Marat Khodoun - Academia.edu (original) (raw)
Papers by Marat Khodoun
Journal of Immunology, May 1, 2014
Food allergy, in mouse models, is mediated by mast cells, FcϵRI and IgE. We recently demonstrated... more Food allergy, in mouse models, is mediated by mast cells, FcϵRI and IgE. We recently demonstrated that rapid desensitization with a hamster mAb to mouse FcϵRIα (MAR-1) safely suppresses IgE-mediated anaphylaxis (JACI, 131:1555-64, 2013). Consequently, we evaluated whether the same approach could suppress established food allergy in BALB/c mice that had been sensitized intraperitoneally with ovalbumin/alum or egg white/alum and challenged repeatedly by oral gavage with ovalbumin or egg white until they had developed shock and diarrhea. Treatment of these mice with 50 µg of MAR-1 every 4 days suppressed both the induction of hypothermia by oral gavage with ovalbumin or egg white and mast cell MMCP1 secretion by 85-90% and decreased the incidence of diarrhea by 70-85%. Although MAR-1 suppression of food allergy was eventually limited by mouse development of IgG antibodies to hamster IgG, this could be prevented by injecting mice with anti-CD4 mAb (GK1.5) at the time of the initial MAR-1 injection. Although GK1.5, by itself, had little effect on established food allergy, the combination of MAR-1 plus GK1.5 completely suppressed the hypothermia, diarrheal, MMCP1, IL-4 and IL-13 responses to oral gavage with ovalbumin or egg white. These observations suggest that rapid desensitization, followed by continuing treatment with a non-immunogenic (humanized) anti-FcϵRIα mAb might effectively suppress IgE-mediated food allergy in people with this disorder.
The Journal of Immunology
Food ingestion generally induces antigen (Ag)-specific tolerance rather than immunity. In contras... more Food ingestion generally induces antigen (Ag)-specific tolerance rather than immunity. In contrast, we recently reported (JACI, 131:442–50, 2013) that Ag-specific, IgE-mediated food allergy (FA) can be induced when a protein Ag is repeatedly ingested with a widely used nutrient, medium chain triglycerides (MCT), without any additional sensitization. Mice that have been repeatedly inoculated orally with MCT plus egg white (EW) develop a Th2 cytokine and an IgE response as well as shock (hypothermia) following oral EW + MCT challenge. Because MCT ingestion induces increased intestinal epithelial cell expression of the pro-Th2 cytokines TSLP, IL-25 and IL-33, we investigated the importance of these cytokines in establishing and maintaining FA. We found that treatment with neutralizing mAbs to any of the pro-Th2 cytokines could suppress MCT + EW-induced FA development, with aTSLP mAb causing near-total suppression and aIL-25 and aIL-33 each causing considerable suppression. In contrast,...
The Journal of Immunology
Food ingestion generally induces antigen (Ag)-specific tolerance rather than immunity. Consistent... more Food ingestion generally induces antigen (Ag)-specific tolerance rather than immunity. Consistent with this, induction of IgE-mediated intestinal FA in mice has required either Ag priming through a parenteral route or ingestion of Ag with a potent toxin. In contrast, we recently reported (JACI, 131:442-50, 2013) that Ag-specific, IgE-mediated FA is induced when a protein Ag is ingested with the widely used nutrient, MCT. We also showed that MCT ingestion induces increased epithelial cell expression of the pro-Th2 cytokines TSLP, IL-25 and IL-33. We now report that MCT ingestion, by itself, can induce shock by damaging intestinal epithelium, with a consequent increase in intestinal permeability. In contrast, ingestion of the anionic detergent, sodium dodecyl sulfate, damages intestinal epithelium but does not promote a Th2 response. Both direct MCT induction of intestinal epithelial damage and MCT promotion of a Th2 response and FA to co-ingested egg white are suppressed in mice trea...
The Journal of Immunology
Several studies have examined the relative roles of complement vs. Fc receptors (FcRs) in host pr... more Several studies have examined the relative roles of complement vs. Fc receptors (FcRs) in host protection and inflammatory disease. Many of these studies have concluded that the more important role is played by stimulatory Fc receptors. These conclusions were based, however, on the assumption that complement activation occurs normally in the absence of stimulatory Fc receptors. We have used FcRγ-deficient mice, which lack all stimulatory FcRs, to examine this assumption. FcRγ-sufficient and -deficient mice were found to have similar levels of C3 in blood. Also, as expected, similar amounts of IgG2a became associated with blood leukocytes from both mouse strains after intravenous injection of a complement fixing IgG2a mAb to MHC class I Ag. Surprisingly, however, >10-fold more C3 became associated with the blood leukocytes from FcRγ-sufficient mice than those from FcRγ-deficient mice. Additionally, >6-fold more C5a was generated in blood from FcRγ-sufficient than deficient mice...
