Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease.

The macrophage, a versatile cell type prominently involved in host defense and immunity, assumes a distinct state of alternative activation in the context of polarized type 2 immune responses such as allergic inflammation and helminth infection. This alternatively activated phenotype is induced by the canonical type 2 cytokines interleukin (IL)-4 and IL-13, which mediate expression of several characteristic markers along with a dramatic shift in macrophage metabolic pathways that influence surrounding cells and tissues. We discuss recent advances in the understanding of IL-4- and IL-13-mediated alternatively activated macrophages and type 2 immune responses; such advances have led to an expanded appreciation for functions of these cells beyond immunity, including maintenance of physiologic homeostasis and tissue repair.

Recent Advancement and Novel Application of Natural Polyphenols for the Treatment of Allergy Asthma: From Phytochemistry to Biological Implications.

Allergic diseases, primarily IgE-mediated, exert a substantial global health burden. A pivotal role in allergic reactions is played by mast cells, with histamine serving as a central mediator. Within this context, plant-based polyphenols, abundantly present in vegetables and fruits, show promising potential for allergy prevention. These natural compounds, particularly flavonoids, possess anti-inflammatory and anti-allergic properties, influencing dendritic cells, modulating macrophages, and fostering the proliferation of B cells and T cells. The potent anti-allergic effects of flavonoids are attributed to their ability to reduce the production of signaling factors, suppress cytokine production, and regulate signal transduction and gene expression in mast cells, basophils, and T cells. Notably, their benefits extend beyond allergy prevention, as they hold promise in the prevention and treatment of autoimmune illnesses such as diabetes, rheumatoid arthritis, and multiple sclerosis. In the context of allergic reactions and autoimmune diseases, polyphenols exhibit immunomodulatory effects by inhibiting autoimmune T cell proliferation and downregulating pro-inflammatory cytokines. In recent times, flavonoids, being the most prevalent polyphenols in food, have garnered significant attention from researchers due to their potential health advantages. This review compiles the latest scientific research to highlight the impact of flavonoids on allergic illnesses and their potential as a beneficial dietary component.

Unveiling chronic spontaneous urticaria pathophysiology through systems biology.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a rare, heterogeneous, severely debilitating, and often poorly controlled skin disease resulting in an itchy eruption that can be persistent. Antihistamines and omalizumab, an anti-IgE mAb, are the only licensed therapies. Although CSU pathogenesis is not yet fully understood, mast cell activation through the IgE:high-affinity IgE receptor (FcεRI) axis appears central to the disease process. OBJECTIVE: We sought to model CSU pathophysiology and identify in silico the mechanism of action of different CSU therapeutic strategies currently in use or under development. METHODS: Therapeutic performance mapping system technology, based on systems biology and machine learning, was used to create a CSU interactome validated with gene expression data from patients with CSU and a CSU model that was used to evaluate CSU pathophysiology and the mechanism of action of different therapeutic strategies. RESULTS: Our models reflect the known role of mast cell activation as a central process of CSU pathophysiology, as well as recognized roles for different therapeutic strategies in this and other innate and adaptive immune processes. They also allow determining similarities and differences between them; anti-IgE and Bruton tyrosine kinase inhibitors play a more direct role in mast cell biology through abrogation of FcεRI signaling activity, whereas anti-interleukins and anti-Siglec-8 have a role in adaptive immunity modulation. CONCLUSION: In silico CSU models reproduced known CSU and therapeutic strategies features. Our results could help advance understanding of therapeutic mechanisms of action and further advance treatment research by patient profile.

Screening of probiotic Lactobacillus to reduce peanut allergy and with potential anti-allergic activity.

