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Antibiotic resistance has become a global issue. The most significant risk is the acquisition of these mechanisms by pathogenic bacteria, which can have a severe clinical impact and pose a public health risk. This problem assumes that bacterial fitness is a constant phenomenon and should be approached from an evolutionary perspective to develop the most appropriate and effective strategies to contain the emergence of strains with pathogenic potential. Resistance mechanisms can be understood as adaptive processes to stressful conditions. This review examines the relevance of homeostatic regulatory mechanisms in antimicrobial resistance mechanisms. We focus on the interactions in the cellular physiology of pathogenic bacteria, particularly Gram-negative bacteria, and specifically Klebsiella pneumoniae. From a clinical research perspective, understanding these interactions is crucial for comprehensively understanding the phenomenon of resistance and developing more effective drugs and treatments to limit or attenuate bacterial sepsis, since the most conserved adjuvant phenomena in bacterial physiology has turned out to be more optimized and, therefore, more susceptible to alterations due to pharmacological action. [ABSTRACT FROM AUTHOR]

Numerous studies have indicated a link between vaccines and the exacerbation of autoimmune diseases including rheumatoid arthritis (RA). However, there is no consensus in clinical practice regarding the optimal timing of immunization. Therefore, this study aimed to investigate the impact of the 3Fluart influenza vaccine on the complete Freund's adjuvant (CFA)-induced chronic arthritis rat model and to identify new biomarkers with clinical utility. CFA was injected into the plantar surface of one hind paw and the root of the tail on day 0, and the tail root injection was repeated on day 1. Flu vaccination was performed on day 1 or 7. Paw volume was measured by plethysmometry, mechanonociceptive threshold by dynamic plantar aesthesiometry, neutrophil myeloperoxidase (MPO) activity, and vascular leakage using in vivo optical imaging throughout the 21-day experiment. Inflammatory markers were determined by Western blot and histopathology. CFA-induced swelling, an increase in MPO activity, plasma extravasation in the tibiotarsal joint. Mechanical hyperalgesia of the hind paw was observed 3 days after the injection, which gradually decreased. Co-administration of the flu vaccine on day 7 but not on day 1 resulted in significantly increased heme oxygenase 1 (HO-1) expression. The influenza vaccination appears to have a limited impact on the progression and severity of the inflammatory response and associated pain. Nevertheless, delayed vaccination could alter the disease activity, as indicated by the findings from assessments of edema and inflammatory biomarkers. HO-1 may serve as a potential marker for the severity of inflammation, particularly in the case of delayed vaccination. However, further investigation is needed to fully understand the regulation and role of HO-1, a task that falls outside the scope of the current study. [ABSTRACT FROM AUTHOR]

Multilayered polymeric particles work as carriers of compounds with controlled release triggered by the layer's disassembly, allowing chemical stability along with transport through the bloodstream and tissues. Here, we present versatile multilayered polymeric particles as a vaccine approach against COVID-19 based on coupling a recombinant form of the receptor binding domain (RBD) antigen of the SARS-CoV-2 Spike proteins. The particle core comprises poly-(d,l-lactide) coated with Triton X-100 and polyethylenimine, prepared by nanoemulsion/solvent evaporation method and functionalized with heparin by layer-by-layer (PLTP-H). The recombinant RBD is anchored to the nanoparticles by the negative outer layer (PLTP-H-RBD). The nanoparticles reached a complexation efficiency of 95% for the RBD and a final hydrodynamic diameter of 140 nm with a zeta potential of −46 mV. No toxicity was recorded with the nanoparticles using cultured mammalian cells or after inoculation into mice. The immunization of mice with antigen-loaded nanoparticles induced strong adjuvant effects on the serum levels of RBD-specific IgG antibodies, which were capable of neutralizing the virus under in vitro conditions. Furthermore, PLTP-H-RBD conferred enhanced protective immunity to mice challenged with the SARS-CoV-2 virus. These findings represent a proof of concept for the use of PLTP-H as a delivery and adjuvant strategy for recombinant vaccine antigens aiming at the induction of neutralizing antibodies. [ABSTRACT FROM AUTHOR]

Respiratory diseases continue to be a major global concern, with allergies and asthma often discussed as critical areas of study. While the role of environmental risk factors, such as non-allergenic pollutants and high humidity, in asthma induction is often mentioned, there is still a lack of thorough research on their co-exposure. This study aims to investigate the adjuvant effect of ultrafine carbon black (30–50 nm) and high humidity (70% relative humidity) on the induction of allergic asthma. A mouse model of asthma was established using ovalbumin, and airway hyperresponsiveness, remodeling, and inflammation were measured as the endpoint effects of asthma. The mediating role of the oxidative stress pathway and the transient receptor potential vanilloid 1 pathway in asthma induction was validated using pathway inhibitors vitamin E and capsaicin, respectively. Co-exposure to ultrafine carbon black and high humidity had a significant impact on metabolic pathways in the lung, including aminoacyl-tRNA biosynthesis, glycerophospholipid metabolism, and ATP-binding cassette transporters. However, administering vitamin E and capsaicin altered the effects of co-exposure on the lung metabolome. These results offer new insights into the health risk assessment of co-exposure to environmental risk factors and provide an important reference point for the prevention and treatment of allergic asthma. [ABSTRACT FROM AUTHOR]

