The role of Toll-like receptor-4 in pertussis vaccine-induced immunity

<p>Abstract</p> <p>Background</p> <p>The gram-negative bacterium <it>Bordetella pertussis </it>is an important causative agent of pertussis, an infectious disease of the respiratory tract. After introduction of whole-cell vaccines (wP) in the 1950's, pertussis incidence has decreased significantly. Because wP were found to be reactogenic, in most developed countries they have been replaced by acellular vaccines (aP). We have previously shown a role for Toll-like receptor 4 (Tlr4) in pertussis-infected mice and the pertussis toxin (Ptx)-IgG response in wP-vaccinated children, raising the issue of the relative importance of Tlr4 in wP vaccination of mice. Here we analyze the effects of wP and aP vaccination and <it>B. pertussis </it>challenge, in <it>Tlr4</it>-deficient C3H/HeJ and wild-type C3H/HeOuJ mice. aP consists of Ptx, filamentous hemagglutinin (FHA), and pertactin (Prn).</p> <p>Results</p> <p>We show an important role of Tlr4 in wP and (to a lesser extent) aP vaccination, induction of Th1 and Th17 cells by wP but not aP vaccination, and induction of Th17 cells by infection, confirming data by Higgins et al. (<it>J Immunol </it>2006, <b>177:</b>7980–9). Furthermore, in <it>Tlr4</it>-deficient mice, compared to wild-type controls (i) after vaccination only, Ptx-IgG (that was induced by aP but not wP vaccination), FHA-IgG, and Prn-IgG levels were similar, (ii) after infection (only), lung IL-1α and IL-1β expression were lower, (iii) after wP vaccination and challenge, Prn-IgG level and lung IL-5 expression were higher, while lung IL-1β, TNF-α, IFN-γ, IL-17, and IL-23 expression were lower, and lung pathology was absent, and (iv) after aP vaccination and challenge, Prn-IgG level and lung IL-5 expression were higher, while Ptx-IgG level was lower.</p> <p>Conclusion</p> <p>Tlr4 does not influence the humoral response to vaccination (without challenge), plays an important role in natural immunity, wP and aP efficacy, and induction of Th1 and Th17 responses, is critical for lung pathology and enhances pro-inflammatory cytokine production after wP vaccination and challenge, and diminishes Th2 responses after both wP and aP vaccination and challenge. wP vaccination does not induce Ptx-IgG. A role for LPS in the efficacy of wP underlines the usefulness of LPS analogs to improve bacterial subunit vaccines such as aP.</p

Исследование изменений твёрдости поверхности при азотировании сталей

Contact allergies are complex diseases, and one of the important challenges for public health and immunology. The German 'Federal Institute for Risk Assessment' hosted an 'International Workshop on Contact Dermatitis'. The scope of the workshop was to discuss new discoveries and developments in the field of contact dermatitis. This included the epidemiology and molecular biology of contact allergy, as well as the development of new in vitro methods. Furthermore, it considered regulatory aspects aiming to reduce exposure to contact sensitisers. An estimated 15-20% of the general population suffers from contact allergy. Workplace exposure, age, sex, use of consumer products and genetic predispositions were identified as the most important risk factors. Research highlights included: advances in understanding of immune responses to contact sensitisers, the importance of autoxidation or enzyme-mediated oxidation for the activation of chemicals, the mechanisms through which hapten-protein conjugates are formed and the development of novel in vitro strategies for the identification of skin-sensitising chemicals. Dendritic cell cultures and structure-activity relationships are being developed to identify potential contact allergens. However, the local lymph node assay (LLNA) presently remains the validated method of choice for hazard identification and characterisation. At the workshop the use of the LLNA for regulatory purposes and for quantitative risk assessment was also discussed

Towards a nanospecific approach for risk assessment.