BACKGROUND: Peanut is a significant source of nutrition and a valuable oilseed crop. It is also a serious allergy source, which poses a threat to 1.1% of the population. This study aimed to screen lactic acid bacteria (LAB) with the capacity to alleviate peanut allergenicity and exhibit anti-allergic properties. RESULT: The results show that LAB can make use of substances in peanuts to reduce the pH of peanut milk from 6.603 to 3.593-4.500 by acid production and that it can utilize the protein in peanuts to reduce the allergenic content (especially Ara h 1) and improve biological activity in peanut pulp. The content of Ara h 1 peanut-sensitizing protein was reduced by 74.65% after fermentation. The protein extracted from fermented peanut pulp is more readily digestible by gastrointestinal juices. The inhibitory activity assay of hyaluronidase (an enzyme with strong correlation to allergy) increased from 46.65% to a maximum of 90.57% to reveal that LAB fermentation of peanut pulp exhibited a robust anti-allergic response. CONCLUSION: The strains identified in this study exhibited the ability to mitigate peanut allergenicity partially and to possess potential anti-allergic properties. Lactobacillus plantarum P1 and Lactobacillus salivarius C24 were identified as the most promising strains and were selected for further research. © 2023 Society of Chemical Industry.

Anti-allergic effect of vitamin C through inhibiting degranulation and regulating TH1/TH2 cell polarization.

BACKGROUND: Food allergy has become a global public health problem. This study aimed to explore the possible anti-allergic effect of vitamin C (VC). A rat basophilic leukemia (RBL)-2H3 cell degranulation model was used to assess the effect of VC on degranulation in vitro, and an ovalbumin (OVA)-induced BALB/c mouse allergy model was used to assess the anti-allergy effect of VC in vivo. RESULTS: In vitro, VC significantly attenuated the release of ß-hexosaminidase, tryptase and histamine, and also reduced cytokine production (interleukins 4 and 6, tumor necrosis factor α) significantly (P < 0.05), with the inhibitory effect demonstrating a positive correlation with VC dose. In vivo, compared with the OVA group, the levels of serum immunoglobulins E and G1 of the VC low-dose (VCL) group (50 mg kg-1) and high-dose (VCH) group (200 mg·kg-1) were significantly reduced (P < 0.05). Furthermore, the plasma histamine level was also significantly decreased (P < 0.05). Moreover, TH2 cell polarization in mice of the VCL and VCH groups was significantly inhibited (P < 0.05), promoting the TH1/TH2 cell polarization balance. Additionally, VC treatment enhanced the expression of CD80 (P < 0.05) in spleen and small intestine tissues, while significantly inhibiting the expression of CD86 (P < 0.05); notably, high-dose VC treatment was more effective. CONCLUSION: VC exerted an anti-allergic effect through inhibiting degranulation and regulating TH1/TH2 cell polarization balance. © 2024 Society of Chemical Industry.

Natural immunomodulating substances used for alleviating food allergy.

Food allergy is a serious health problem affecting more than 10% of the human population worldwide. Medical treatments for food allergy remain limited because immune therapy is risky and costly, and anti-allergic drugs have many harmful side effects and can cause drug dependence. In this paper, we review natural bioactive substances capable of alleviating food allergy. The sources of the anti-allergic substances reviewed include plants, animals, and microbes, and the types of substances include polysaccharides, oligosaccharides, polyphenols, phycocyanin, polyunsaturated fatty acids, flavonoids, terpenoids, quinones, alkaloids, phenylpropanoids, and probiotics. We describe five mechanisms involved in anti-allergic activities, including binding with epitopes located in allergens, affecting the gut microbiota, influencing intestinal epithelial cells, altering antigen presentation and T cell differentiation, and inhibiting the degranulation of effector cells. In the discussion, we present the limitations of existing researches as well as promising advances in the development of anti-allergic foods and/or immunomodulating food ingredients that can effectively prevent or alleviate food allergy. This review provides a reference for further research on anti-allergic materials and their hyposensitizing mechanisms.

Structures and Anti-Allergic Activities of Natural Products from Marine Organisms.