The Journal of Immunology
IgE-mediated mast cell and basophils activation is critical for the pathogenesis of anaphylaxis, ... more IgE-mediated mast cell and basophils activation is critical for the pathogenesis of anaphylaxis, drug allergy, food allergy and allergic skin disorders and contributes to the pathogenesis of asthma and allergic rhinitis. We recently demonstrated that IgE-mediated anaphylaxis in mice can be safely blocked by rapid desensitization with ascending doses of an anti-mouse FcεR1α Abs, starting with a dose too small to induce detectable disease and ending with a dose that induces anaphylaxis if injected into previously untreated mice (JACI, 131:1555-64, 2013). We have now modified this approach, which removes IgE from mast cells, to make it human-applicable, faster and safer. To do this, we: (1) generated a chimeric anti-human FcεR1α mAb that has V regions from a mouse anti-human FcεR1α mAb (15.1) and C regions from human IgG1; (2) substituted a mAb that binds FcεR1 regardless of whether it is associated with IgE for a mAb that only binds FcεR1 that is not IgE-associated; and (3) mutated th...
The Journal of Immunology
Epidemiologic evidence suggests that IgA, the main mucosal Ig isotype, inhibits allergy, but it i... more Epidemiologic evidence suggests that IgA, the main mucosal Ig isotype, inhibits allergy, but it is not known whether it suppresses anaphylaxis. We used mouse models to evaluate whether IgA can suppress systemic anaphylactic responses to ingested allergens by neutralizing them before or after their systemic absorption. Passive systemic anaphylaxis (PSA), measured as hypothermia, was induced by sensitizing mice with IgE anti-TNP mAb, then challenging them orally (og) with TNP-OVA. The ability of IgA to inhibit PSA by neutralizing Ag prior to or after systemic absorption was evaluated by pretreating mice with IgA anti-TNP mAb either og or iv. TNP-OVA was detectible in serum by 5 min after og administration. PSA developed within 5 min and was inhibited by iv, but not og IgA. Extent of inhibition was proportional to the IgA dose and Fcα/μR- and FcγRIIb-independent. Intestinal anaphylaxis (IA), defined as diarrhea <60 minutes after OVA challenge, was induced by priming mice ip with OVA...
Transdermal drug delivery provides convenient and pain-free self-administration for personalized ... more Transdermal drug delivery provides convenient and pain-free self-administration for personalized therapy. However, challenges remain in treating acute disease largely due to their inability to timely administrate therapeutics and precisely regulate pharmacokinetics within a short time window. Here we report the development of active acoustic metamaterials driven transdermal drug delivery for rapid and on-demand management of the acute disease. Through the integration of active acoustic metamaterials, a compact therapeutic patch is integrated for penetration of skin stratum corneum and active percutaneous transport of therapeutics with precise control of dose and rate over time. Moreover, the patch device quantitatively regulates the dosage and release kinetics of therapeutics and achieves better delivery performance in vivo than through subcutaneous injection. As a proof-of-concept application, our method can reverse life-threatening acute allergic reactions in a mouse model of anap...
Journal of Immunology, May 1, 2016
Endoplasmic reticulum (ER) stress and an unfolded protein response (UPR) are stimulated by satura... more Endoplasmic reticulum (ER) stress and an unfolded protein response (UPR) are stimulated by saturated, but not unsaturated fatty acids. We previously showed that saturated medium chain triglycerides (MCT) promote food allergy induction and increase epithelial cell expression of 3 pro-Th2 cytokines, TSLP, IL-25 and IL-33, which stimulate a Th2 cytokine response. These observations led us to hypothesize that the high concentrations of saturated triglycerides in two common food allergens, cow’s milk and chicken eggs, promote food allergy by inducing an epithelial cell UPR response, which in turn, causes these cells to express pro-Th2 cytokines. Indeed, studies with transformed human intestinal epithelial CACO2 cells demonstrated that MCT, egg yolk plasma (the liquid, triglyceride fraction of eggs) and cow’s milk cream each increase expression of the UPR-associated PERK, BiP, CHOP, XBP1 and/or XBP1s genes after 6 hours, followed by increased expression of all 3 pro-Th2 cytokine genes after 24 hours. Each of these stimuli, but not but not protein-rich, lipid-poor egg white, also increase epithelial permeability. Further, the increases in pro-Th2 cytokine expression are blocked by each of 3 UPR inhibitors: metformin, 4PBA and TUCDA, and the egg yolk plasma-induced increase in epithelial permeability is blocked by the only UPR inhibitor tested (metformin). Additionally, monoclonal antibodies (mAbs) to IL-25, IL-33 and TSLP each individually block the induction of egg white food allergy by a combination of egg white and MCTs, and a combination of these mAbs strongly suppress established egg white food allergy. These observations support our hypothesis and provide an explanation for the strong allergenicity of cow’s milk and chicken eggs.