Antibiotic resistance has become a global issue. The most significant risk is the acquisition of these mechanisms by pathogenic bacteria, which can have a severe clinical impact and pose a public health risk. This problem assumes that bacterial fitness is a constant phenomenon and should be approached from an evolutionary perspective to develop the most appropriate and effective strategies to contain the emergence of strains with pathogenic potential. Resistance mechanisms can be understood as adaptive processes to stressful conditions. This review examines the relevance of homeostatic regulatory mechanisms in antimicrobial resistance mechanisms. We focus on the interactions in the cellular physiology of pathogenic bacteria, particularly Gram-negative bacteria, and specifically Klebsiella pneumoniae. From a clinical research perspective, understanding these interactions is crucial for comprehensively understanding the phenomenon of resistance and developing more effective drugs and treatments to limit or attenuate bacterial sepsis, since the most conserved adjuvant phenomena in bacterial physiology has turned out to be more optimized and, therefore, more susceptible to alterations due to pharmacological action.

Rui Deng,1 Ya Zhu,2 Xinyue Wu,3 Mingpu Wang1 1Joint International Research Laboratory of Green Buildings and Built Environments (Ministry of Education), School of Civil Engineering, Chongqing University, Chongqing, 400045, People’s Republic of China; 2The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China; 3Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Department of Environmental Science, Zhejiang University, Hangzhou, 310058, People’s Republic of ChinaCorrespondence: Rui Deng, School of Civil Engineering, Chongqing University, Chongqing, 400045, People’s Republic of China, Email dengrui@cqu.edu.cnAbstract: Asthma is a chronic respiratory disease that is highly sensitive to environmental pollutants, including engineered nanoparticles (NPs). Exposure to NPs has become a growing concern for human health, especially for susceptible populations. Toxicological studies have demonstrated strong associations between ubiquitous NPs and allergic asthma. In this review, we analyze articles that focus on adverse health effects induced by NPs in animal models of allergic asthma to highlight their critical role in asthma. We also integrate potential mechanisms that could stimulate and aggravate asthma by NPs. The toxic effects of NPs are influenced by their physicochemical properties, exposure dose, duration, route, as well as the exposure order between NPs and allergens. The toxic mechanisms involve oxidative stress, various inflammasomes, antigen presenting cells, immune cells, and signaling pathways. We suggest that future research should concentrate on establishing standardized models, exploring mechanistic insights at the molecular level, assessing the combined effects of binary exposures, and determining safe exposure levels of NPs. This work provides concrete evidence of the hazards posed by NPs in animals with compromised respiratory health and supports the modifying role of NPs exposure in allergic asthma.Graphical Abstract: Keywords: engineered nanoparticles, allergic asthma, mouse model, toxicity, mechanisms, adjuvant effect

Bacterial flagellin (FliC) can be used as a TLR5 ligand-like adjuvant. However, the sequences of hypervariable regions(HVR) of FliC from different bacteria vary, and their effects on adjuvants remain unclear. In this study, FliCΔ274–406 (deleting of D3 domain) and FliCΔ174–506 (deleting of D2-D3 domain) from Escherichia coli Nissle 1917 FliC (FliCEcN) were constructed and expressed in host bacteria, BL21. Purification was conducted using affinity chromatography on a Ni-NTA column, validation was done using SDS-PAGE and western blotting, the antigenicity and immunogenicity were detected using ELISA, and adjuvant effects were evaluated in Caco-2 cells and mice. The results showed that FliCEcN was mainly expressed in the bacterial supernatant, and the two truncated flagellins were expressed as inclusion bodies. Compared with FliCEcN, both FliCΔ274–406 and FliCΔ174–506 had considerable decreased antigenicity and immunogenicity. In Caco-2 cells, FliCΔ174–506 had a higher ability to promote the secretion of IL-8 than FliCEcN and FliCΔ274–406. In mice, FliCΔ174–506 showed a comparable adjuvant level to FliCEcN, while FliCΔ274–406 was less effective. Our data shows that adjuvant effects of FliCEcN with deletion of different regions of its HVR are inconsistent, and deleting its entire D2–D3 domain is better. [ABSTRACT FROM AUTHOR]