In recent years, allergic diseases have occurred frequently, affecting more than 20% of the global population. The current first-line treatment of anti-allergic drugs mainly includes topical corticosteroids, as well as adjuvant treatment of antihistamine drugs, which have adverse side effects and drug resistance after long-term use. Therefore, it is essential to find alternative anti-allergic agents from natural products. High pressure, low temperature, and low/lack of light lead to highly functionalized and diverse functional natural products in the marine environment. This review summarizes the information on anti-allergic secondary metabolites with a variety of chemical structures such as polyphenols, alkaloids, terpenoids, steroids, and peptides, obtained mainly from fungi, bacteria, macroalgae, sponges, mollusks, and fish. Molecular docking simulation is applied by MOE to further reveal the potential mechanism for some representative marine anti-allergic natural products to target the H1 receptor. This review may not only provide insight into information about the structures and anti-allergic activities of natural products from marine organisms but also provides a valuable reference for marine natural products with immunomodulatory activities.

Silibinin attenuated pseudo-allergic reactions and mast cell degranulation via PLCγ and PI3K/Akt signaling pathway.

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.

Wheatgrass-and-Aronia-Mixed Extract Suppresses Immunoglobulin E-Mediated Allergic Reactions In Vitro and In Vivo.

Mast cells are an important component of immune responses. Immunoglobulin (Ig) E-sensitized mast cells release substances within minutes of allergen exposure, triggering allergic responses. Until now, numerous pharmacological effects of wheatgrass and aronia have been verified, but the effects of wheatgrass and aronia (TAAR)-mixed extract on allergic reactions have not been identified. Therefore, the aim of this study was to demonstrate the anti-allergic effect of TAAR extract on mast cell activation and cutaneous anaphylaxis. In this study, we investigated the anti-allergic effects and related mechanisms of TAAR extract in IgE-activated mast cells in vitro. We also assessed the ameliorating effect of TAAR extract on IgE-mediated passive cutaneous anaphylaxis mice in vivo. The TAAR extract significantly reduced the expression of ß-hexosaminidase, histamine, and pro-inflammatory cytokines, which are mediators related to mast cell degranulation, via the regulation of various signaling pathways. The TAAR extract also regulated oxidative-stress-related factors through the Nrf2 signaling pathway. Additionally, treatment of TAAR extract to the passive cutaneous anaphylaxis mouse model improved ear thickness and local ear pigmentation. Taken together, our results suggest that TAAR extract is a potential candidate natural product to treat overall IgE-mediated allergic inflammation and oxidative-stress-related diseases by suppressing mast cell activity.

Antiallergic Activity of 3-O-Dodecyl-l-ascorbic Acid.

2-O-Alkyl-l-ascorbic acids and 3-O-alkyl-l-ascorbic acids were synthesized, and their degranulation inhibitory activities were evaluated. Among ascorbic acid derivatives with butyl, octyl, dodecyl, hexadecyl, and octadecyl groups introduced at the C-2 or C-3 positions, an AA derivative with a dodecyl group introduced at the C-3 position, 3-O-dodecyl-l-ascorbic acid (compound 8), showed the strongest inhibitory activity against antigen-stimulated degranulation. Compound 8 also inhibited calcium ionophore-stimulated degranulation. Compound 11, in which the hydroxyl group at the C-6 position of compound 8 was substituted with an amino group, and compound 12, in which the dodecyloxy group at the C-3 position of compound 8 was exchanged with a dodecylamino group, were synthesized, and these derivatives showed weaker inhibitory activity against antigen-stimulated degranulation than that of compound 8. In addition, orally administered compound 8 inhibited passive cutaneous anaphylaxis reactions in mice with a potency equal to that of oxatomide, an antiallergic agent. These results suggest that compound 8 may be a candidate for antiallergic treatment.

PI3K/mTOR Inhibitor Dactolisib Attenuates Allergic Response Through Inhibitions of the Sensitization and Mast Cell Activation.