Journal of Immunology, Apr 1, 2007
Journal of Allergy and Clinical Immunology, 2021
Background: Mast cell and basophil activation by antigen crosslinking of FcεRI-bound IgE is centr... more Background: Mast cell and basophil activation by antigen crosslinking of FcεRI-bound IgE is central to allergy pathogenesis. We previously demonstrated global suppression of this process by rapid desensitization with anti-FcεRIα mAbs. Objective: 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 V regions and huIgG1 or huIgG4 C regions, and used to suppress murine IgEmediated 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.
Inflammatory bowel diseases, Nov 4, 2016
We have previously shown that CD64 surface expression on circulating neutrophils is significantly... more We have previously shown that CD64 surface expression on circulating neutrophils is significantly elevated in children with newly diagnosed Crohn's disease (CD). Our primary aim was to investigate whether elevations in neutrophil CD64 in asymptomatic patients could be used to predict treatment failure during maintenance infliximab. Pediatric CD subjects receiving maintenance infliximab in clinical remission (short pediatric CD activity index [shPCDAI] <15) were enrolled. We measured neutrophil CD64 expression (CD64 index, Trillium Diagnostics, LLC) and infliximab trough concentrations. Infliximab failure was defined as an shPCDAI >15 on 2 consecutive infusions, discontinuation of infliximab, hospitalization, endoscopic ulcerations, or surgery during the following year of maintenance infliximab. We enrolled 36 subjects, 22/36 were male and 29/36 were white. Mean (SD) age at study entry was 15 (4) years with a median of 14 (5-20) infusions before study entry. 4/36 were recei...
The Journal of allergy and clinical immunology, May 9, 2015
IgE-allergen complexes induce mast cell and basophil activation and thus immediate allergic infla... more IgE-allergen complexes induce mast cell and basophil activation and thus immediate allergic inflammation. They are also important for IgE-facilitated allergen presentation to T cells by antigen-presenting cells. To investigate whether the proximity of IgE binding sites on an allergen affects immune complex shape and subsequent effector cell activation in vitro and in vivo. We constructed artificial allergens by grafting IgE epitopes in different numbers and proximity onto a scaffold protein. The shape of immune complexes formed between artificial allergens and the corresponding IgE was studied by negative-stain electron microscopy. Allergenic activity was determined using basophil activation assays. Mice were primed with IgE, followed by injection of artificial allergens to evaluate their in vivo allergenic activity. Severity of systemic anaphylaxis was measured by changes in body temperature. We could demonstrate simultaneous binding of 4 IgE antibodies in close vicinity to each ot...
Journal of Allergy and Clinical Immunology, 2013
Background-Rapid desensitization,a procedure in which individuals allergic to an antigen are trea... more Background-Rapid desensitization,a procedure in which individuals allergic to an antigen are treated at short intervals with increasing doses of that antigen until they tolerate a large dose, is an effective, but risky way to induce temporary tolerance. Objective-To determine whether this approach can be adapted to suppress all IgE-mediated in mice by injecting serially increasing doses of monoclonal antibodies (mAbs) to IgE or FcεRIα. Methods-Active and passive models of antigen-and anti-IgE mAb-induced IgE-mediated anaphylaxis were used. Mice were desensitized with serially increasing doses of anti-IgE mAb, anti-FcεRIα mAb or antigen. Development of shock (hypothermia), histamine and mast cell protease release, cytokine secretion, calcium flux and changes in cell number and FcεRI and IgE expression were evaluated.
Toxicology, 2014
Several low weight molecules have often been implicated in the induction of occupational asthma. ... more Several low weight molecules have often been implicated in the induction of occupational asthma. Glyphosate, a small molecule herbicide, is widely used in the world. There is a controversy regarding a role of glyphosate in developing asthma and rhinitis among farmers, the mechanism of which is unexplored. The aim of this study was to explore the mechanisms of glyphosate induced pulmonary pathology by utilizing murine models and real environmental samples. C57BL/6, TLR4−/−, and IL-13−/− mice inhaled extracts of glyphosate-rich air samples collected on farms during spraying of herbicides or inhaled different doses of glyphosate and ovalbumin. The cellular response, humoral response, and lung function of exposed mice were evaluated. Exposure to glyphosate-rich air samples as well as glyphosate alone to the lungs increased: eosinophil and neutrophil counts, mast cell degranulation, and production of IL-33, TSLP, IL-13, and IL-5. In contrast, in vivo systemic IL-4 production was not increased. Co-administration of ovalbumin with glyphosate did not substantially change the inflammatory immune response. However, IL-13deficiency resulted in diminished inflammatory response but did not have a significant effect on airway resistance upon methacholine challenge after 7 or 21 days of glyphosate exposure. Glyphosate-rich farm air samples as well as glyphosate alone were found to induce pulmonary IL-13-dependent inflammation and promote Th2 type cytokines, but not IL-4 for glyphosate alone.