In the current paper, a new strategy for risk assessment of nanomaterials is described, which builds upon previous project outcomes and is developed within the FP7 NANoREG project. NANoREG has the aim to develop, for the long term, new testing strategies adapted to a high number of nanomaterials where many factors can affect their environmental and health impact. In the proposed risk assessment strategy, approaches for (Quantitative) Structure Activity Relationships ((Q)SARs), grouping and read-across are integrated and expanded to guide the user how to prioritise those nanomaterial applications that may lead to high risks for human health. Furthermore, those aspects of exposure, kinetics and hazard assessment that are most likely to be influenced by the nanospecific properties of the material under assessment are identified. These aspects are summarised in six elements, which play a key role in the strategy: exposure potential, dissolution, nanomaterial transformation, accumulation, genotoxicity and immunotoxicity. With the current approach it is possible to identify those situations where the use of nanospecific grouping, read-across and (Q)SAR tools is likely to become feasible in the future, and to point towards the generation of the type of data that is needed for scientific justification, which may lead to regulatory acceptance of nanospecific applications of these tools.The research leading to these results has been partially funded by the European Union Seventh Framework Programme (FP7/ 2007e2013) under the project NANoREG (A common European approach to the regulatory testing of nanomaterials), grant agreement 310584.info:eu-repo/semantics/publishedVersio

Overcoming scientific barriers in the transition from in vivo to non-animal batch testing of human and veterinary vaccines

INTRODUCTION : Before release, vaccine batches are assessed for quality to evaluate whether they meet the product specifications. Vaccine batch tests, in particular of inactivated and toxoid vaccines, still largely rely on in vivo methods. Improved vaccine production processes, ethical concerns, and suboptimal performance of some in vivo tests have led to the development of in vitro alternatives. AREAS COVERED : This review describes the scientific constraints that need to be overcome for replacement of in vivo batch tests, as well as potential solutions. Topics include the critical quality attributes of vaccines that require testing, the use of cell-based assays to mimic aspects of in vivo vaccine-induced immune responses, how difficulties with testing adjuvanted vaccines in vitro can be overcome, the use of altered batches to validate new in vitro test methods, and how cooperation between different stakeholders is key to moving the transition forward. EXPERT OPINION : For safety testing, many in vitro alternatives are already available or at an advanced level of development. For potency testing, in vitro alternatives largely comprise immunochemical methods that assess several, but not all critical vaccine properties. One-to-one replacement by in vitro alternatives is not always possible and a combination of methods may be required.The Dutch Ministry of Agriculture, Nature and Food Quality, the National Institute of Public Health & the Environment and Intravacc.https://www.tandfonline.com/loi/ierv20am2022Veterinary Tropical Disease

An Air-liquid Interface Bronchial Epithelial Model for Realistic, Repeated Inhalation Exposure to Airborne Particles for Toxicity Testing.

For toxicity testing of airborne particles, air-liquid interface (ALI) exposure systems have been developed for in vitro tests in order to mimic realistic exposure conditions. This puts specific demands on the cell culture models. Many cell types are negatively affected by exposure to air (e.g., drying out) and only remain viable for a few days. This limits the exposure conditions that can be used in these models: usually relatively high concentrations are applied as a cloud (i.e., droplets containing particles, which settle down rapidly) within a short period of time. Such experimental conditions do not reflect realistic long-term exposure to low concentrations of particles. To overcome these limitations the use of a human bronchial epithelial cell line, Calu-3 was investigated. These cells can be cultured at ALI conditions for several weeks while retaining a healthy morphology and a stable monolayer with tight junctions. In addition, this bronchial model is suitable for testing the effects of repeated exposures to low, realistic concentrations of airborne particles using an ALI exposure system. This system uses a continuous airflow in contrast to other ALI exposure systems that use a single nebulization producing a cloud. Therefore, the continuous flow system is suitable for repeated and prolonged exposure to airborne particles while continuously monitoring the particle characteristics, exposure concentration, and delivered dose. Taken together, this bronchial model, in combination with the continuous flow exposure system, is able to mimic realistic, repeated inhalation exposure conditions that can be used for toxicity testing

Cytotoxicity of ZnO Nanoparticles Can Be Tailored by Modifying Their Surface Structure: A Green Chemistry Approach for Safer Nanomaterials