The aim of this study was to evaluate the anti-allergic potentials of dactolisib, a dual PI3K/mTOR kinase inhibitor, on two important events for allergy: sensitization and the onset of anaphylactic symptoms. After sensitization with the antigen ovalbumin (OVA), five successive oral administrations of dactolisib effectively decreased serum anti-OVA antibody-an indicator of sensitization-levels in mice. In parallel with the antibody levels in their serum, anaphylactic rectal temperature decrease induced by the re-administration of OVA to dactolisib-treated mice was strongly diminished compared to that in vehicle-treated mice. The inhibitor also inhibited ex vivo splenic B cell activation indicated by the increase of phosphorylation of Akt, CD69 expression levels, and proliferation upon anti-B cell receptor antibody treatment, suggesting that suppressive effects of the inhibitor on B cell activation plays a role in its ability to decrease sensitization in vivo. We concurrently observed the anti-anaphylactic ability of dactolisib in vivoand in vitro. A single oral administration of the inhibitor attenuated the anaphylactic rectal temperature decrease induced in a mouse model of passive systemic anaphylaxis. In in vitro mast cell models, pretreatment with the drug inhibited the degranulation response and cytokine production in RBL2H3 cells triggered by IgE and antigens, without affecting cell viability. These results suggest that dactolisib, as well as other PI3K/mTOR inhibitors, might be a good candidate for anti-allergic drugs that exhibit both anti-sensitizing and anti-anaphylactic effects.

Drug repositioning of tranilast to sensitize a cancer therapy by targeting cancer-associated fibroblast.

Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment that mediate resistance of cancer cells to anticancer drugs. Tranilast is an antiallergic drug that suppresses the release of cytokines from various inflammatory cells. In this study, we investigated the inhibitory effect of tranilast on the interactions between non-small cell lung cancer (NSCLC) cells and the CAFs in the tumor microenvironment. Three EGFR-mutant NSCLC cell lines, two KRAS-mutant cell lines, and three CAFs derived from NSCLC patients were used. To mimic the tumor microenvironment, the NSCLC cells were cocultured with the CAFs in vitro, and the molecular profiles and sensitivity to molecular targeted therapy were assessed. Crosstalk between NSCLC cells and CAFs induced multiple biological effects on the NSCLC cells both in vivo and in vitro, including activation of the STAT3 signaling pathway, promotion of xenograft tumor growth, induction of epithelial-mesenchymal transition (EMT), and acquisition of resistance to molecular-targeted therapy, including EGFR-mutant NSCLC cells to osimertinib and of KRAS-mutant NSCLC cells to selumetinib. Treatment with tranilast led to inhibition of IL-6 secretion from the CAFs, which, in turn, resulted in inhibition of CAF-induced phospho-STAT3 upregulation. Tranilast also inhibited CAF-induced EMT in the NSCLC cells. Finally, combined administration of tranilast with molecular-targeted therapy reversed the CAF-mediated resistance of the NSCLC cells to the molecular-targeted drugs, both in vitro and in vivo. Our results showed that combined administration of tranilast with molecular-targeted therapy is a possible new treatment strategy to overcome drug resistance caused by cancer-CAF interaction.

Anti-allergic effect of ascorbic acid derivative DDH-1 in a mouse model of atopic dermatitis.