European journal of immunology, Jan 29, 2015
Studies examining the role of PD-1 family members in allergic asthma have yielded conflicting res... more Studies examining the role of PD-1 family members in allergic asthma have yielded conflicting results. Using a mouse model of allergic asthma, we demonstrate that blockade of PD-1/PD-L1 has distinct influences on different CD4(+) T-cell subsets. PD-1/PD-L1 blockade enhances airway hyperreactivity (AHR), not by altering the magnitude of the underlying Th2-type immune response, but by allowing the development of a concomitant Th17-type immune response. Supporting differential CD4(+) T-cell responsiveness to PD-1-mediated inhibition, naïve PD-1(-/-) mice displayed elevated Th1 and Th17 levels, but diminished Th2 cytokine levels, and ligation of PD-1 in wild-type cells limited cytokine production by in vitro-polarized Th1 and Th17 cells, but slightly enhanced cytokine production by in vitro-polarized Th2 cells. Furthermore, PD-1 ligation enhanced Th2 cytokine production by naïve T cells cultured under non-polarizing conditions. These data demonstrate that different CD4(+) T-cell subsets...
The Journal of Immunology, 2009
IL-10 plays a central role in restraining the vigor of inflammatory responses, but the critical c... more IL-10 plays a central role in restraining the vigor of inflammatory responses, but the critical cellular sources of this counter-regulatory cytokine remain speculative in many disease models. Using a novel IL-10 transcriptional reporter mouse, we found an unexpected predominance of B cells (including plasma cells) among IL-10-expressing cells in peripheral lymphoid tissues at baseline and during diverse models of in vivo immunological challenge. Use of a novel B cell-specific IL-10 knockout mouse revealed that B cell-derived IL-10 nonredundantly decreases virus-specific CD8+ T cell responses and plasma cell expansion during murine cytomegalovirus infection and modestly restrains immune activation after challenge with foreign Abs to IgD. In contrast, no role for B cell-derived IL-10 was evident during endotoxemia; however, although B cells dominated lymphoid tissue IL-10 production in this model, myeloid cells were dominant in blood and liver. These data suggest that B cells are an u...
The Journal of Immunology, 2006
Eosinophils are involved in a variety of allergic, parasitic, malignant, and idiopathic disorders... more Eosinophils are involved in a variety of allergic, parasitic, malignant, and idiopathic disorders by releasing a variety of factors including specific granule proteins, lipid mediators, and proinflammatory and immunoregulatory cytokines and chemokines. In addition, they interact with various cell types in the inflamed tissue. Yet, the mechanism of eosinophil activation is still poorly understood. Recently, we described the expression and function of the CD2-subfamily of receptors and especially 2B4 on human eosinophils. In this study we focus on CD48, the high-affinity ligand of 2B4. CD48 is a GPI-anchored protein involved in cellular activation, costimulation, and adhesion, but has not been studied on eosinophils. We demonstrate that human eosinophils from atopic asthmatics display enhanced levels of CD48 expression and that IL-3 up-regulates CD48 expression. Furthermore, cross-linking CD48 on human eosinophils triggers release of eosinophil granule proteins. Assessment of CD48 exp...
The Journal of Immunology, 2007
IL-4 and IL-13 are each bound by soluble receptors (sRs) that block their activity. Both of these... more IL-4 and IL-13 are each bound by soluble receptors (sRs) that block their activity. Both of these sRs (sIL-4R␣ and sIL-13R␣2) are present in low nanogram per milliliter concentrations in the serum from unstimulated mice, but differences in affinity and half-life suggest differences in function. Serum IL-4/sIL-4R␣ complexes rapidly dissociate, releasing active IL-4, whereas sIL-13R␣2 and IL-13 form a stable complex that has a considerably longer half-life than uncomplexed IL-13, sIL-13R␣2, IL-4, or sIL-4R␣. Approximately 25% of sIL-13R␣2 in serum is complexed to IL-13; this percentage and the absolute quantity of sIL-13R␣2 in serum increase considerably during a Th2 response. sIL-13R␣2 gene expression is up-regulated by both IL-4 and IL-13; the effect of IL-4 is totally IL-4R␣-dependent while the effect of IL-13 is partially IL-4R␣-independent. Inhalation of an IL-13/ sIL-13R␣2 complex does not affect the expression of IL-13-inducible genes but increases the expression of two genes, Vnn1 and Pira-1, whose products activate APCs and promote neutrophilic inflammation. These observations suggest that sIL-4R␣ predominantly sustains, increases, and diffuses the effects of IL-4, whereas sIL-13R␣2 limits the direct effects of IL-13 to the site of IL-13 production and forms a stable complex with IL-13 that may modify the quality and intensity of an allergic inflammatory response.
