Oral immunotherapy is an emerging experimental treatment for peanut allergy, but its benefits and harms are unclear. We systematically reviewed the efficacy and safety of oral immunotherapy versus ...allergen avoidance or placebo (no oral immunotherapy) for peanut allergy.
In the Peanut Allergen immunotherapy, Clarifying the Evidence (PACE) systematic review and meta-analysis, we searched MEDLINE, EMBASE, Cochrane Controlled Register of Trials, Latin American & Caribbean Health Sciences Literature, China National Knowledge Infrastructure, WHO's Clinical Trials Registry Platform, US Food and Drug Administration, and European Medicines Agency databases from inception to Dec 6, 2018, for randomised controlled trials comparing oral immunotherapy versus no oral immunotherapy for peanut allergy, without language restrictions. We screened studies, extracted data, and assessed risk of bias independently in duplicate. Main outcomes included anaphylaxis, allergic or adverse reactions, epinephrine use, and quality of life, meta-analysed by random effects. We assessed certainty (quality) of evidence by the GRADE approach. This study is registered with PROSPERO, number CRD42019117930.
12 trials (n=1041; median age across trials 8·7 years IQR 5·9–11·2) showed that oral immunotherapy versus no oral immunotherapy increased anaphylaxis risk (risk ratio RR 3·12 95% CI 1·76–5·55, I2=0%, risk difference RD 15·1%, high-certainty), anaphylaxis frequency (incidence rate ratio IRR 2·72 1·57–4·72, I2=0%, RD 12·2%, high-certainty), and epinephrine use (RR 2·21 1·27–3·83, I2=0%, RD 4·5%, high-certainty) similarly during build-up and maintenance (pinteraction=0·92). Oral immunotherapy increased serious adverse events (RR 1·92 1·00–3·66, I2=0%, RD 5·7%, moderate-certainty), and non-anaphylactic reactions (vomiting: RR 1·79 95%CI 1·35–2·38, I2=0%, high-certainty; angioedema: 2·25 1·13–4·47, I2=0%, high-certainty; upper tract respiratory reactions: 1·36 1·02–1·81, I2=0%, moderate-certainty; lower tract respiratory reactions: 1·55 0·96–2·50, I2=28%, moderate-certainty). Passing a supervised challenge, a surrogate for preventing out-of-clinic reactions, was more likely with oral immunotherapy (RR 12·42 95% CI 6·82–22·61, I2=0%, RD 36·5%, high-certainty). Quality of life was not different between groups (combined parents and self report RR 1·21 0·87–1·69, I2=0%, RD 0·03%, low-certainty). Findings were robust to IRR, trial sequential, subgroup, and sensitivity analyses.
In patients with peanut allergy, high-certainty evidence shows that available peanut oral immunotherapy regimens considerably increase allergic and anaphylactic reactions over avoidance or placebo, despite effectively inducing desensitisation. Safer peanut allergy treatment approaches and rigorous randomised controlled trials that evaluate patient-important outcomes are needed.
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The emerging SARS-CoV-2 variants of concern (VOCs) threaten the effectiveness of current COVID-19 vaccines administered intramuscularly and designed to only target the spike protein. There is a ...pressing need to develop next-generation vaccine strategies for broader and long-lasting protection. Using adenoviral vectors (Ad) of human and chimpanzee origin, we evaluated Ad-vectored trivalent COVID-19 vaccines expressing spike-1, nucleocapsid, and RdRp antigens in murine models. We show that single-dose intranasal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal trained innate immunity. We further show that intranasal immunization provides protection against both the ancestral SARS-CoV-2 and two VOC, B.1.1.7 and B.1.351. Our findings indicate that respiratory mucosal delivery of Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity against current and future VOC.
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•Two trivalent adenoviral-vectored COVID-19 vaccines were developed and evaluated•Intranasal, but not intramuscular, immunization induces tripartite mucosal immunity•Intranasal immunization protects against ancestral and variant strains of SARS-CoV-2•Optimal protection requires B and T cell immunity and trained innate immunity
Respiratory mucosal immunization with a next-generation adenoviral-vectored trivalent COVID-19 vaccine expressing spike, nucleocapsid, and RdRp antigens, induces all-around protective mucosal immunity against SARS-CoV-2 via induction of systemic and local antibodies, lung-tissue-resident memory T cells, and trained alveolar macrophages.
