ABSTRACT
Asthma is a chronic inflammatory condition that affects the lung airways. Chronic use of oral glucocorticoids in patients with severe asthma is associated with several adverse events (AEs). Biologics (omalizumab, benralizumab, mepolizumab, reslizumab, and dupilumab) have been developed as alternative therapies for the treatment of asthma. In this study, we aimed to evaluate the risk of anaphylactic reactions associated with these five biologics based on a large global database. We utilized individual case reports from the Uppsala Monitoring Center from January 1968 to December 29, 2019. A disproportionality analysis was performed over all drugs and monoclonal antibodies. Anaphylactic reactions were defined according to the "anaphylactic reaction" of the standardized MedDRA queries. Contrary to dupilumab, omalizumab, benralizumab, and mepolizumab demonstrated positive signals related to anaphylactic reactions over all drugs and monoclonal antibodies. Reslizumab, which represented only 315 cases of all AEs, requires more reports to determine its association with anaphylactic reactions. More anaphylactic reactions have been identified than are known, and most cases (96.2%) are reported to be serious. Our findings indicate that omalizumab, benralizumab, and mepolizumab for asthma treatment are associated with a high risk of anaphylactic reactions; thus, more careful monitoring in the post-administration period is recommended.
Subject(s)
Anaphylaxis , Anti-Asthmatic Agents , Asthma , Biological Products , Humans , Omalizumab/adverse effects , Anti-Asthmatic Agents/adverse effects , Biological Products/adverse effects , Pharmacovigilance , Anaphylaxis/chemically induced , Anaphylaxis/drug therapy , Antibodies, Monoclonal/therapeutic useABSTRACT
BACKGROUND: Mast cells (MCs) are important effector cells in anaphylaxis and anaphylactic disease. 3',4',5,7-tetrahydroxyflavone (THF) presents in many medicinal plants and exerts a variety of pharmacological effects. In this study, we evaluated the effect of THF on C48/80-induced anaphylaxis and the mechanisms underlying its effects, including the role of secreted phosphoprotein 1 (SPP1), which has not been reported to IgE-independent MC activation. RESULTS: THF inhibited C48/80-induced Ca2+ flow and degranulation via the PLCγ/PKC/IP3 pathway in vitro. RNA-seq showed that THF inhibited the expression of SPP1 and downstream molecules. SPP1 is involved in pseudo-anaphylaxis reactions. Silencing SPP1 affects the phosphorylation of AKT and P38. THF suppressed C48/80-induced paw edema, hypothermia and serum histamine, and chemokines release in vivo. CONCLUSIONS: Our results validated SPP1 is involved in IgE-independent MC activation anaphylactoid reactions. THF inhibited C48/80-mediated anaphylactoid reactions both in vivo and in vitro, suppressed calcium mobilization and inhibited SPP1-related pathways.
Subject(s)
Anaphylaxis , Humans , Anaphylaxis/chemically induced , Anaphylaxis/drug therapy , Luteolin/pharmacology , Osteopontin/metabolism , Osteopontin/pharmacology , Mast Cells , Inflammation/metabolism , Cell Degranulation , Immunoglobulin E/metabolismABSTRACT
Food-dependent, exercise-induced anaphylaxis (FDEIA) is a potentially life-threatening disorder that often occurs with exercise, and patients typically have eaten a specific food within hours before disease onset. This disease is exceedingly rare, with a prevalence of 0.02%. No well-recognized prevention or treatment strategy has been available for FDEIA except avoiding triggers strictly. Here we report an 11-year-old boy with a history of recurrent anaphylaxis of unknown etiology more than 10 times within two years. As the anaphylactic symptoms had not been controlled after traditional treatments, the patient was given subcutaneous injection of dupilumab seven times within 33 weeks. During dupilumab treatments, the patient was exposed to culprit mushrooms plus exercises at least twice a month but without notable anaphylaxis. Thus, Dupilumab may improve the allergic reactions in FDEIA patients.