Journal of Immunology, May 1, 2014
Food allergy, in mouse models, is mediated by mast cells, FcϵRI and IgE. We recently demonstrated... more Food allergy, in mouse models, is mediated by mast cells, FcϵRI and IgE. We recently demonstrated that rapid desensitization with a hamster mAb to mouse FcϵRIα (MAR-1) safely suppresses IgE-mediated anaphylaxis (JACI, 131:1555-64, 2013). Consequently, we evaluated whether the same approach could suppress established food allergy in BALB/c mice that had been sensitized intraperitoneally with ovalbumin/alum or egg white/alum and challenged repeatedly by oral gavage with ovalbumin or egg white until they had developed shock and diarrhea. Treatment of these mice with 50 µg of MAR-1 every 4 days suppressed both the induction of hypothermia by oral gavage with ovalbumin or egg white and mast cell MMCP1 secretion by 85-90% and decreased the incidence of diarrhea by 70-85%. Although MAR-1 suppression of food allergy was eventually limited by mouse development of IgG antibodies to hamster IgG, this could be prevented by injecting mice with anti-CD4 mAb (GK1.5) at the time of the initial MAR-1 injection. Although GK1.5, by itself, had little effect on established food allergy, the combination of MAR-1 plus GK1.5 completely suppressed the hypothermia, diarrheal, MMCP1, IL-4 and IL-13 responses to oral gavage with ovalbumin or egg white. These observations suggest that rapid desensitization, followed by continuing treatment with a non-immunogenic (humanized) anti-FcϵRIα mAb might effectively suppress IgE-mediated food allergy in people with this disorder.
The Journal of Immunology
Food ingestion generally induces antigen (Ag)-specific tolerance rather than immunity. In contras... more Food ingestion generally induces antigen (Ag)-specific tolerance rather than immunity. In contrast, we recently reported (JACI, 131:442–50, 2013) that Ag-specific, IgE-mediated food allergy (FA) can be induced when a protein Ag is repeatedly ingested with a widely used nutrient, medium chain triglycerides (MCT), without any additional sensitization. Mice that have been repeatedly inoculated orally with MCT plus egg white (EW) develop a Th2 cytokine and an IgE response as well as shock (hypothermia) following oral EW + MCT challenge. Because MCT ingestion induces increased intestinal epithelial cell expression of the pro-Th2 cytokines TSLP, IL-25 and IL-33, we investigated the importance of these cytokines in establishing and maintaining FA. We found that treatment with neutralizing mAbs to any of the pro-Th2 cytokines could suppress MCT + EW-induced FA development, with aTSLP mAb causing near-total suppression and aIL-25 and aIL-33 each causing considerable suppression. In contrast,...
The Journal of Immunology
Food ingestion generally induces antigen (Ag)-specific tolerance rather than immunity. Consistent... more Food ingestion generally induces antigen (Ag)-specific tolerance rather than immunity. Consistent with this, induction of IgE-mediated intestinal FA in mice has required either Ag priming through a parenteral route or ingestion of Ag with a potent toxin. In contrast, we recently reported (JACI, 131:442-50, 2013) that Ag-specific, IgE-mediated FA is induced when a protein Ag is ingested with the widely used nutrient, MCT. We also showed that MCT ingestion induces increased epithelial cell expression of the pro-Th2 cytokines TSLP, IL-25 and IL-33. We now report that MCT ingestion, by itself, can induce shock by damaging intestinal epithelium, with a consequent increase in intestinal permeability. In contrast, ingestion of the anionic detergent, sodium dodecyl sulfate, damages intestinal epithelium but does not promote a Th2 response. Both direct MCT induction of intestinal epithelial damage and MCT promotion of a Th2 response and FA to co-ingested egg white are suppressed in mice trea...
The Journal of Immunology
Several studies have examined the relative roles of complement vs. Fc receptors (FcRs) in host pr... more Several studies have examined the relative roles of complement vs. Fc receptors (FcRs) in host protection and inflammatory disease. Many of these studies have concluded that the more important role is played by stimulatory Fc receptors. These conclusions were based, however, on the assumption that complement activation occurs normally in the absence of stimulatory Fc receptors. We have used FcRγ-deficient mice, which lack all stimulatory FcRs, to examine this assumption. FcRγ-sufficient and -deficient mice were found to have similar levels of C3 in blood. Also, as expected, similar amounts of IgG2a became associated with blood leukocytes from both mouse strains after intravenous injection of a complement fixing IgG2a mAb to MHC class I Ag. Surprisingly, however, >10-fold more C3 became associated with the blood leukocytes from FcRγ-sufficient mice than those from FcRγ-deficient mice. Additionally, >6-fold more C5a was generated in blood from FcRγ-sufficient than deficient mice...