The requirement of type I interferon (IFN) for natural killer (NK) cell activation in response to viral infection is known, but the underlying mechanism remains unclear. Here, we demonstrate that ...type I IFN signaling in inflammatory monocytes, but not in dendritic cells (DCs) or NK cells, is essential for NK cell function in response to a mucosal herpes simplex virus type 2 (HSV-2) infection. Mice deficient in type I IFN signaling,
and
mice, had significantly lower levels of inflammatory monocytes, were deficient in IL-18 production, and lacked NK cell-derived IFN-γ. Depletion of inflammatory monocytes, but not DCs or other myeloid cells, resulted in lower levels of IL-18 and a complete abrogation of NK cell function in HSV-2 infection. Moreover, this resulted in higher susceptibility to HSV-2 infection. Although
mice had normal levels of inflammatory monocytes, their NK cells were unresponsive to HSV-2 challenge. This study highlights the importance of type I IFN signaling in inflammatory monocytes and the induction of the early innate antiviral response.
Background Allergen exposure at lung and gut mucosae can lead to aberrant TH 2 immunity and allergic disease. The epithelium-associated cytokines thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 ...are suggested to be important for the initiation of these responses. Objective We sought to investigate the contributions of TSLP, IL-25, and IL-33 in the development of allergic disease to the common allergens house dust mite (HDM) or peanut. Methods Neutralizing antibodies or mice deficient in TSLP, IL-25, or IL-33 signaling were exposed to HDM intranasally or peanut intragastrically, and immune inflammatory and physiologic responses were evaluated. In vitro assays were performed to examine specific dendritic cell (DC) functions. Results We showed that experimental HDM-induced allergic asthma and food allergy and anaphylaxis to peanut were associated with TSLP production but developed independently of TSLP, likely because these allergens functionally mimicked TSLP inhibition of IL-12 production and induction of OX40 ligand (OX40L) on DCs. Blockade of OX40L significantly lessened allergic responses to HDM or peanut. Although IL-25 and IL-33 induced OX40L on DCs in vitro , only IL-33 signaling was necessary for intact allergic immunity, likely because of its superior ability to induce DC OX40L and expand innate lymphoid cells in vivo. Conclusion These data identify a nonredundant, IL-33–driven mechanism initiating TH 2 responses to the clinically relevant allergens HDM and peanut. Our findings, along with those in infectious and transgenic/surrogate allergen systems, favor a paradigm whereby multiple molecular pathways can initiate TH 2 immunity, which has implications for the conceptualization and manipulation of these responses in health and disease.
Monocyte phenotype and output changes with age, but why this occurs and how it impacts anti-bacterial immunity are not clear. We found that, in both humans and mice, circulating monocyte phenotype ...and function was altered with age due to increasing levels of TNF in the circulation that occur as part of the aging process. Ly6C+ monocytes from old (18-22 mo) mice and CD14+CD16+ intermediate/inflammatory monocytes from older adults also contributed to this "age-associated inflammation" as they produced more of the inflammatory cytokines IL6 and TNF in the steady state and when stimulated with bacterial products. Using an aged mouse model of pneumococcal colonization we found that chronic exposure to TNF with age altered the maturity of circulating monocytes, as measured by F4/80 expression, and this decrease in monocyte maturation was directly linked to susceptibility to infection. Ly6C+ monocytes from old mice had higher levels of CCR2 expression, which promoted premature egress from the bone marrow when challenged with Streptococcus pneumoniae. Although Ly6C+ monocyte recruitment and TNF levels in the blood and nasopharnyx were higher in old mice during S. pneumoniae colonization, bacterial clearance was impaired. Counterintuitively, elevated TNF and excessive monocyte recruitment in old mice contributed to impaired anti-pneumococcal immunity since bacterial clearance was improved upon pharmacological reduction of TNF or Ly6C+ monocytes, which were the major producers of TNF. Thus, with age TNF impairs inflammatory monocyte development, function and promotes premature egress, which contribute to systemic inflammation and is ultimately detrimental to anti-pneumococcal immunity.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although most novel tuberculosis (TB) vaccines are designed for delivery via the muscle or skin for enhanced protection in the lung, it has remained poorly understood whether systemic vaccine-induced ...memory T cells can readily home to the lung mucosa prior to and shortly after pathogen exposure. We have investigated this issue by using a model of parenteral TB immunization and intravascular immunostaining. We find that systemically induced memory T cells are restricted to the blood vessels in the lung, unable to populate either the lung parenchymal tissue or the airway under homeostatic conditions. We further find that after pulmonary TB infection, it still takes many days before such T cells can enter the lung parenchymal tissue and airway. We have identified the acquisition of CXCR3 expression by circulating T cells to be critical for their entry to these lung mucosal compartments. Our findings offer new insights into mucosal T cell biology and have important implications in vaccine strategies against pulmonary TB and other intracellular infections in the lung.