Subject(s)
Anaphylaxis , Exercise-Induced Allergies , Food Hypersensitivity , Male , Humans , Child , Anaphylaxis/drug therapy , Anaphylaxis/diagnosis , Anaphylaxis/etiology , Food Hypersensitivity/drug therapy , Food Hypersensitivity/complications , Food Hypersensitivity/diagnosis , Antibodies, Monoclonal, Humanized/therapeutic useABSTRACT
Anaphylaxis is a type of potentially fatal hypersensitivity reaction resulting from the activation of mast cells. Many endogenous or exogenous factors could cause this reaction. Silibinin is the main chemical component of silymarin and has been reported to have pharmacological activities. However, the anti-allergic reaction effect of silibinin has not yet been investigated. This study aimed to evaluate the effect of silibinin to attenuate pseudo-allergic reactions in vivo and to investigate the underlying mechanism in vitro. In this study, calcium imaging was used to assess Ca2+ mobilization. The levels of cytokines and chemokines, released by stimulated mast cells, were measured using enzyme immunoassay kits. The activity of silibinin was evaluated in a mouse model of passive cutaneous anaphylaxis (PCA). Western blotting was used to explore the related molecular signaling pathways. In results, silibinin markedly inhibited mast cell degranulation, calcium mobilization, and preventing the release of cytokines and chemokines in a dose-dependent manner via the PLCγ and PI3K/Akt signaling pathway. Silibinin also attenuated PCA in a dose-dependent manner. In summary, silibinin has an anti-pseudo-allergic pharmacological activity, which makes it a potential candidate for the development of a novel agent to arrest pseudo-allergic reactions.
Subject(s)
Anaphylaxis , Anti-Allergic Agents , Mice , Animals , Silybin/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Cell Degranulation , Mast Cells , Calcium/metabolism , Signal Transduction , Anaphylaxis/drug therapy , Cytokines/metabolism , Chemokines/metabolism , Anti-Allergic Agents/pharmacologyABSTRACT
Bee venom is used to treat various diseases but can cause a tickling sensation and anaphylaxis during clinical treatment. Adverse events (AEs) associated with bee venom may vary depending on the dosage, method, route of administration, and the country, region, and user. We summarized the AEs of bee venom used in various ways, such as by the injection of extracts, venom immunotherapy (VIT), live bee stings, or external preparations. We conducted a search in eight databases up to 28 February 2022. It took one month to set the topic and about 2 weeks to set the search terms and the search formula. We conducted a search in advance on 21 February to see if there were omissions in the search terms and whether the search formula was correct. There were no restrictions on the language or bee venom method used and diseases treated. However, natural stings that were not used for treatment were excluded. A total of 105 studies were selected, of which 67, 26, 8, and 4 were on the injection of extracts, VIT, live bee stings, and external preparation, respectively. Sixty-three studies accurately described AEs, while 42 did not report AEs. Thirty-five randomized controlled trials (RCTs) were evaluated for the risk of bias, and most of the studies had low significance. A large-scale clinical RCT that evaluates results based on objective criteria is needed. Strict criteria are needed for the reporting of AEs associated with bee venom.
Subject(s)
Anaphylaxis , Bee Venoms , Insect Bites and Stings , Anaphylaxis/chemically induced , Anaphylaxis/drug therapy , Desensitization, Immunologic/methods , Humans , Insect Bites and Stings/complications , Wasp VenomsABSTRACT
Neobavaisoflavone (NBIF), a monomolecular compound extracted from Psoralea corylifolia (Leguminosae), is commonly used in traditional Chinese medicine for multiple purposes. NBIF is known to exert anti-fungal and anti-tumor effects, and promote bone formation. Whether NBIF exhibits anti-allergic effects by regulating mast cell activation remains unclear. Therefore, we designed this study to investigate the anti-allergic effects of NBIF on IgE/Ag-induced mouse bone marrow-derived mast cells and ovalbumin-induced asthma, and the passive systemic anaphylaxis (PSA) reaction in mice. Our results showed that NBIF suppresses the production of leukotriene C4, prostaglandin D2 and inflammatory cytokines, and decreases the degranulation of BMMCs stimulated by IgE/Ag. A thorough investigation ascertained that NBIF suppresses the phosphorylation of mitogen-activated protein kinases, and represses the nuclear factor-κB-related signaling pathway. In addition, the oral administration of NBIF in mice inhibited the IgE-induced PSA reaction in a dose-dependent manner. Overall, we provide new insights into how NBIF regulates the IgE/Ag-mediated signaling pathways. Moreover, our investigation promotes the potential use of NBIF in treating allergy and asthma.