The Journal of Immunology
IgE-mediated mast cell and basophils activation is critical for the pathogenesis of anaphylaxis, ... more IgE-mediated mast cell and basophils activation is critical for the pathogenesis of anaphylaxis, drug allergy, food allergy and allergic skin disorders and contributes to the pathogenesis of asthma and allergic rhinitis. We recently demonstrated that IgE-mediated anaphylaxis in mice can be safely blocked by rapid desensitization with ascending doses of an anti-mouse FcεR1α Abs, starting with a dose too small to induce detectable disease and ending with a dose that induces anaphylaxis if injected into previously untreated mice (JACI, 131:1555-64, 2013). We have now modified this approach, which removes IgE from mast cells, to make it human-applicable, faster and safer. To do this, we: (1) generated a chimeric anti-human FcεR1α mAb that has V regions from a mouse anti-human FcεR1α mAb (15.1) and C regions from human IgG1; (2) substituted a mAb that binds FcεR1 regardless of whether it is associated with IgE for a mAb that only binds FcεR1 that is not IgE-associated; and (3) mutated th...
The Journal of Immunology
Epidemiologic evidence suggests that IgA, the main mucosal Ig isotype, inhibits allergy, but it i... more Epidemiologic evidence suggests that IgA, the main mucosal Ig isotype, inhibits allergy, but it is not known whether it suppresses anaphylaxis. We used mouse models to evaluate whether IgA can suppress systemic anaphylactic responses to ingested allergens by neutralizing them before or after their systemic absorption. Passive systemic anaphylaxis (PSA), measured as hypothermia, was induced by sensitizing mice with IgE anti-TNP mAb, then challenging them orally (og) with TNP-OVA. The ability of IgA to inhibit PSA by neutralizing Ag prior to or after systemic absorption was evaluated by pretreating mice with IgA anti-TNP mAb either og or iv. TNP-OVA was detectible in serum by 5 min after og administration. PSA developed within 5 min and was inhibited by iv, but not og IgA. Extent of inhibition was proportional to the IgA dose and Fcα/μR- and FcγRIIb-independent. Intestinal anaphylaxis (IA), defined as diarrhea <60 minutes after OVA challenge, was induced by priming mice ip with OVA...
Transdermal drug delivery provides convenient and pain-free self-administration for personalized ... more Transdermal drug delivery provides convenient and pain-free self-administration for personalized therapy. However, challenges remain in treating acute disease largely due to their inability to timely administrate therapeutics and precisely regulate pharmacokinetics within a short time window. Here we report the development of active acoustic metamaterials driven transdermal drug delivery for rapid and on-demand management of the acute disease. Through the integration of active acoustic metamaterials, a compact therapeutic patch is integrated for penetration of skin stratum corneum and active percutaneous transport of therapeutics with precise control of dose and rate over time. Moreover, the patch device quantitatively regulates the dosage and release kinetics of therapeutics and achieves better delivery performance in vivo than through subcutaneous injection. As a proof-of-concept application, our method can reverse life-threatening acute allergic reactions in a mouse model of anap...
Journal of Immunology, May 1, 2016
Endoplasmic reticulum (ER) stress and an unfolded protein response (UPR) are stimulated by satura... more Endoplasmic reticulum (ER) stress and an unfolded protein response (UPR) are stimulated by saturated, but not unsaturated fatty acids. We previously showed that saturated medium chain triglycerides (MCT) promote food allergy induction and increase epithelial cell expression of 3 pro-Th2 cytokines, TSLP, IL-25 and IL-33, which stimulate a Th2 cytokine response. These observations led us to hypothesize that the high concentrations of saturated triglycerides in two common food allergens, cow’s milk and chicken eggs, promote food allergy by inducing an epithelial cell UPR response, which in turn, causes these cells to express pro-Th2 cytokines. Indeed, studies with transformed human intestinal epithelial CACO2 cells demonstrated that MCT, egg yolk plasma (the liquid, triglyceride fraction of eggs) and cow’s milk cream each increase expression of the UPR-associated PERK, BiP, CHOP, XBP1 and/or XBP1s genes after 6 hours, followed by increased expression of all 3 pro-Th2 cytokine genes after 24 hours. Each of these stimuli, but not but not protein-rich, lipid-poor egg white, also increase epithelial permeability. Further, the increases in pro-Th2 cytokine expression are blocked by each of 3 UPR inhibitors: metformin, 4PBA and TUCDA, and the egg yolk plasma-induced increase in epithelial permeability is blocked by the only UPR inhibitor tested (metformin). Additionally, monoclonal antibodies (mAbs) to IL-25, IL-33 and TSLP each individually block the induction of egg white food allergy by a combination of egg white and MCTs, and a combination of these mAbs strongly suppress established egg white food allergy. These observations support our hypothesis and provide an explanation for the strong allergenicity of cow’s milk and chicken eggs.