Purpose: To assess the optimal time of intravitreal conbercept (IVC) treatment prior to pars plana vitrectomy (PPV) in patients with severe proliferative diabetic retinopathy (PDR). Method: This study was exploratory in nature. Forty-eight consecutive patients (48 eyes) with PDR were divided into four groups according to different IVC times (0.5 mg/0.05 mL) before PPV: group A (3 days), group B (7 days), group C (14 days), and group D (non-IVC). Intraoperative and postoperative effectiveness were assessed, and vitreous VEGF concentrations were detected. Result: For intraoperative effectiveness, groups A and D had a higher incidence of intraoperative bleeding than groups B and C (P = 0.041). Furthermore, groups AC required less surgical time than group D (P < 0.05). For postoperative effectiveness, group B had a significantly higher proportion of visual acuity that improved or remained unchanged than group D (P = 0.014), and groups A-C had lower proportions of postoperative bleeding than group D. The vitreous VEGF concentration of group B (67.04 ± 47.24 pg/mL) was significantly lower than that of group D (178.29 ± 110.50 pg/mL) (P = 0.005). Conclusion: IVC treatment that was administered 7 days preoperatively was associated with better effectiveness and a lower vitreous VEGF concentration than its administration at other time points. [ABSTRACT FROM AUTHOR]

Bacterial lipopolysaccharides (LPS) are potent innate immunostimulants targeting the Toll-like receptor 4 (TLR4), an attractive and validated target for immunostimulation in cancer therapy. Although LPS possess anti-tumor activity, toxicity issues prevent their systemic administration at effective doses in humans. We first demonstrated that LPS formulated in liposomes preserved a potent antitumor activity per se upon systemic administration in syngeneic models, and significantly enhance the antitumor activity of the anti-CD20 antibody rituximab in mice xenografted with the human RL lymphoma model. Liposomal encapsulation also allowed a 2-fold reduction in the induction of proinflammatory cytokines by LPS. Mice receiving an intravenous administration demonstrated a significant increase of neutrophils, monocytes and macrophages at the tumor site as well as an increase of macrophages in spleen. Further, we chemically detoxified LPS to obtain MP-LPS that was associated with a 200-fold decrease in the induction of proinflammatory cytokines. When encapsulated in a clinically approved liposomal formulation, toxicity, notably pyrogenicity (10-fold), was limited while the antitumor activity and immunoadjuvant effect were maintained. This improved tolerance profile of liposomal MP-LPS was associated with the preferential activation of the TLR4-TRIF pathway. Finally, in vitro studies demonstrated that stimulation with encapsulated MP-LPS reversed the polarization of M2 macrophages towards an M1 phenotype, and a phase 1 trial in healthy dogs validated its tolerance upon systemic administration up to very high doses (10µg/kg). Altogether, our results demonstrate the strong therapeutic potential of MPLPS formulated in liposomes as a systemically active anticancer agent, supporting its evaluation in patients with cancer. [ABSTRACT FROM AUTHOR]

Micro- and nanoplastics (MNP) are ubiquitously present in the environment due to their high persistence and bioaccumulative properties. Humans get exposed to MNP via various routes and consequently, they will encounter dendritic cells (DC) which are antigen-presenting cells involved in regulating immune responses. The consequences of DC exposure to MNP are an important, yet understudied, cause of concern. Therefore, this study aimed to assess the uptake and effect of MNP in vitro by exposing human monocyte-derived dendritic cells (MoDC) to virgin and environmentally weathered polystyrene (PS) particles of different sizes (0.2, 1, and 10 µm), at different concentrations ranging from 1 to 100 µg/ml. The effects of these particles were examined by measuring co-stimulatory surface marker (i.e. CD83 and CD86) expression. In addition, T-cell proliferation was measured via a mixed-leukocyte reaction (MLR) assay. The results showed that MoDC were capable of absorbing PS particles, and this was facilitated by pre-incubation in heat-inactivated (HI) plasma. Furthermore, depending on their size, weathered PS particles in particular caused increased expression of CD83 and CD86 on MoDC. Lastly, weathered 0.2 µm PS particles were able to functionally activate MoDC, leading to an increase in T-cell activation. These in vitro data suggest that, depending on their size, weathered PS particles might act as an immunostimulating adjuvant, possibly leading to T-cell sensitization.

Seasonal influenza is a major upper respiratory tract infection occurring in winter. Vaccination is the best method for preventing this infection. We conducted two randomized, double-blind, placebo-controlled trials to examine whether consumption of yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1, which has been reported to reduce the risk of catching the common cold, augments serum antibody titers against seasonal influenza vaccines. In the first trial, which included university students, serum antibody titers against influenza A (H3N2) and B viruses were significantly higher in the yogurt group than in the placebo group. According to the guidelines established by the European Medicines Agency (EMA) for the assessment of vaccines, the seroconversion rate and mean geometric increase of influenza A (H3N2) and seroprotection of influenza B met the criteria only in the yogurt group. In the second trial, which included healthy adults, serum antibody titers against influenza A (H1N1) and B viruses were significantly higher in the yogurt group than in the placebo group. The seroconversion rate and mean geometric increase of influenza B met the EMA criteria only in the yogurt group. Furthermore, the cumulative days of ill health, such as throat complaints, upper respiratory inflammation, and cold, were significantly lower in the yogurt group than in the placebo group. Therefore, daily intake of yogurt fermented with L. bulgaricus OLL1073R-1 could reduce the duration of symptoms caused by respiratory infections and act as a mucosal adjuvant enhancing acquired immune responses against vaccines, leading to the improvement of public health. [ABSTRACT FROM AUTHOR]