Influenza viral infection is well-known to predispose to subsequent bacterial superinfection in the lung but the mechanisms have remained poorly defined. We have established a murine model of ...heterologous infections by an H1N1 influenza virus and Staphylococcus aureus. We found that indeed prior influenza infection markedly increased the susceptibility of mice to secondary S. aureus superinfection. Severe sickness and heightened bacterial infection in flu and S. aureus dual-infected animals were associated with severe immunopathology in the lung. We further found that flu-experienced lungs had an impaired NK cell response in the airway to subsequent S. aureus bacterial infection. Thus, adoptive transfer of naive NK cells to the airway of prior flu-infected mice restored flu-impaired antibacterial host defense. We identified that TNF-alpha production of NK cells played an important role in NK cell-mediated antibacterial host defense as NK cells in flu-experienced lungs had reduced TNF-alpha expression and adoptive transfer of TNF-alpha-deficient NK cells to the airway of flu-infected mice failed to restore flu-impaired antibacterial host defense. Defected NK cell function was found to be an upstream mechanism of depressed antibacterial activities by alveolar macrophages as contrast to naive wild-type NK cells, the NK cells from flu-infected or TNF-alpha-deficient mice failed to enhance S. aureus phagocytosis by alveolar macrophages. Together, our study identifies the weakened NK cell response in the lung to be a novel critical mechanism for flu-mediated susceptibility to bacterial superinfection.
Alterations in the intestinal microbiota, characterized by depletion of anti-inflammatory bacteria, such as Firmicutes, in patients with ulcerative colitis (UC) have prompted interest in ...microbiota-modulating strategies for this condition. The aim of this study was to evaluate the role of fecal and synthetic human microbial ecosystems, low or enriched in Firmicutes, on colitis susceptibility and host immune responses.
The microbiota of selected healthy and UC human donors was characterized by culture method and 16S rRNA-based sequencing. Germ-free mice were colonized with fecal or a synthetic ecosystem enriched (healthy donors) or low (UC donors) in Firmicutes. Experimental colitis was induced using dextran sodium sulfate. Colon transcriptome and colon lamina propria cells were evaluated in mice postcolonization by RNA-seq and flow cytometry, respectively, and T helper (TH) 17 differentiation was assessed in vitro.
Mice colonized with microbiota from patients with UC low in Firmicutes had increased sensitivity to colitis compared with mice colonized with fecal or synthetic ecosystems rich in Firmicutes. Microbiota low in Firmicutes increased expression of TH17-related genes and expansion of interleukin-17A-expressing CD4 cells in vivo. Supplementation with bacterial isolates belonging to the Firmicutes phylum abrogated the heightened TH17 responses in vitro.
A microbiota rich in Firmicutes derived from fecal samples of a healthy human donor, or assembled synthetically, downregulated colonic inflammation and TH17 pathways in mice. The results support the use of ecobiotherapy strategies, enriched in Firmicutes, for the prevention or treatment of UC.
Eosinophils natively inhabit the small intestine, but a functional role for them there has remained elusive. Here, we show that eosinophil-deficient mice were protected from induction of Th2-mediated ...peanut food allergy and anaphylaxis, and Th2 priming was restored by reconstitution with il4(+/+) or il4(-/-) eosinophils. Eosinophils controlled CD103(+) dendritic cell (DC) activation and migration from the intestine to draining lymph nodes, events necessary for Th2 priming. Eosinophil activation in vitro and in vivo led to degranulation of eosinophil peroxidase, a granule protein whose enzymatic activity promoted DC activation in mice and humans in vitro, and intestinal and extraintestinal mouse DC activation and mobilization to lymph nodes in vivo. Further, eosinophil peroxidase enhanced responses to ovalbumin seen after immunization. Thus, eosinophils can be critical contributors to the intestinal immune system, and granule-mediated shaping of DC responses can promote both intestinal and extraintestinal adaptive immunity.
While type 2 immunity has been conventionally viewed as beneficial against helminths, venoms, and poisons, and harmful in allergy, contemporary research has uncovered its critical role in the ...maintenance of homeostasis. The initiation of a type 2 immune response involves an intricate crosstalk between structural and immune cells. Structural cells react to physical and chemical tissue perturbations by secreting alarmins, which signal the innate immune system to restore homeostasis. This pathway acts autonomously in the context of sterile injury and in the presence of foreign antigen initiates an adaptive Th2 response that is beneficial in the context of venoms, toxins, and helminths, but not food allergens. The investigation of the triggers and mechanisms underlying food allergic sensitization in humans is elusive because sensitization is a silent process. Therefore, the central construct driving food allergy modeling is based on introducing perturbations of tissue homeostasis along with an allergen which will result in an immunological and clinical phenotype that is consistent with that observed in humans. The collective evidence from multiple models has revealed the pre-eminent role of innate cells and molecules in the elicitation of allergic sensitization. We posit that, with the expanding use of technologies capable of producing formidable datasets, models of food allergy will continue to have an indispensable role to delineate mechanisms and establish causal relationships.
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