Subject(s)
Anaphylaxis , Anti-Allergic Agents , Asthma , Hypersensitivity , Anaphylaxis/drug therapy , Animals , Anti-Allergic Agents/pharmacology , Anti-Allergic Agents/therapeutic use , Asthma/drug therapy , Asthma/metabolism , Cell Degranulation , Hypersensitivity/drug therapy , Immunoglobulin E/metabolism , Isoflavones , Mast Cells , Mice , Mice, Inbred BALB CABSTRACT
Luteolin is a flavonoid found in many fruits, vegetables, and herbs. The antiinflammatory effects of luteolin have been reported. In this study, the effect of luteolin on allergic diseases and the underlying molecular mechanism were investigated. We found that luteolin inhibits Fc epsilon RΙ (FcεRΙ)- and Mas-related G protein-coupled receptor X2 (MRGPRX2)-mediated mast cells (MCs) activation, including degranulation and release of cytokines in vitro. Moreover, luteolin reduces the degree of swelling and Evans blue exudation of mice paw in a dose-dependent manner. The concentrations of histamine, TNF-α, MCP-1, IL-8, and IL-13 in mice serum are also decreased by luteolin administration. Our study reveals that luteolin can inhibit FcεRΙ- and MRGPRX2-mediated allergic responses in vivo and in vitro, and our results discover luteolin inhibited mast cells mediated anaphylactic reaction by inhibiting the phosphorylation level of PLCγ.
Subject(s)
Anaphylaxis , Calcium Signaling , Anaphylaxis/drug therapy , Animals , Calcium/metabolism , Cell Degranulation , Cell Line , Luteolin/pharmacology , Mast Cells , Mice , Mice, Inbred C57BL , Receptors, G-Protein-Coupled/metabolismSubject(s)
Anaphylaxis , Dengue , Homeopathy , Materia Medica , Severe Dengue , Anaphylaxis/drug therapy , Humans , Materia Medica/therapeutic useABSTRACT
Dengue, with four viral serotypes, causes epidemics in tropical and sub-tropical regions. Allopathic antiviral therapies and a vaccine of general use are lacking. The homeopathic medicine Apis mellifica, advised in anaphylaxis from honeybee sting, is proposed to address the life-threatening dengue shock syndrome, which develops from dengue hemorrhagic fever and has features of anaphylaxis. In both dengue and anaphylaxis, immunoglobulin E activates, and released vasoactive mediators (importantly histamine, tryptase and platelet-activating factor) cause, a vascular permeability enabling shock. In dengue, another mechanism, namely antibody-dependent enhancement, due to secondary infection with a heterologous dengue serotype, is associated with release of vasoactive mediators. The homeopathic medicine Apis mellifica indicates plasma leak, shock, and the serous effusion that is noted in dengue patients, and is a suggested prophylactic and therapeutic medicine for dengue shock syndrome.
Subject(s)
Anaphylaxis , Dengue Virus , Dengue , Homeopathy , Insect Bites and Stings , Materia Medica , Severe Dengue , Anaphylaxis/complications , Anaphylaxis/drug therapy , Animals , Bees , Humans , Insect Bites and Stings/complications , Severe Dengue/complications , Severe Dengue/drug therapyABSTRACT
Anaphylactoid reactions are potentially fatal allergic diseases caused by mast cells (MCs), which release histamine and lipid mediators under certain stimuli. Therefore, there is an urgent need to develop new drug candidates to treat anaphylactoid reactions. The MrgX2 receptor mediates anaphylactoid reactions that cause inflammatory diseases. Cortex dictamni is a Chinese herb used for treating allergy-related diseases; however, its active compound is still unknown and its mechanism of action has not yet been reported. The aim of this study was to screen the anti-anaphylactoid compound from C. dictamni extracts. An MrgX2/CMC-HPLC method was established for screening MrgX2-specific compounds retained from the alcohol extract of C. dictamni. A mouse model of hindpaw extravasation was used to evaluate the anti-anaphylactoid effect of this ingredient. Intracellular Ca2+ mobilization was assessed using a calcium imaging assay. Enzyme immunoassays were performed to measure cytokine and chemokine release levels. The molecular signaling pathways were explored by western blotting. As a result, dictamnine was identified as an effective compound using the MrgX2/CMC method, which remarkably suppressed MC intracellular Ca2+ mobilization and the release of de novo degranulated substances, and inhibited PKC-PLCγ-IP3R-associated protein signaling molecules. Hence, dictamnine is a novel therapeutic candidate for anaphylactoid reactions via MrgX2.