Bacterial lipopolysaccharides (LPS) are potent innate immunostimulants targeting the Toll-like receptor 4 (TLR4), an attractive and validated target for immunostimulation in cancer therapy. Although LPS possess anti-tumor activity, toxicity issues prevent their systemic administration at effective doses in humans. We first demonstrated that LPS formulated in liposomes preserved a potent antitumor activity per se upon systemic administration in syngeneic models, and significantly enhance the antitumor activity of the anti-CD20 antibody rituximab in mice xenografted with the human RL lymphoma model. Liposomal encapsulation also allowed a 2-fold reduction in the induction of pro-inflammatory cytokines by LPS. Mice receiving an intravenous administration demonstrated a significant increase of neutrophils, monocytes and macrophages at the tumor site as well as an increase of macrophages in spleen. Further, we chemically detoxified LPS to obtain MP-LPS that was associated with a 200-fold decrease in the induction of proinflammatory cytokines. When encapsulated in a clinically approved liposomal formulation, toxicity, notably pyrogenicity (10-fold), was limited while the antitumor activity and immunoadjuvant effect were maintained. This improved tolerance profile of liposomal MP-LPS was associated with the preferential activation of the TLR4-TRIF pathway. Finally, in vitro studies demonstrated that stimulation with encapsulated MP-LPS reversed the polarization of M2 macrophages towards an M1 phenotype, and a phase 1 trial in healthy dogs validated its tolerance upon systemic administration up to very high doses (10µg/kg). Altogether, our results demonstrate the strong therapeutic potential of MPLPS formulated in liposomes as a systemically active anticancer agent, supporting its evaluation in patients with cancer.

Micro- and nanoplastics (MNP) are ubiquitously present in the environment due to their high persistence and bioaccumulative properties. Humans get exposed to MNP via various routes and consequently, they will encounter dendritic cells (DC) which are antigen-presenting cells involved in regulating immune responses. The consequences of DC exposure to MNP are an important, yet understudied, cause of concern. Therefore, this study aimed to assess the uptake and effect of MNP in vitro by exposing human monocyte-derived dendritic cells (MoDC) to virgin and environmentally weathered polystyrene (PS) particles of different sizes (0.2, 1, and 10 µm), at different concentrations ranging from 1 to 100 µg/ml. The effects of these particles were examined by measuring co-stimulatory surface marker (i.e. CD83 and CD86) expression. In addition, T-cell proliferation was measured via a mixed-leukocyte reaction (MLR) assay. The results showed that MoDC were capable of absorbing PS particles, and this was facilitated by pre-incubation in heat-inactivated (HI) plasma. Furthermore, depending on their size, weathered PS particles in particular caused increased expression of CD83 and CD86 on MoDC. Lastly, weathered 0.2 µm PS particles were able to functionally activate MoDC, leading to an increase in T-cell activation. These in vitro data suggest that, depending on their size, weathered PS particles might act as an immunostimulating adjuvant, possibly leading to T-cell sensitization. [ABSTRACT FROM AUTHOR]

Aim: Patients with cancer of the oral cavity and oropharynx (COCO) often exhibit signs of immunosuppression, affecting their prognosis. Understanding the dynamics of humoral immunity in these patients during chemoradiation therapy is crucial for developing effective treatments. Materials & methods: This prospective study included 105 COCO patients undergoing different treatment regimens, with or without alpha/beta-defensins therapy. Serum concentrations of IgG, IgM, IgA and salivary sIgA were analyzed. Patients were divided into five groups based on treatment protocols. Results & conclusion: Treatment variations impacted serum immunoglobulin levels, notably in Group III, whose patients received radiation treatment and immunotherapy with higher alpha/beta-defensins doses. Significant IgG changes correlated with oral mucositis risk and outcomes. Further trials are necessary for validation and clinical application.

The efficacy and safety of mRNA vaccines both rely on a fine-tuning of specific humoral and cellular immune responses. Instead of adjustments in vaccine component, we proposed a concept of chronological management of adjuvant effect to modulate the adaptive immune potency and preference inspired by natural virus infection. By simulating type I interferon expression dynamics during viral infection, three vaccine strategies employing distinct exposure sequences of adjuvant and mRNA have been developed, namely Precede , Coincide , and Follow . Follow , the strategy of adjuvant administration following mRNA, effectively suppressed tumor progression, which was attributed to enhanced mRNA translation, augmented p-MHC I expression, and elevated CD8 + T cell response. Meanwhile, Follow exhibited improved biosafety, characterized by reduced incidences of cardiac and liver toxicity, owing to its alteration to the vaccination microenvironment between successive injections. Our strategy highlights the importance of fine-tuning adjuvant effect dynamics in optimizing mRNA vaccines for clinical application.