Atopic dermatitis (AD) is the most common inflammatory skin disease, which is characterized by excessive Th2 immune responses. In AD patients, the expression of the chemokines CCL17 and CCL22 is increased in skin lesions, leading to the infiltration of Th2 cells. In addition, typical pro-inflammatory cytokines, including TNF-α, IL-1ß and IL-6, have also been shown to be associated with the pathogenesis of AD. Recently, DDH-1, an ascorbic acid derivative, has been synthesized and demonstrated to have a more stabilized structure and better skin penetrability. Furthermore, DDH-1 has been shown to suppress pro-inflammatory cytokine expression in vitro and in vivo. Therefore, using an AD mouse model, we evaluated the effect of DDH-1 to reduce allergic skin inflammation. We found that cutaneous administration of DDH-1 significantly reduced the expression levels of TNF-α, IL-1ß and IL-6 in the skin lesions of AD-like mice. Additionally, DDH-1 administration also significantly reduced the expression levels of CCL17 and CCL22, resulting in decreased skin infiltration of Th2 cells. Consequently, DDH-1 reduced ear and epidermal thickness, the serum IgE levels and the number of infiltrating inflammatory cells and mast cells into the AD-like skin lesions. Combination treatment with DDH-1 and corticosteroid more efficiently improved the skin lesions compared with corticosteroid alone. Collectively, our results suggest that DDH-1 has an anti-allergic effect in an AD mouse model by reducing not only the pro-inflammatory cytokine expression but also the Th2-associated chemokine expression. Thus, DDH-1 may be beneficial for AD treatment and prevention as a monotherapy or in combination with corticosteroids.

Juzentaihoto Exerts Anti-Allergic Effects by Inhibiting Effector T-Cell Activation and Inducing and/or Activating Regulatory T Cells in a Murine Model of Contact Hypersensitivity.

BACKGROUND: Juzentaihoto (JTT) is a Kampo prescription that has been used clinically for treating skin diseases such as atopic dermatitis in Japan. We have previously studied the anti-allergic effects of JTT on 2,4,6-trinitrochlorobenzene (TNCB)-induced contact hypersensitivity (CHS) in mice and demonstrated that it significantly suppresses ear swelling in a dose-dependent manner. However, the mechanism underlying the anti-allergic actions of JTT is obscure. METHODS: We investigated the mechanism underlying the anti-allergic effects of JTT using a TNCB-induced murine CHS model and adoptive cell transfer experiments. RESULTS: We showed that the anti-allergic effects of JTT are due to inhibition of effector T-cell activation and induction and/or activation of regulatory T cells. Furthermore, ex vivo experiments confirmed the effect of JTT on the activation of effector T cells and regulatory T cells, as interferon-γ production decreased, whereas interleukin (IL)-10 production increased, in the cultured lymphocytes obtained from 5% TNCB-sensitized mice treated with anti-CD3ε and anti-CD28 monoclonal antibodies. Flow cytometry showed that the CD4+CD25+Foxp3+, CD4+CD25+Foxp3-, and CD8+CD122+ cell population increased after oral administration of JTT. Finally, the anti-allergic effect of JTT by inducing and/or activating regulatory T cells (Tregs) was confirmed to be mediated by IL-10 through in vivo neutralization experiments with anti-IL-10 monoclonal antibodies. CONCLUSION: We suggested that JTT exerts anti-allergic effects by regulating the activation of effector T cells and Tregs involved in murine CHS model.

Synthesis and evaluation of new potential anti-pseudo-allergic agents.

Pseudo-allergic reactions frequently occur following clinical drug use and sometimes even cause mortal danger. Mas-related G-protein-coupled receptor member X2 (MRGPRX2) is a novel receptor that mediates pseudo-allergy and is an important target in the treatment of allergies. However, to date, there are no synthetic small-molecule inhibitors that prevent anaphylactoid reactions through this pathway. Our preliminary research suggested that B10-S and mubritinib effectively inhibited LAD2 cells. Therefore, two novel derivatives were synthesized by integrating the active substructures of B10-S and mubritinib, according to the molecular docking results. The antiallergic inhibitory effects of the two compounds were preliminarily evaluated in vitro using ß-hexosaminidase release, histamine release, and intracellular Ca2+ mobilization assays, and their binding sites on MRGPRX2 were analyzed by molecular docking. Both substances inhibited ß-hexosaminidase and histamine release in LAD2 cells and decreased intracellular Ca2+ by inhibiting MRGPRX2 in MRGPRX2-HEK293 cells treated with C48/80 in a dose-dependent manner. The docking results suggested that the molecules could competitively bind to the active site on MRGPRX2 and Glu141, which were combined by C48/80. Our study indicated that the two compounds have potential anti-allergic properties, which may provide evidence that will facilitate the development of synthetic molecules with anti-pseudo-allergic activity for clinical use in the future.