Subject(s)
Anaphylaxis/drug therapy , Mast Cells/drug effects , Nerve Tissue Proteins/metabolism , Quinolines/pharmacology , Receptors, G-Protein-Coupled/metabolism , Receptors, Neuropeptide/metabolism , Animals , Calcium/metabolism , Cell Degranulation/drug effects , Chemokines/metabolism , Cytokines/metabolism , Disease Models, Animal , Histamine/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Signal TransductionABSTRACT
PURPOSE OF REVIEW: Anaphylaxis is a severe, life-threatening, systemic allergic reaction that should be recognized and treated promptly. Intramuscular (IM) epinephrine is the first-line treatment for anaphylaxis and there are no absolute contraindications to its use. Despite its established track record of efficacy and safety, physicians and patients face barriers in the recognition and treatment of anaphylaxis, including the maintenance and appropriate use of epinephrine auto-injectors. This has led to investigation into potential alternatives to IM epinephrine administration in anaphylaxis. RECENT FINDINGS: This review investigates the current standard of care in the treatment of anaphylaxis, barriers to IM epinephrine use, and alternative therapies under investigation for administration in anaphylaxis. Alternative routes under investigation include intranasal, sublingual, inhaled, and needle-free intramuscular administration of epinephrine. There are currently numerous investigational alternatives to IM epinephrine therapy which could hold promise as future effective treatments in the emergent management of anaphylaxis.
Subject(s)
Anaphylaxis , Epinephrine/therapeutic use , Anaphylaxis/drug therapy , Humans , Injections, Intramuscular , Self Administration , Treatment OutcomeABSTRACT
PURPOSE: Ephedra herb (Mao) exerts potent anti-allergic effects. This study aimed to examine the underlying mechanisms of Mao on allergic inflammation using in vitro cultured mast cells (MCs) and an in vivo model of MC-dependent anaphylaxis. METHODS: Bone marrow-derived MCs (BMMCs) were presensitized with anti-2,4-dinitrophenol (DNP) immunoglobulin E (IgE) and challenged with antigens (Ag; DNP-human serum albumin). Degranulation responses and cell surface high-affinity receptor for IgE (FcεRI) expression were assessed with/without Mao treatment. Passive systemic anaphylaxis (PSA)-treated mice were administered Mao and the pathophysiological responses were evaluated. RESULTS: Mao inhibited Ag-induced BMMC degranulation, but not polyclonal activation with phorbol 12-myristate 13-acetate (PMA) and ionomycin, indicating that Mao inhibits IgE-dependent activation of BMMCs. Mao-treated BMMCs exhibited significant reductions in expression of surface IgE and its receptor FcεRI. Analysis of subcellular localization revealed that Mao induces FcεRI internalization in BMMCs without degranulation. In the PSA mouse model, Mao administration prevented antigen-induced hypothermia. Mao administration significantly reduced cell surface expression of IgE-bound FcεRI on peritoneal MCs. CONCLUSIONS: Mao induced FcεRI internalization in MCs, thereby inhibiting Ag-induced IgE-dependent degranulation. The inhibitory effects of Mao on MC degranulation may offer a novel therapeutic approach for allergic diseases.