In respiratory diseases, the induction of allergic asthma is one of the hottest issues of international concern. The adjuvant effect of air pollutants including nanoparticles (NPs) has be pointed out to facilitate the occurrence and development of allergic asthma. This work studied the development of allergic asthma upon exposures of carbon black nanoparticles (CB NPs, 30–50 nm) and/or high environmental humidity (90% relative humidity). The mechanisms involved were investigated from perspectives of the activation of oxidative stress and transient receptor potential vanilloid 1 (TRPV1) pathways and the alteration in intestinal microbiota. Both high humidity and CB NPs aggravated the airway hyperreactivity, remodeling, and inflammation in Balb/c mice sensitized by ovalbumin. The co-exposure of these two risk factors exhibited adjuvant effect on the development of asthma likely through activating oxidative stress pathway and TRPV1 pathway and then facilitating type I hypersensitivity. Additionally, exposures of high humidity and/or CB NPs reduced the richness of intestinal microbes, altered microbial community composition, and weakened corresponding biological functions, which may interact with the development of asthma. The findings will add new toxicological knowledge to the health risk assessment and management of co-exposures of NPs and other risk factors in the environment.

Biomaterials are known to modulate immune cell functions, which subsequently determine the host inflammatory and immune responses. Poly(lactic‐co‐glycolic acid) or PLGA, a biodegradable and biocompatible biomaterial, induces a pro‐inflammatory, mature phenotype in antigen presentation cells, namely dendritic cells (DCs) in vitro. In vivo, PLGA can boost the humoral immune response to a co‐delivered model antigen, a phenomenon known as the PLGA‐adjuvant effect. This study elucidates the link between PLGA's effect on the DC phenotype in vitro and its adjuvant effect in vivo using the CD11c‐DTR mouse model. These mice undergo conditional ablation of DCs upon treatment with diphtheria toxin. To measure immune activation, the mice were first given ovalbumin (OVA)‐reactive T cells from OT‐II/OT‐I mice. Later, the same mice received subcutaneous OVA‐loaded PLGA scaffold implants. In response to the scaffold implants, OVA‐reactive OT‐II CD4+ T cells showed decreased proliferation in the absence of CD11c+ DCs, indicating an attenuation of the PLGA‐adjuvant effect. Furthermore, PLGA may also influence the antigen cross‐presentation function of DCs, as evident with the lowered OVA‐reactive OT‐I CD8+ T‐cell response. Understanding the immunomodulatory ability of biomaterials in the context of DCs will aid in designing improved DC‐based immunotherapies against infectious diseases and cancer. [ABSTRACT FROM AUTHOR]

Probiotics are live microorganisms that, confer health benefits to the host when supplemented in adequate amounts. They can promote immunomodulation by inducing phagocyte activity, leukocyte proliferation, antibody production, and cytokine expression. Lactic acid bacteria (BAL) are important probiotic specimens with properties that can improves ruminant nutrition, productivity and immunity. The aim of the present study was to evaluate the immunomodulatory effect of the supplementation with Lacticaseibacillus casei CB054 in calve vaccinated against bovine infectious rhinotracheitis (IBR). Calve were vaccinated with a commercial IBR vaccine, on day 0 and received a booster dose on day 21. L. casei CB054 was orally administered (4 ×109 UFC) for 35 days, while a non-supplemented control group received Phosphate Buffer Saline (PBS). Stimulation of bovine splenocytes with L. casei CB054 markedly enhanced mRNA transcription levels of cytokines IL2, IL4 , IL10 and IL17 genes. Calves supplemented with L. casei CB054 showed significantly higher (p < 0.05) specific anti-BoHV-1 IgG levels, higher serum neutralization, as well as higher mRNA transcription for IL2, IL4 , IL10 and IL17 genes in Peripheral Blood Mononuclear Cells (PBMCs) comparing with control calves. Supplemented calve had an average weight gain of ∼14 kg more than non-supplemented during the experimental period. These results suggest that L. casei CB054 supplementation increase immunogenicity of a commercial IBR vaccine in cattle and improve weight gain. • Lacticaseibacillus casei CB054 improve commercial IBR vaccine response. • Caves supplemented with L. casei has a higher antibodies and S/N against BoHV-1. • L. casei increase cytokines IL2, IL4 , IL10 and IL17 transcription in PBMCs. • Caves supplemented with L. casei CB054 has an increase weight. [ABSTRACT FROM AUTHOR]