MrgX2-SNAP-tag/cell membrane chromatography model coupled with liquid chromatography-mass spectrometry for anti-pseudo-allergic compound screening in Arnebiae Radix.

Pseudo-allergic reactions (PARs) are IgE-independent hypersensitivity reactions. Mas-related G protein-coupled receptor-X2 (MrgX2) was proved the key receptor of PAR. The anti-pseudo-allergic compound discovery based on MrgX2 was of great value. Cell membrane chromatography (CMC) based on MrgX2 provides a convenient and effective tool in anti-pseudo-allergic compound screening and discovery, and further improvements of this method are still needed. In this work, SNAP-tag was introduced at C-terminal of Mas-related G protein-coupled receptor (MrgX2-SNAP-tag), and an MrgX2-SNAP-tag/CMC model was then conducted using CMC technique. Comparative experiments showed that the new model not only satisfied the good selectivity and specificity of screening but also exhibited more stable and longer life span than traditional MrgX2/CMC model. By coupling with HPLC-MS, two compounds were screened out from Arnebiae Radix and identified as shikonin and acetylshikonin. Nonlinear chromatography was performed to study the interactions between two screened compounds and MrgX2, and binding constant (KA) of shikonin and acetylshikonin with MrgX2 were 2075.67 ± 0.34 M-1 and 32201.36 ± 0.35 M-1, respectively. Furthermore, ß-hexosaminidase and histamine release assay in vitro demonstrated that shikonin (1-5 µM) and acetylshikonin (2.5-10 µM) could both antagonize C48/80-induced allergic reaction. In conclusion, the MrgX2-SNAP-tag/CMC could be a reliable model for screening pseudo-allergy-related components from complex systems.

Potential Anti-allergic Effects of Bibenzyl Derivatives from Liverworts, Radula perrottetii.

The liverwort Radula perrottetii contains various bibenzyl derivatives which are known to possess various biological activities, such as anti-inflammatory effects. Mast cells (MC) play crucial roles in allergic and inflammatory diseases; thus, inhibition of MC activation is pivotal for the treatment of allergic and inflammatory disorders. We investigated the effects of perrottetin D (perD), isolated from Radula perrottetii, and perD diacetate (Ac-perD) on antigen-induced activation of MCs. Bone marrow-derived MCs (BMMCs) were generated from C57BL/6 mice. The degranulation ratio, histamine release, and the interleukin (IL)-4 and leukotriene B4 productions on antigen-triggered BMMC were investigated. Additionally, the effects of the bibenzyls on binding of IgE to FcεRI were observed by flow cytometry, and signal transduction proteins was examined by Western blot. Furthermore, binding of the bibenzyls to the Fyn kinase domain was calculated. At 10 µM, perD decreased the degranulation ratio (p < 0.01), whereas 10 µM Ac-perD down-regulated IL-4 production (p < 0.05) in addition to decreasing the degranulation ratio (p < 0.01). Both compounds tended to decrease histamine release at a concentration of 10 µM. Although 10 µM perD reduced only Syk phosphorylation, 10 µM Ac-perD diminished phosphorylation of Syk, Gab2, PLC-γ, and p38. PerD appeared to selectively bind Fyn, whereas Ac-perD appeared to act as a weak but broad-spectrum inhibitor of kinases, including Fyn. In conclusion, perD and Ac-perD suppressed the phosphorylation of signal transduction molecules downstream of the FcεRI and consequently inhibited degranulation, and/or IL-4 production. These may be beneficial potential lead compounds for the development of novel anti-allergic and anti-inflammatory drugs.