Subject(s)
Anaphylaxis/drug therapy , Anti-Allergic Agents/pharmacology , Ephedra/chemistry , Mast Cells/drug effects , Plant Extracts/pharmacology , Anaphylaxis/immunology , Animals , Anti-Allergic Agents/therapeutic use , Cell Degranulation/drug effects , Cell Degranulation/immunology , Cells, Cultured , Disease Models, Animal , Female , Humans , Immunoglobulin E/metabolism , Ionomycin/immunology , Mast Cells/immunology , Medicine, Kampo/methods , Mice , Plant Extracts/therapeutic use , Plant Stems/chemistry , Primary Cell Culture , Signal Transduction/drug effects , Signal Transduction/immunology , Tetradecanoylphorbol Acetate/immunologyABSTRACT
Jing-Fang powder (Schizonepeta tenuifolia Briq. and Saposhnikovia divaricata (Turcz.) Schischk.) was used to treat chronic bronchitis, asthma and chronic urticaria. Based on the preliminary results of screening research on the antiallergic effective parts of Jing-Fang powder, its ethyl acetate extract fractions (JFEE) and isolate D (JFEE-D) showed the best anti-allergic effect. RBL-2H3 cell activation degranulation model and mice passive cutaneous anaphylaxis (PCA) reaction model were used to investigate the effects and mechanisms of JFEE and JFEE-D on IgE-mediated type I allergic reactions. LC-MS was utilized to determine the composition of JFEE and JFEE-D. We found that JFEE and JFEE-D significantly reduced ß-HEX, histamine, IL-4, IL-6 levels in cell supernatants, and improved the degree and morphology of cell degranulation. JFEE and JFEE-D significantly inhibited the increase of ear vascular permeability and abnormal increase of serum IgE, TNF-α, IL-6 levels. JFEE and JFEE-D inhibited mRNA expression of PI3K and Akt and down-regulated protein expression of PI3K, Akt, p-Akt, and PLCγ1 in sensitized RBL-2H3 cells. The combined use of JFEE and JFEE-D with pathway inhibitor Wortmannin revealed synergistic down-regulation of PI3K, Akt, and p-Akt protein expression. The combined use of pathway agonist IGF-1, JFEE and JFEE-D down-regulated increase of p-Akt/Akt protein expression. Moreover, JFEE and JFEE-D significantly inhibited protein expression of PI3K, p-Akt and PLCγ1 in PCA model mice. These results show that JFEE and JFEE-D inhibit type I allergic reactions by inhibiting PI3K/Akt signaling pathway.
Subject(s)
Anti-Allergic Agents/pharmacology , Apiaceae/chemistry , Lamiaceae/chemistry , Phosphatidylinositol 3-Kinases/metabolism , Plant Extracts/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Anaphylaxis/drug therapy , Anaphylaxis/prevention & control , Animals , Asthma/drug therapy , Bronchitis, Chronic/drug therapy , Capillary Permeability/drug effects , Cell Degranulation/drug effects , Cell Line , Chronic Urticaria/drug therapy , Mice , Phosphatidylinositol 3-Kinases/biosynthesis , Proto-Oncogene Proteins c-akt/biosynthesis , Rats , Wortmannin/pharmacologyABSTRACT
Background: Bee venom has been used as a therapeutic compound for various human diseases in oriental medicine; however, it can induce anaphylaxis in hypersensitive patients during treatment. Anaphylaxis is an acute allergic reaction that occurs after allergen exposure. IgE is released from immune-related cells such as mast cells and basophils during anaphylaxis. Various inflammatory mediators are also released into the bloodstream during the acute response. Objectives: We aimed to identify specific proteins from bee venom-hypersensitive patients. Methods: We analyzed the blood serum of control and bee venom-hypersensitive patients using two-dimensional (2D) electrophoresis. Results: An interesting protein spot with a molecular size of 10 kDa was identified at an isoelectric point (p.I.) of 5.5. Spots detected both before and after sweet bee venom therapy were not proteins induced by sweet bee venom. The 10 kDa protein was identified as the cleaved form of haptoglobin through liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Statistical analysis indicated that the presence of the spot was highly significant in the bee venom-hypersensitive group. Conclusion: The findings suggest that cleaved haptoglobin may be a significant diagnostic protein for anaphylaxis. In addition, a high incidence of bee venom hypersensitivity may be associated with the haptoglobin genotype.
Subject(s)
Anaphylaxis , Bee Venoms , Allergens , Anaphylaxis/chemically induced , Anaphylaxis/drug therapy , Chromatography, Liquid , Haptoglobins , Humans , Immunoglobulin E , Serum , Tandem Mass SpectrometryABSTRACT
BACKGROUND: Tripterine (TRI), an active monomer in Tripterygium wilfordii, has significant pharmacological activities, such as anti-inflammatory, immunosuppressive and anti-tumor activities. TRI may be used to treat allergic diseases because of its characteristics of immunosuppression. OBJECTIVE: This study aims to explore the anti-allergic effect of TRI. METHODS: It was tested in vivo and in vitro in this study. RESULTS: The results showed that TRI could significantly inhibit histamine release from rat peritoneal mast cells; the inhibitory effect of TRI on histamine release was stronger than that of other known histamine inhibitors such as disodium cromoglyceride. TRI also significantly inhibited systemic anaphylactic shock induced by compound 48/80 and skin allergy induced by IgE, and inhibited the expression of inflammatory factors secreted by Human Mast Cells (HMC-1) induced by Phorbol 12-Myristate 13- Acetate (PMA) and calcium carrier A23187. In the animal model of allergic rhinitis induced by Ovalbumin (OA), the scores of friction, histamine, IgE, inflammatory factors and inflammatory cells decreased after TRI was administered orally or nasally. CONCLUSION: TRI, as an active immunoregulatory factor, has great potential in the treatment of mast cell-mediated allergic diseases.