Immune privilege (IP), a term introduced to explain the unpredicted acceptance of allogeneic grafts by the eye and the brain, is considered a unique property of these tissues. However, immune responses are modified by the tissue in which they occur, most of which possess IP to some degree. The eye therefore displays a spectrum of IP because it comprises several tissues. IP as originally conceived can only apply to the retina as it contains few tissue-resident bone-marrow derived myeloid cells and is immunologically shielded by a sophisticated barrier – an inner vascular and an outer epithelial barrier at the retinal pigment epithelium. The vascular barrier comprises the vascular endothelium and the glia limitans. Immune cells do not cross the blood-retinal barrier (BRB) despite two-way transport of interstitial fluid, governed by tissue oncotic pressure. The BRB, and the blood-brain barrier (BBB) mature in the neonatal period under signals from the expanding microbiome and by 18 months are fully established. However, the adult eye is susceptible to intraocular inflammation (uveitis; frequency ~200/100,000 population). Uveitis involving the retinal parenchyma (posterior uveitis, PU) breaches IP, while IP is essentially irrelevant in inflammation involving the ocular chambers, uveal tract and ocular coats (anterior/intermediate uveitis/sclerouveitis, AU). Infections cause ~50% cases of AU and PU but infection may also underlie the pathogenesis of immune-mediated “non-infectious” uveitis. Dysbiosis accompanies the commonest form, HLA-B27–associated AU, while latent infections underlie BRB breakdown in PU. This review considers the pathogenesis of uveitis in the context of IP, infection, environment, and the microbiome.

Immune privilege (IP), a term introduced to explain the unpredicted acceptance of allogeneic grafts by the eye and the brain, is considered a unique property of these tissues. However, immune responses are modified by the tissue in which they occur, most of which possess IP to some degree. The eye therefore displays a spectrum of IP because it comprises several tissues. IP as originally conceived can only apply to the retina as it contains few tissue-resident bone-marrow derived myeloid cells and is immunologically shielded by a sophisticated barrier – an inner vascular and an outer epithelial barrier at the retinal pigment epithelium. The vascular barrier comprises the vascular endothelium and the glia limitans. Immune cells do not cross the blood-retinal barrier (BRB) despite two-way transport of interstitial fluid, governed by tissue oncotic pressure. The BRB, and the blood-brain barrier (BBB) mature in the neonatal period under signals from the expanding microbiome and by 18 months are fully established. However, the adult eye is susceptible to intraocular inflammation (uveitis; frequency ~200/100,000 population). Uveitis involving the retinal parenchyma (posterior uveitis, PU) breaches IP, while IP is essentially irrelevant in inflammation involving the ocular chambers, uveal tract and ocular coats (anterior/intermediate uveitis/sclerouveitis, AU). Infections cause ~50% cases of AU and PU but infection may also underlie the pathogenesis of immune-mediated "non-infectious" uveitis. Dysbiosis accompanies the commonest form, HLA-B27–associated AU, while latent infections underlie BRB breakdown in PU. This review considers the pathogenesis of uveitis in the context of IP, infection, environment, and the microbiome. [ABSTRACT FROM AUTHOR]

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: In Field experiments, a logarithmic sprayer was used to screen the efficacy of 28.5% mixture of nicosulfuron and mesotrione, and the herbicides applied separately. Three adjuvants were also used to assess how they affected the potency of the mixture. The objectives were to test whether a mixture was enhancing or detracting the effect relative to ADM (Additive Dose Model). The test plants were canola and barley. The 28.5% nicosulfuron mixture was acting antagonistic, irrespective of plant species. The antagonistic effect of the nicosulfuron mixture decreased the more developed the plants became; for barley, it almost disappeared 40 days after treatment. For both canola and barley, one adjuvant stood out as being highly effective in decreasing ED50 of the mixture. Antagonism was not alarmingly high, which is found for many herbicides. Results are discussed in relation to the practice of testing mixtures in the literature and the requirements for getting mixture patents.

Abstract Channel catfish is one of the most extensively cultured species worldwide, which is widely used as a classical model for comparative immunology. Interleukin-1β (IL1β) is an immunoregulatory cytokine with the potential to enhance the immune response induced by vaccines in many animals. To characterize the molecular characterization and identify the immunoadjuvant role of channel catfish IL1β, molecular cloning, phylogenetic analysis, and expression of two IL1β genes were performed, the bioactivity of their recombinant proteins (rIL1β1 and rIL1β2) were detected in vitro and their adjuvant effects on a subunit vaccine encoding C5a peptidase (pSCPI) of Streptococcus iniae were evaluated. The results indicated that two IL1βs remained highly conserved possessing five conserved motifs compared with other fish IL1βs, although there were 28 nucleotide differences and 16 amino acid differences between channel catfish IL1β1 and IL1β2. Analysis of the ratios of nonsynonymous (dN) and synonymous (dS) substitutions revealed that fish IL1β genes were subjected to negative/purifying selection with global dN/dS ratios value 0.425. The results of adjuvant effect showed that compared with injection of pSCPI alone, co-injecting pSCPI with both rIL1β1 and rIL1β2 significantly enhanced antibody levels, serum bactericidal activity, lysozyme activity, alternative complement hemolytic activity, and the expression of endogenous IL1β and TNF-α in head kidney and spleen. Although vaccination with rIL1β1 or rIL1β2 failed to offer immunoprotection against S. iniae infection, the RPS (relative percent survival) of pSCPI+rIL1β1 and pSCPI+rIL1β2 groups were both higher than pSCPI alone (RPS, 50%), with 64.26% and 60.71%, respectively. Moreover, pSCPI+rIL1β1+rIL1β2 offered significantly higher (P < 0.05) immunoprotection (RPS, 75%) against S. iniae infection than pSCPI alone. Our present results not only enrich the molecular structure study of fish IL1βs but also signify that two recombinant channel catfish IL1βs can be used as potential adjuvants in a subunit vaccine model against bacterial infection, which are of profound importance to prevent and control bacterial disease in channel catfish. Highlights • Fish IL1βs were subjected to negative/purifying selection throughout the evolution. • Channel catfish IL1βs were highly conserved with five conserved motifs. • Channel catfish IL1βs can be used as molecular adjuvants in subunit vaccine model. • rIL1β1 as adjuvant was slightly better than rIL1β2 to enhance the immune response. • Co-injection of rIL1β1+rIL1β2 induced higher immune response and immunoprotection. [ABSTRACT FROM AUTHOR]