Anti-Allergic Effect of 3,4-Dihydroxybenzaldehyde Isolated from Polysiphonia morrowii in IgE/BSA-Stimulated Mast Cells and a Passive Cutaneous Anaphylaxis Mouse Model.

In this study, we investigated the anti-allergic effects of 3,4-dihydroxybenzaldehyde (DHB) isolated from the marine red alga, Polysiphonia morrowii, in mouse bone-marrow-derived cultured mast cells (BMCMCs) and passive cutaneous anaphylaxis (PCA) in anti-dinitrophenyl (DNP) immunoglobulin E (IgE)-sensitized mice. DHB inhibited IgE/bovine serum albumin (BSA)-induced BMCMCs degranulation by reducing the release of ß-hexosaminidase without inducing cytotoxicity. Further, DHB dose-dependently decreased the IgE binding and high-affinity IgE receptor (FcεRI) expression and FcεRI-IgE binding on the surface of BMCMCs. Moreover, DHB suppressed the secretion and/or the expression of the allergic cytokines, interleukin (IL)-4, IL-5, IL-6, IL-13, and tumor necrosis factor (TNF)-α, and the chemokine, thymus activation-regulated chemokine (TARC), by regulating the phosphorylation of IκBα and the translocation of cytoplasmic NF-κB into the nucleus. Furthermore, DHB attenuated the passive cutaneous anaphylactic (PCA) reaction reducing the exuded Evans blue amount in the mouse ear stimulated by IgE/BSA. These results suggest that DHB is a potential therapeutic candidate for the prevention and treatment of type I allergic disorders.

Investigation of the effect of IFN-γ/TNF-α-treated mesenchymal stem cells on Th9- and Treg cell-related parameters in a mouse model of ovalbumin-induced allergic asthma.

OBJECTIVE: Th9- and regulatory T (Treg) cells exert pro- and anti-allergic activity, respectively. Mesenchymal stem cell (MSC)-related immunomodulatory impacts can be enhanced by inflammatory cytokines. Here, the modulatory effects of IFN-γ/TNF-α-induced MSCs on Th9- and Treg cell-related parameters were investigated using an asthma model. METHODS: Allergic asthma was induced in BALB/c mice using sensitized and challenging with ovalbumin (OVA). The asthmatic groups were treated intraperitoneally with PBS, MSCs, IFN-γ-induced MSCs, TNF-α-induced MSCs and 'IFN-γ + TNF-α'-induced MSCs before the challenge phase. The mice were sacrificed 24 h after challenge. The serum IL-9 and IL-35 levels, as well as gene expression of IL-9, PU.1, IL-35-EBI3, and FOXP3 in the lung tissues were assessed using ELISA and real time-PCR, respectively. RESULTS: The differences of Th9 and Treg-related parameters were not significant between untreated asthmatic mice and those treated with non-induced MSCs. In comparison with untreated asthmatic group, treatment with IFN-γ-induced MSCs significantly reduced serum IL-9 levels, reduced lung expression of IL-9 and PU.1, while increasing serum IL-35 levels as well as lung expression of FOXP3; treatment with TNF-α-induced MSCs significantly reduced serum IL-9 levels as well as lung expression of IL-9, and treatment with 'IFN-γ + TNF-α'-induced MSCs, significantly modulated all investigated Th9 and Treg-related parameters. In comparison to mice treated with non-induced MSCs, serum IL-9 levels were remarkably decreased in mice treated with IFN-γ-induced and 'IFN-γ + TNF-α'-induced MSCs. CONCLUSIONS: IFN-γ-and 'IFN-γ + TNF-α' treated MSCs exerted almost comparable impacts, but were more efficient than TNF-α-exposed MSCs. Thus, IFN-γ alone can be sufficient to promote immunomodulatory effects of MSCs.

Suppression of IgE-mediated anaphylaxis and food allergy with monovalent anti-FcεRIα mAbs.

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.