Journal of Immunology, Apr 1, 2007
Journal of Allergy and Clinical Immunology, 2021
Background: Mast cell and basophil activation by antigen crosslinking of FcεRI-bound IgE is centr... more Background: Mast cell and basophil activation by antigen crosslinking of FcεRI-bound IgE is central to allergy pathogenesis. We previously demonstrated global suppression of this process by rapid desensitization with anti-FcεRIα mAbs. Objective: 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 V regions and huIgG1 or huIgG4 C regions, and used to suppress murine IgEmediated 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.
Inflammatory bowel diseases, Nov 4, 2016
We have previously shown that CD64 surface expression on circulating neutrophils is significantly... more We have previously shown that CD64 surface expression on circulating neutrophils is significantly elevated in children with newly diagnosed Crohn's disease (CD). Our primary aim was to investigate whether elevations in neutrophil CD64 in asymptomatic patients could be used to predict treatment failure during maintenance infliximab. Pediatric CD subjects receiving maintenance infliximab in clinical remission (short pediatric CD activity index [shPCDAI] <15) were enrolled. We measured neutrophil CD64 expression (CD64 index, Trillium Diagnostics, LLC) and infliximab trough concentrations. Infliximab failure was defined as an shPCDAI >15 on 2 consecutive infusions, discontinuation of infliximab, hospitalization, endoscopic ulcerations, or surgery during the following year of maintenance infliximab. We enrolled 36 subjects, 22/36 were male and 29/36 were white. Mean (SD) age at study entry was 15 (4) years with a median of 14 (5-20) infusions before study entry. 4/36 were recei...
The Journal of allergy and clinical immunology, May 9, 2015
IgE-allergen complexes induce mast cell and basophil activation and thus immediate allergic infla... more IgE-allergen complexes induce mast cell and basophil activation and thus immediate allergic inflammation. They are also important for IgE-facilitated allergen presentation to T cells by antigen-presenting cells. To investigate whether the proximity of IgE binding sites on an allergen affects immune complex shape and subsequent effector cell activation in vitro and in vivo. We constructed artificial allergens by grafting IgE epitopes in different numbers and proximity onto a scaffold protein. The shape of immune complexes formed between artificial allergens and the corresponding IgE was studied by negative-stain electron microscopy. Allergenic activity was determined using basophil activation assays. Mice were primed with IgE, followed by injection of artificial allergens to evaluate their in vivo allergenic activity. Severity of systemic anaphylaxis was measured by changes in body temperature. We could demonstrate simultaneous binding of 4 IgE antibodies in close vicinity to each ot...
Journal of Allergy and Clinical Immunology, 2013
Background-Rapid desensitization,a procedure in which individuals allergic to an antigen are trea... more Background-Rapid desensitization,a procedure in which individuals allergic to an antigen are treated at short intervals with increasing doses of that antigen until they tolerate a large dose, is an effective, but risky way to induce temporary tolerance. Objective-To determine whether this approach can be adapted to suppress all IgE-mediated in mice by injecting serially increasing doses of monoclonal antibodies (mAbs) to IgE or FcεRIα. Methods-Active and passive models of antigen-and anti-IgE mAb-induced IgE-mediated anaphylaxis were used. Mice were desensitized with serially increasing doses of anti-IgE mAb, anti-FcεRIα mAb or antigen. Development of shock (hypothermia), histamine and mast cell protease release, cytokine secretion, calcium flux and changes in cell number and FcεRI and IgE expression were evaluated.
Toxicology, 2014
Several low weight molecules have often been implicated in the induction of occupational asthma. ... more Several low weight molecules have often been implicated in the induction of occupational asthma. Glyphosate, a small molecule herbicide, is widely used in the world. There is a controversy regarding a role of glyphosate in developing asthma and rhinitis among farmers, the mechanism of which is unexplored. The aim of this study was to explore the mechanisms of glyphosate induced pulmonary pathology by utilizing murine models and real environmental samples. C57BL/6, TLR4−/−, and IL-13−/− mice inhaled extracts of glyphosate-rich air samples collected on farms during spraying of herbicides or inhaled different doses of glyphosate and ovalbumin. The cellular response, humoral response, and lung function of exposed mice were evaluated. Exposure to glyphosate-rich air samples as well as glyphosate alone to the lungs increased: eosinophil and neutrophil counts, mast cell degranulation, and production of IL-33, TSLP, IL-13, and IL-5. In contrast, in vivo systemic IL-4 production was not increased. Co-administration of ovalbumin with glyphosate did not substantially change the inflammatory immune response. However, IL-13deficiency resulted in diminished inflammatory response but did not have a significant effect on airway resistance upon methacholine challenge after 7 or 21 days of glyphosate exposure. Glyphosate-rich farm air samples as well as glyphosate alone were found to induce pulmonary IL-13-dependent inflammation and promote Th2 type cytokines, but not IL-4 for glyphosate alone.