Effective priming and activation of tumor-specific CD8+ cytotoxic T lymphocytes (CTLs) is crucial for realizing the potential of therapeutic cancer vaccination. This requires cytosolic antigens that feed into the MHC class I presentation pathway, which is not efficiently achieved with most current vaccination technologies. Photochemical internalization (PCI) provides an emerging technology to route endocytosed material to the cytosol of cells, based on light-induced disruption of endosomal membranes using a photosensitizing compound. Here, we investigated the potential of PCI as a novel, minimally invasive, and well-tolerated vaccination technology to induce priming of cancer-specific CTL responses to peptide antigens. We show that PCI effectively promotes delivery of peptide antigens to the cytosol of antigen-presenting cells (APCs) in vitro. This resulted in a 30-fold increase in MHC class I/peptide complex formation and surface presentation, and a subsequent 30- to 100-fold more efficient activation of antigen-specific CTLs compared to using the peptide alone. The effect was found to be highly dependent on the dose of the PCI treatment, where optimal doses promoted maturation of immature dendritic cells, thus also providing an adjuvant effect. The effect of PCI was confirmed in vivo by the successful induction of antigen-specific CTL responses to cancer antigens in C57BL/6 mice following intradermal peptide vaccination using PCI technology. We thus show new and strong evidence that PCI technology holds great potential as a novel strategy for improving the outcome of peptide vaccines aimed at triggering cancer-specific CD8+ CTL responses.

Effective priming and activation of tumor-specific CD8+ cytotoxic T lymphocytes (CTLs) is crucial for realizing the potential of therapeutic cancer vaccination. This requires cytosolic antigens that feed into the MHC class I presentation pathway, which is not efficiently achieved with most current vaccination technologies. Photochemical internalization (PCI) provides an emerging technology to route endocytosed material to the cytosol of cells, based on light-induced disruption of endosomal membranes using a photosensitizing compound. Here, we investigated the potential of PCI as a novel, minimally invasive, and well-tolerated vaccination technology to induce priming of cancer-specific CTL responses to peptide antigens. We show that PCI effectively promotes delivery of peptide antigens to the cytosol of antigen-presenting cells (APCs) in vitro. This resulted in a 30-fold increase in MHC class I/peptide complex formation and surface presentation, and a subsequent 30- to 100-fold more efficient activation of antigen-specific CTLs compared to using the peptide alone. The effect was found to be highly dependent on the dose of the PCI treatment, where optimal doses promoted maturation of immature dendritic cells, thus also providing an adjuvant effect. The effect of PCI was confirmed in vivo by the successful induction of antigen-specific CTL responses to cancer antigens in C57BL/6 mice following intradermal peptide vaccination using PCI technology. We thus show new and strong evidence that PCI technology holds great potential as a novel strategy for improving the outcome of peptide vaccines aimed at triggering cancer-specific CD8+ CTL responses. [ABSTRACT FROM AUTHOR]

A series of amino acid derivatives of oxalic acid were obtained. In combination therapy with conventional cytostatics used in lower doses, the new compounds substantially increase the efficacy of the drugs in the treatment of experimental P388 murine leukemia and some its drug-resistant strains. [ABSTRACT FROM AUTHOR]

Silicone oil microdroplets may act as adjuvants, promoting unwanted immune responses against both foreign and self-proteins. Proteins often unfold upon adsorption to silicone oil microdroplets, but it is unclear how such unfolding might affect the immune response. In this study, we found that hen egg lysozyme (HEL) readily adsorbed to silicone oil microdroplets and perturbed the conformation of HEL. We compared the immune response to injections of HEL formulated in the presence and absence of silicone oil microdroplets in both wild-type mice and transgenic littermates that express a soluble form of HEL (sHEL), thus rendering them immunologically tolerant to this nominal self-antigen. Following 2 subcutaneous injections of a HEL formulation containing silicone oil microdroplets, wild-type mice exhibited a stronger IgG1 antibody response against HEL compared to the response in wild-type mice that administered an oil-free HEL formulation. However, when HEL was subcutaneously administered to sHEL-transgenic mice, immunological tolerance to sHEL was not broken in the presence of silicone oil microdroplets. Thus, although structural perturbations in proteins adsorbed to silicone oil microdroplets may augment the immune response, in the case of endogenously expressed proteins, such structural perturbations may not be sufficient to result in a breach of immunological tolerance. [ABSTRACT FROM AUTHOR]

