasally instilled UFP is significantly enhanced in Nrf2 knockout (Nrf2(-/-)) mice compared with their wild-type (Nrf2(+/+)) counterparts. Under resting conditions, Nrf2(-/-) DC displayed an intrinsic predilection to a T helper 2-favoring cytokine profile characterized by a low level of IL-12p70 and a high level of IL-6 as compared to Nrf2(+/+) DC. Adoptive transfer of OVA/UFP-treated Nrf2(-/-) DC provoked a more severe allergic inflammation in the lung than Nrf2(+/+) DC in the same treatment group. We conclude that Nrf2 deficiency in DC may promote a constitutive immune-polarizing cytokine milieu, which we propose may have contributed to the augmented adjuvant effect of UFP on allergic sensitization.

Abstract: The immunological adjuvant effect of silver nanoparticles (AgNPs) was investigated both in vitro and in vivo. The in vivo adjuvant effect of AgNPs was evaluated with model antigen ovalbumin (OVA) and bovine serum albumin (BSA) in mice by intraperitoneal and subcutaneous immunization. Serum antigen-specific IgG level significantly increased in AgNPs-treated mice comparing to the control group. AgNPs induced the increase of IgG1/IgG2a ratio and antigen-specific IgE, indicating that AgNPs elicited Th2-biased immune responses. By in vitro assay, the mechanism of adjuvant effect was explored. After 48h treatment with AgNPs, both the number of leukocytes and levels of cytokines TNF-α and IFN-γ in abdominal lavage fluid of mice increased. The expression of the major histocompatibility complex class II molecule on the surface of peritoneal macrophages significantly increased. AgNPs can be easily phagocytosed by peritoneal macrophages, while do not affect antigen uptake by the cell. We therefore conclude that AgNPs have significant adjuvant effect and the mechanism of this effect is mainly ascribed to the recruitment and activation of local leukocytes and especially macrophages. For the first time we found the remarkable adjuvant effect of AgNPs, and the result is beneficial for the future applications, especially in biomedicine. [Copyright &y& Elsevier]

Abstract: Phthalates, including di(2-ethylhexyl) phthalate (DEHP), are widely used and have been linked with the development of wheezing and asthma. The main metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP), was investigated for adjuvant effects in a mouse inhalation model. BALB/cJ mice were exposed to aerosols of 0.03 or 0.4mg/m3 MEHP 5 days/week for 2 weeks and thereafter weekly for 12 weeks together with a low dose of ovalbumin (OVA) as a model allergen. Mice exposed to OVA alone or OVA+Al(OH)3 served as negative and positive controls, respectively. Finally, all groups were exposed to a nebulized 1% OVA solution on 3 consecutive days to investigate the development of an inflammatory response. Serum, bronchoalveolar lavage (BAL) fluid, and draining lymph nodes were collected 24h later. In the OVA+Al(OH)3 group, significantly increased levels of OVA-specific IgE and IgG1 in serum as well as of eosinophils in BAL fluid were observed. OVA-specific IgG1 production in both MEHP groups was significantly increased. OVA-specific IgE and IgG2a were not increased significantly. A dose-dependent increase in inflammatory cells was observed in BAL fluid, leading to significantly higher lymphocyte and eosinophil numbers in the OVA+0.4mg/m3 MEHP group. Ex vivo cytokine secretion by cultures of draining lymph nodes suggested a TH2 profile of MEHP. In conclusion, MEHP acted as a TH2 adjuvant after inhalation. However, it is suggested that the inflammation in the MEHP groups was primarily mediated by an IgG1-dependent mechanism. To address implications for humans, a margin-of-exposure was estimated based on the lack of significant effects on IgE production and inflammation after exposures to 0.03mg/m3 MEHP observed in the present study and estimated human exposure levels. [Copyright &y& Elsevier]