Publications (8) View all
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Article: Distinct immune effector pathways contribute to the full expression of peanut-induced anaphylactic reactions in mice.
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ABSTRACT: Food-induced anaphylaxis is often a severe allergic reaction characterized by multiorgan dysfunction and a potentially fatal outcome. We sought to investigate the relative contribution of immunoglobulin-dependent effector pathways to anaphylactic responses to food (ie, peanut). Wild-type and various mutant mice were sensitized with peanut protein and cholera toxin by means of oral gavage weekly for 4 weeks. Mice were subjected to different cellular depletion and Fc receptor blocking strategies before challenge with peanut 1 week after the last sensitization. Our data indicate that pathways other than the classical mast cell (MC)-IgE pathway contribute to the full spectrum of anaphylactic reactions to peanut. We show that the single deletion of MCs, basophils, or phagocytes (ie, macrophages) prevents the most significant clinical outcome: death. Remarkably, the combined deficiency of MCs and phagocytes, but not MCs and basophils, averted nearly all clinical and physiological signs of anaphylaxis. Furthermore, blockade of both IgE and IgG1 signaling was necessary to abolish anaphylactic responses to peanut. Although MC responses occurred through IgE and IgG1, phagocyte responses were fully mediated through IgG1. Peanut-induced anaphylaxis is a process that involves the concerted action of multiple immune effector pathways, and thus interventions targeting a single pathway (eg, MC-IgE) might not be sufficient to fully prevent anaphylactic responses.The Journal of allergy and clinical immunology 06/2011; 127(6):1552-61.e1. · 9.17 Impact Factor -
Article: Eosinophils are dispensable for allergic remodeling and immunity in a model of house dust mite-induced airway disease.
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ABSTRACT: Current thinking accredits eosinophils with preeminent contributions to allergic airway responses, including a major role in the development of airway remodeling, a process thought to significantly contribute to airway dysfunction. However, direct evidence in support of this notion is limited and often controversial. We elucidated the requirement for eosinophils in the generation of allergic sensitization, airway inflammation, and remodeling in a model involving chronic respiratory exposure to house dust mite (HDM). We used three methods to selectively eliminate eosinophils, a depleting antibody (anti-CCR3), and two strains of eosinophil-deficient mice (ΔdblGATA and the transgenic line PHIL). Anti-CCR3 treatment markedly reduced pulmonary eosinophilia (> 80%) over the course of HDM exposure but had no effect on the remaining inflammatory response, the extent of lung Th2 cells, or the development of remodeling-associated changes, including subepithelial collagen deposition and smooth muscle thickening. In addition, we observed that, despite the absence of eosinophils, HDM-exposed GATA mice mounted robust airway and lung inflammation and hyperresponsiveness and showed a remodeling response equivalent to that observed in wild-type mice. Moreover, these mice had similar serum HDM-specific IgE levels and Th2-associated splenocyte cytokine production as HDM-exposed wild-type control mice. Similar observations were made in PHIL eosinophil-deficient mice subjected to chronic HDM exposure, although slight decreases in airway mononuclear cells, but not lung Th2 cells, and remodeling were noted. Collectively, these data demonstrate that, at variance with the prevailing paradigm, eosinophils play negligible roles in the generation of HDM-induced allergic immunity and airway remodeling.American Journal of Respiratory and Critical Care Medicine 01/2011; 183(2):179-88. · 11.08 Impact Factor -
Article: Management of food-induced anaphylaxis: unsolved challenges.
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ABSTRACT: Anaphylaxis is an acute and often severe systemic allergic reaction. The prevalence of food allergy has been increasing and is currently estimated at approximately 3.5%. Food allergic reactions account for one-third to one-half of anaphylaxis cases worldwide. It is estimated that approximately 30,000 food-related anaphylactic reactions are treated in United States emergency departments (ED) every year resulting in approximately 2000 hospitalizations and 150 deaths. The increasing rate of food-induced anaphylactic episodes in the last few decades underlines the existence of major challenges. This review will critically appraise current guidelines for the diagnosis as well as the acute and long-term management of food-induced anaphylaxis (FIA). Importantly, it will outline existing challenges and suggest measures to improve outcomes in patients with FIA. We propose that the discovery of novel diagnostic (i.e. biomarkers and predictors) and therapeutic approaches is a major challenge that may be overcome as the mechanisms underlying FIA are better delineated. We further propose that better dissemination, implementation and compliance with the consensus management guidelines are urgently needed. This will require education of ED personnel, patient empowerment as well as effective multilateral communication among patients, emergency and family physicians, allergists and specialized volunteer organizations.Current Clinical Pharmacology 06/2009; 4(2):113-25. -
Article: Concurrent blockade of platelet-activating factor and histamine prevents life-threatening peanut-induced anaphylactic reactions.
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ABSTRACT: Food anaphylaxis is an acute and life-threatening systemic allergic reaction. Fatality registries place peanut as the most common culprit of fatal and near-fatal reactions in North America. Because prophylaxis and treatment have advanced little in recent years, it is imperative to evaluate novel therapies. To investigate the impact of blocking mast cell mediators in a mouse model of peanut-induced anaphylaxis. Mice were sensitized with peanut protein and cholera toxin via oral gavage weekly for 4 weeks. One week after the last sensitization, separate groups of mice were treated with either a (1) 5-lypoxygenase inhibitor, (2) a platelet-activating factor (PAF) receptor antagonist, (3) histamine receptor antagonists, or (4) a PAF receptor antagonist along with histamine receptor antagonists before peanut challenge. Treatment targeting either leukotrienes or histamine alone had no beneficial effects. In contrast, PAF antagonism significantly attenuated the magnitude and duration of the anaphylactic reactions. Particularly, it prevented severe reactions. Moreover, 83% of PAF-treated versus 43% of untreated mice reached recovery within 120 minutes after peanut challenge. Notably, combined blockade of PAF and histamine had a clearly greater beneficial effect. In fact, all but 1 mouse developed mild, if any, anaphylactic reactions. In addition, combination therapy was associated with a significant decrease in vascular leakage and release of vasoactive mediators after peanut challenge. Combination therapy blocking both PAF and histamine markedly reduces the severity of peanut-induced anaphylaxis, and thus it may be a potential life-saving therapeutic approach in peanut and, likely, other food-induced anaphylaxis.The Journal of allergy and clinical immunology 05/2009; 124(2):307-14, 314.e1-2. · 9.17 Impact Factor -
Article: Spontaneous and induced variability of allergens in commodity crops: Ara h 2 in peanut as a case study.
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ABSTRACT: Many commodity crops are grown for human consumption, and the resulting food products usually contain proteins, some of which may be allergenic. The legumes, peanut and soybean, as well as tree nuts and some cereal grains are well recognized sources of food allergens. In peanut, there are 11 documented allergenic proteins, although the major allergens are considered to be Ara h 1 and Ara h 2, both of which are seed storage proteins. Methods to reduce or eliminate these proteins from seeds are available and allow the feasibility of this approach to be tested. Greatly reduced amounts of Ara h 2 can be achieved by RNA silencing in transgenic peanut; however, mutagenesis is a more viable and socially acceptable approach to allergen elimination. Although the techniques for mutagenesis are not new, methods for mutant detection at the molecular level have recently been developed. However, these methods are dependent on genome sequence. These methods will facilitate discovery of spontaneous and induced mutations that may be useful over the long term to eliminate certain allergens from peanut.Regulatory Toxicology and Pharmacology 12/2008; 54(3 Suppl):S37-40. · 2.43 Impact Factor