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 (200 μg) 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. [ABSTRACT FROM AUTHOR]

Purpose: To assess the optimal time of intravitreal conbercept (IVC) treatment prior to pars plana vitrectomy (PPV) in patients with severe proliferative diabetic retinopathy (PDR)., Method: This study was exploratory in nature. Forty-eight consecutive patients (48 eyes) with PDR were divided into four groups according to different IVC times (0.5 mg/0.05 mL) before PPV: group A (3 days), group B (7 days), group C (14 days), and group D (non-IVC). Intraoperative and postoperative effectiveness were assessed, and vitreous VEGF concentrations were detected., Result: For intraoperative effectiveness, groups A and D had a higher incidence of intraoperative bleeding than groups B and C ( P = 0.041). Furthermore, groups A-C required less surgical time than group D ( P < 0.05). For postoperative effectiveness, group B had a significantly higher proportion of visual acuity that improved or remained unchanged than group D ( P = 0.014), and groups A-C had lower proportions of postoperative bleeding than group D. The vitreous VEGF concentration of group B (67.04 ± 47.24 pg/mL) was significantly lower than that of group D (178.29 ± 110.50 pg/mL) ( P = 0.005)., Conclusion: IVC treatment that was administered 7 days preoperatively was associated with better effectiveness and a lower vitreous VEGF concentration than its administration at other time points., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Di, Ye, Yu and Guo.)

Seasonal influenza is a major upper respiratory tract infection occurring in winter. Vaccination is the best method for preventing this infection. We conducted two randomized, double-blind, placebo-controlled trials to examine whether consumption of yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1, which has been reported to reduce the risk of catching the common cold, augments serum antibody titers against seasonal influenza vaccines. In the first trial, which included university students, serum antibody titers against influenza A (H3N2) and B viruses were significantly higher in the yogurt group than in the placebo group. According to the guidelines established by the European Medicines Agency (EMA) for the assessment of vaccines, the seroconversion rate and mean geometric increase of influenza A (H3N2) and seroprotection of influenza B met the criteria only in the yogurt group. In the second trial, which included healthy adults, serum antibody titers against influenza A (H1N1) and B viruses were significantly higher in the yogurt group than in the placebo group. The seroconversion rate and mean geometric increase of influenza B met the EMA criteria only in the yogurt group. Furthermore, the cumulative days of ill health, such as throat complaints, upper respiratory inflammation, and cold, were significantly lower in the yogurt group than in the placebo group. Therefore, daily intake of yogurt fermented with L. bulgaricus OLL1073R-1 could reduce the duration of symptoms caused by respiratory infections and act as a mucosal adjuvant enhancing acquired immune responses against vaccines, leading to the improvement of public health., (©2023 BMFH Press.)

Pollen coating, located on the exine, includes an extractible lipid fraction. The modification of the pollen coating by air pollutants may have implications on the interactions of pollen with plant stigmas and human cells. Pinus halepensis pollen was exposed to ozone in vitro and the pollen coating was extracted with organic solvent and analyzed by GC-MS. Ozone has induced chemical changes in the coating as observed with an increase in dicarboxylic acids, short-chain fatty acids and aldehydes. 4-Hydroxybenzaldehyde was identified as the main reaction product and its formation was shown to occur both on native pollen and on defatted pollen. 4-Hydroxybenzaldehyde is very likely formed via the ozonolysis of acid coumaric-like monomers constitutive of the sporopollenin. Modification of pollen coating by air pollutants should be accounted for in further studies on effect of pollution on germination and on allergenicity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Therapeutic protein products can cause adverse immune responses in patients. The presence of subvisible particles is a potential contributing factor to the immunogenicity of parenterally administered therapeutic protein formulations. Silicone oil microdroplets, which derive from silicone oil used as a lubricating coating on barrels of prefilled glass syringes, are often found in formulations. In this study, we investigated the potential of silicone oil microdroplets to act as adjuvants to induce an immune response in mice against a recombinant murine protein. Antibody responses in mice to subcutaneous injections of formulations of recombinant murine growth hormone (rmGH) that contained silicone oil microdroplets were measured and compared to responses to oil-free rmGH formulations. When rmGH formulations containing silicone oil microdroplets were administered once every other week, anti-rmGH antibodies were not detected. In contrast, mice exhibited a small IgG1 response against rmGH when silicone oil–containing rmGH formulations were administered daily, and an anti-rmGH IgM response was observed at later time points. Our findings showed that silicone oil microdroplets can act as an adjuvant to promote a break in immunological tolerance and induce antibody responses against a recombinant self-protein. [ABSTRACT FROM AUTHOR]