ZnO nanoparticles (NP) are extensively used in numerous nanotechnology applications; however, they also happen to be one of the most toxic nanomaterials. This raises significant environmental and health concerns and calls for the need to develop new synthetic approaches to produce safer ZnO NP, while preserving their attractive optical, electronic, and structural properties. In this work, we demonstrate that the cytotoxicity of ZnO NP can be tailored by modifying their surface-bound chemical groups, while maintaining the core ZnO structure and related properties. Two equally sized (9.26 ± 0.11 nm) ZnO NP samples were synthesized from the same zinc acetate precursor using a forced hydrolysis process, and their surface chemical structures were modified by using different reaction solvents. X-ray diffraction and optical studies showed that the lattice parameters, optical properties, and band gap (3.44 eV) of the two ZnO NP samples were similar. However, FTIR spectroscopy showed significant differences in the surface structures and surface-bound chemical groups. This led to major differences in the zeta potential, hydrodynamic size, photocatalytic rate constant, and more importantly, their cytotoxic effects on Hut-78 cancer cells. The ZnO NP sample with the higher zeta potential and catalytic activity displayed a 1.5-fold stronger cytotoxic effect on cancer cells. These results suggest that by modifying the synthesis parameters/conditions and the surface chemical structures of the nanocrystals, their surface charge density, catalytic activity, and cytotoxicity can be tailored. This provides a green chemistry approach to produce safer ZnO NP

Drivers and barriers in the consistency approach for vaccine batch release testing: Report of an international workshop

Safety and potency assessment for batch release testing of established vaccines still relies partly on animal tests. An important avenue to move to batch release without animal testing is the consistency approach. This approach is based on thorough characterization of the vaccine, and the principle that the quality of subsequent batches is the consequence of the application of consistent production of batches monitored by a GMP quality system. Efforts to implement the consistency approach are supported by several drivers from industry, government, and research, but there are also several barriers that must be overcome. A workshop entitled “Consistency Approach, Drivers and Barriers” was organized, which aimed to discuss and identify drivers and barriers for the implementation of the 3Rs in the consistency approach from three different perspectives/domains (industry, regulatory and science frameworks). The workshop contributed to a better understanding of these drivers and barriers and resulted in recommendations to improve the overall regulatory processes for the consistency approach. With this report, we summarise the outcome of this workshop and intend to offer a constructive contribution to the international discussion on regulatory acceptance of the consistency approach

Role of chemical composition and redox modification of poorly soluble nanomaterials on their ability to enhance allergic airway sensitisation in mice

BACKGROUND: Engineered nanoparticles (NPs) have been shown to enhance allergic airways disease in mice. However, the influence of the different physicochemical properties of these particles on their adjuvant properties is largely unknown. Here we investigate the effects of chemical composition and redox activity of poorly soluble NPs on their adjuvant potency in a mouse model of airway hypersensitivity. RESULTS: NPs of roughly similar sizes with different chemical composition and redox activity, including CeO2, Zr-doped CeO2, Co3O4, Fe-doped Co3O4(using Fe2O3 or Fe3O4) and TiO2 NPs, all showed adjuvant activity. OVA induced immune responses following intranasal exposure of BALB/c mice to 0.02% OVA in combination with 200 μg NPs during sensitization (on day 1, 3, 6 and 8) and 0.5% OVA only during challenge (day 22, 23 and 24) were more pronounced compared to the same OVA treatment regime without NPs. Changes in OVA-specific IgE and IgG1 plasma levels, differential cell count and cytokines in bronchoalveolar lavage fluid (BALF), and histopathological detection of mucosa cell metaplasia and eosinophil density in the conducting airways were observed. Adjuvant activity of the CeO2 NPs was primarily mediated via the Th2 response, while that of the Co3O4 NPs was characterised by no or less marked increases in IgE plasma levels, BALF IL-4 and IL-5 concentrations and percentages of eosinophils in BALF and more pronounced increases in BALF IL-6 concentrations and percentages of lymphocytes in BALF. Co-exposure to Co3O4 NPs with OVA and subsequent OVA challenge also induced perivascular and peribronchiolar lymphoid cell accumulation and formation of ectopic lymphoid tissue in lungs. Responses to OVA combined with various NPs were not affected by the amount of doping or redox activity of the NPs. CONCLUSIONS: The findings indicate that chemical composition of NPs influences both the relative potency of NPs to exacerbate allergic airway sensitization and the type of immune response. However, no relation between the acellular redox activity and the observed adjuvant activity of the different NPs was found. Further research is needed to pinpoint the precise physiological properties of NPs and biological mechanisms determining adjuvant activity in order to facilitate a safe-by-design approach to NP development