Subject(s)
Anaphylaxis/drug therapy , Anti-Allergic Agents/pharmacology , Histamine Release/drug effects , Mast Cells/drug effects , Rhinitis, Allergic/drug therapy , Triterpenes/pharmacology , Animals , Anti-Allergic Agents/therapeutic use , Calcimycin/pharmacology , Cytokines/metabolism , Disease Models, Animal , Drugs, Chinese Herbal/therapeutic use , Humans , Male , Mast Cells/metabolism , Mice, Inbred BALB C , NF-kappa B/metabolism , Pentacyclic Triterpenes , Rats , Rhinitis, Allergic/immunology , Tetradecanoylphorbol Acetate/pharmacology , Triterpenes/therapeutic use , p-Methoxy-N-methylphenethylamine/pharmacologyABSTRACT
BACKGROUND: Pseudo-allergic reactions are potentially fatal hypersensitivity responses caused by mast cell activation. α-linolenic acid (ALA) is known for its anti-allergic properties. However, its potential anti-pseudo-allergic effects were not much investigated. PURPOSE: To investigate the inhibitory effects of ALA on IgE-independent allergy in vitro, and in vivo, as well as the mechanism underlying its effects. METHODS/STUDY DESIGNS: The anti-anaphylactoid activity of ALA was evaluated in passive cutaneous anaphylaxis reaction (PCA) and systemic anaphylaxis models. Calcium imaging was used to assess intracellular Ca2+ mobilization. The release of cytokines and chemokines was measured using enzyme immunoassay kits. Western blot analysis was conducted to investigate the molecules of Lyn-PLCγ-IP3R-Ca2+ and Lyn-p38/NF-κB signaling pathway. RESULTS: ALA (0, 1.0, 2.0, and 4.0 mg/kg) dose-dependently reduced serum histamine, chemokine release, vasodilation, eosinophil infiltration, and the percentage of degranulated mast cells in C57BL/6 mice. In addition, ALA (0, 50, 100, and 200 µM) reduced Compound 48/80 (C48/80) (30 µg/ml)-or Substance P (SP) (4 µg/ml)-induced calcium influx, mast cell degranulation and cytokines and chemokine release in Laboratory of Allergic Disease 2 (LAD2) cells via Lyn-PLCγ-IP3R-Ca2+ and Lyn-p38/NF-κB signaling pathway. Moreover, ALA (0, 50, 100, and 200 µM) inhibited C48/80 (30 µg/ml)- and SP (4 µg/ml)-induced calcium influx in Mas-related G-protein coupled receptor member X2 (MrgX2)-HEK293 cells and in vitro kinase assays confirmed that ALA inhibited the activity of Lyn kinase. In response to 200 µM of ALA, the activity of Lyn kinase by (7.296 ± 0.03751) × 10-5 units/µl and decreased compared with C48/80 (30 µg/ml) by (8.572 ± 0.1365) ×10-5 units/µl. CONCLUSION: Our results demonstrate that ALA might be a potential Lyn kinase inhibitor, which could be used to treat pseudo-allergic reaction-related diseases such as urticaria.