European journal of immunology, Jan 29, 2015
Studies examining the role of PD-1 family members in allergic asthma have yielded conflicting res... more Studies examining the role of PD-1 family members in allergic asthma have yielded conflicting results. Using a mouse model of allergic asthma, we demonstrate that blockade of PD-1/PD-L1 has distinct influences on different CD4(+) T-cell subsets. PD-1/PD-L1 blockade enhances airway hyperreactivity (AHR), not by altering the magnitude of the underlying Th2-type immune response, but by allowing the development of a concomitant Th17-type immune response. Supporting differential CD4(+) T-cell responsiveness to PD-1-mediated inhibition, naïve PD-1(-/-) mice displayed elevated Th1 and Th17 levels, but diminished Th2 cytokine levels, and ligation of PD-1 in wild-type cells limited cytokine production by in vitro-polarized Th1 and Th17 cells, but slightly enhanced cytokine production by in vitro-polarized Th2 cells. Furthermore, PD-1 ligation enhanced Th2 cytokine production by naïve T cells cultured under non-polarizing conditions. These data demonstrate that different CD4(+) T-cell subsets...
The Journal of Immunology, 2009
IL-10 plays a central role in restraining the vigor of inflammatory responses, but the critical c... more IL-10 plays a central role in restraining the vigor of inflammatory responses, but the critical cellular sources of this counter-regulatory cytokine remain speculative in many disease models. Using a novel IL-10 transcriptional reporter mouse, we found an unexpected predominance of B cells (including plasma cells) among IL-10-expressing cells in peripheral lymphoid tissues at baseline and during diverse models of in vivo immunological challenge. Use of a novel B cell-specific IL-10 knockout mouse revealed that B cell-derived IL-10 nonredundantly decreases virus-specific CD8+ T cell responses and plasma cell expansion during murine cytomegalovirus infection and modestly restrains immune activation after challenge with foreign Abs to IgD. In contrast, no role for B cell-derived IL-10 was evident during endotoxemia; however, although B cells dominated lymphoid tissue IL-10 production in this model, myeloid cells were dominant in blood and liver. These data suggest that B cells are an u...
The Journal of Immunology, 2006
Eosinophils are involved in a variety of allergic, parasitic, malignant, and idiopathic disorders... more Eosinophils are involved in a variety of allergic, parasitic, malignant, and idiopathic disorders by releasing a variety of factors including specific granule proteins, lipid mediators, and proinflammatory and immunoregulatory cytokines and chemokines. In addition, they interact with various cell types in the inflamed tissue. Yet, the mechanism of eosinophil activation is still poorly understood. Recently, we described the expression and function of the CD2-subfamily of receptors and especially 2B4 on human eosinophils. In this study we focus on CD48, the high-affinity ligand of 2B4. CD48 is a GPI-anchored protein involved in cellular activation, costimulation, and adhesion, but has not been studied on eosinophils. We demonstrate that human eosinophils from atopic asthmatics display enhanced levels of CD48 expression and that IL-3 up-regulates CD48 expression. Furthermore, cross-linking CD48 on human eosinophils triggers release of eosinophil granule proteins. Assessment of CD48 exp...
The Journal of Immunology, 2007
IL-4 and IL-13 are each bound by soluble receptors (sRs) that block their activity. Both of these... more IL-4 and IL-13 are each bound by soluble receptors (sRs) that block their activity. Both of these sRs (sIL-4R␣ and sIL-13R␣2) are present in low nanogram per milliliter concentrations in the serum from unstimulated mice, but differences in affinity and half-life suggest differences in function. Serum IL-4/sIL-4R␣ complexes rapidly dissociate, releasing active IL-4, whereas sIL-13R␣2 and IL-13 form a stable complex that has a considerably longer half-life than uncomplexed IL-13, sIL-13R␣2, IL-4, or sIL-4R␣. Approximately 25% of sIL-13R␣2 in serum is complexed to IL-13; this percentage and the absolute quantity of sIL-13R␣2 in serum increase considerably during a Th2 response. sIL-13R␣2 gene expression is up-regulated by both IL-4 and IL-13; the effect of IL-4 is totally IL-4R␣-dependent while the effect of IL-13 is partially IL-4R␣-independent. Inhalation of an IL-13/ sIL-13R␣2 complex does not affect the expression of IL-13-inducible genes but increases the expression of two genes, Vnn1 and Pira-1, whose products activate APCs and promote neutrophilic inflammation. These observations suggest that sIL-4R␣ predominantly sustains, increases, and diffuses the effects of IL-4, whereas sIL-13R␣2 limits the direct effects of IL-13 to the site of IL-13 production and forms a stable complex with IL-13 that may modify the quality and intensity of an allergic inflammatory response.