Subject(s)
Anaphylaxis/drug therapy , Anti-Allergic Agents/pharmacology , Passive Cutaneous Anaphylaxis/drug effects , alpha-Linolenic Acid/pharmacology , src-Family Kinases/antagonists & inhibitors , Animals , Cell Degranulation/drug effects , Chemokines/metabolism , Dose-Response Relationship, Drug , Humans , Immunoglobulin E/immunology , Male , Mast Cells/drug effects , Mast Cells/immunology , Mice, Inbred C57BL , Nerve Tissue Proteins/metabolism , Protein Kinase Inhibitors/pharmacology , Receptors, G-Protein-Coupled/metabolism , Receptors, Neuropeptide/metabolism , p-Methoxy-N-methylphenethylamine/toxicity , src-Family Kinases/chemistry , src-Family Kinases/immunology , src-Family Kinases/metabolismABSTRACT
BACKGROUND: Mast cell and basophil activation by antigen cross-linking of FcεRI-bound IgE is central to allergy pathogenesis. We previously demonstrated global suppression of this process by rapid desensitization with anti-FcεRIα mAbs. OBJECTIVES: We sought to determine whether use of monovalent (mv) anti-FcεRIα mAbs increases desensitization safety without loss of efficacy. METHODS: mv anti-human (hu) FcεRIα mAbs were produced with mouse-derived immunoglobulin variable regions and huIgG1 or huIgG4 C regions and were used to suppress murine IgE-mediated anaphylaxis and food allergy. mAbs were administered as a single dose or as serially increasing doses to mice that express hu instead of mouse FcεRIα; mice that additionally have an allergy-promoting IL-4Rα mutation; and hu cord blood-reconstituted immunodeficient, hu cytokine-secreting, mice that have large numbers of activated hu mast cells. Anaphylaxis susceptibility was sometimes increased by treatment with IL-4 or a ß-adrenergic receptor antagonist. RESULTS: mv anti-hu FcεRIα mAbs are considerably less able than divalent mAbs are to induce anaphylaxis and deplete mast cell and basophil IgE, but mv mAbs still strongly suppress IgE-mediated disease. The mv mAbs can be safely administered as a single large dose to mice with typical susceptibility to anaphylaxis, while a rapid desensitization approach safely suppresses disease in mice with increased susceptibility. Our huIgG4 variant of mv anti-huFcεRIα mAb is safer than our huIgG1 variant is, apparently because reduced interactions with FcεRs decrease ability to indirectly cross-link FcεRI. CONCLUSIONS: mv anti-FcεRIα mAbs more safely suppress IgE-mediated anaphylaxis and food allergy than divalent variants of the same mAbs do. These mv mAbs may be useful for suppression of huIgE-mediated disease.
Subject(s)
Anaphylaxis/drug therapy , Anti-Allergic Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Food Hypersensitivity/drug therapy , Immunoglobulin E/immunology , Receptors, IgE/immunology , Anaphylaxis/immunology , Animals , Anti-Allergic Agents/pharmacology , Antibodies, Monoclonal/pharmacology , Female , Food Hypersensitivity/immunology , Immunoglobulin G/immunology , Male , Mast Cells/drug effects , Mast Cells/immunology , Mice, Inbred BALB C , Mice, Transgenic , Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases/immunology , Receptors, IgE/genetics , Syk Kinase/immunologyABSTRACT
BACKGROUND: Immunoglobulin E (IgE)-mediated mast cell (MC) activation is crucial in multiple allergic diseases. Parkinson disease protein 7 (DJ-1) and Lyn kinase were reported as the receptor-proximal events in IgE receptor (FcεRI) signals in human MC. Kaempferol, a natural flavonol mainly derived from the rhizome of traditional Chinese herb Kaempferia galanga L. (Zingiberaceae), has been known to inhibit allergic reactions, but it was limited to the receptor-distal signals on rat basophilic leukemia cells. A thorough investigation of the inhibitory effects of kaempferol on human MC has not been done. PURPOSE: To investigate the inhibitory effects of kaempferol on IgE-mediated anaphylaxis in vivo and in human MCs, as well as the mechanism underlying its effects, especially the receptor-proximal signals. METHODS: IgE-mediated passive cutaneous anaphylaxis and systemic anaphylaxis model were applied to elucidate the antiallergic activity of kaempferol in vivo. The degranulation assay, calcium imaging, the release of cytokines and chemokines on the laboratory of allergic disease 2 (LAD2) cells were used to evaluate the antiallergic effect of kaempferol in vitro. Western blot analysis was performed to investigate the DJ-1/Lyn signaling pathway and downstream molecules. Kinase activity assay, immunofluorescence, and molecular docking were conducted to confirm the influence of kaempferol on DJ-1/Lyn molecules. RESULTS: Kaempferol dose-dependently attenuated ovalbumin/IgE-induced mice paw swelling, primary MC activation from paw skin, as well as rehabilitated the hypothermia, and reduced the serum concentrations of histamine, tumor necrosis factor-alpha, interleukin-8, and monocyte chemo-attractant protein-1. Additionally, kaempferol suppressed IgE-mediated LAD2 cell degranulation and calcium fluctuation. Remarkably, kaempferol was found to bind with DJ-1 protein, and initially prevented DJ-1 from translocating to the plasma membrane, thereby inhibited full activation of Lyn, and eventually restrained those receptor-distal signaling molecules, involved Syk, Btk, PLCγ, IP3R, PKC, MAPKs, Akt and NF-κB. CONCLUSION: Kaempferol could be used as a DJ-1 modulator for preventing MC-mediated allergic disorders through attenuating Lyn activation.
Subject(s)
Anaphylaxis/drug therapy , Anti-Allergic Agents/pharmacology , Kaempferols/pharmacology , Mast Cells/drug effects , Anaphylaxis/immunology , Animals , Cell Degranulation/drug effects , Cell Line , Dose-Response Relationship, Drug , Humans , Immunoglobulin E/adverse effects , Immunoglobulin E/metabolism , Kaempferols/chemistry , Male , Mast Cells/immunology , Mast Cells/metabolism , Mice, Inbred C57BL , Molecular Docking Simulation , Ovalbumin/toxicity , Passive Cutaneous Anaphylaxis/drug effects , Phospholipase C gamma/metabolism , Protein Deglycase DJ-1/metabolism , Receptors, IgE/metabolism , Signal Transduction/drug effects , src-Family Kinases/metabolismABSTRACT
Plant lipid transfer proteins (LTPs) are widespread plant food allergens, highly resistant to food processing and to the gastrointestinal environment, which have been described as the most common food allergens in the Mediterranean area. LTP allergy is widely described in adults, but it represents an emerging allergen also in the pediatric population. Little is known about the real prevalence and the clinical features of this allergy in children and it still often remains underdiagnosed in these patients. An early identification and a deeper knowledge of this allergy in childhood can avoid severe systemic reactions and improve the child's quality of life. Pediatricians should always consider the possibility of LTP involvement in cases of plant-derived food allergy.
Subject(s)
Allergens/adverse effects , Anaphylaxis/immunology , Antigens, Plant/adverse effects , Carrier Proteins/adverse effects , Food Hypersensitivity/diagnosis , Plant Proteins, Dietary/adverse effects , Plant Proteins/adverse effects , Allergens/immunology , Anaphylaxis/drug therapy , Antigens, Plant/immunology , Carrier Proteins/immunology , Child , Cross Reactions , Food Hypersensitivity/complications , Food Hypersensitivity/diet therapy , Food Hypersensitivity/immunology , Humans , Immunoglobulin E/immunology , Patient Education as Topic , Plant Proteins/immunology , Plant Proteins, Dietary/immunology , Pollen/adverse effects , Pollen/immunology , Quality of Life , Severity of Illness IndexABSTRACT
Eckol, a precursor compound belonging to the dibenzo-1,4-dioxin class of phlorotannins, is a phloroglucinol derivative that exerts various activities. In the present study, we investigated the antiallergic effects of eckol isolated from the marine brown algae, Ecklonia cava using immunoglobulin E (IgE)/bovine serum albumin (BSA)-stimulated mouse bone marrow-derived cultured mast cells (BMCMC) and a mouse model of anaphylaxis. Eckol inhibited IgE/BSA-induced BMCMC degranulation by reducing ß-hexosaminidase release. A flow cytometric analysis revealed that eckol decreases FcεRI expression on cell surface and IgE binding to the FcεRI in BMCMC. Moreover, eckol suppressed the production of the cytokines, interleukin (IL)-4, IL-5, IL-6, and IL-13 and the chemokine, thymus activation-regulated chemokine (TARC) by downregulating, IκB-α degradation and NF-κB nuclear translocation. Furthermore, it attenuated the passive cutaneous anaphylactic reaction induced by IgE/BSA-stimulation in the ear of BALB/c mice. These results suggest that eckol is a potential therapeutic candidate for the prevention and treatment of allergic disorders.