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1.  Kinetics of mast cell, basophil, and oral food challenge responses in omalizumab-treated adults with peanut allergy 
Background
Monoclonal antibodies directed at IgE demonstrate clinical efficacy in subjects with peanut allergy, but previous studies have not addressed the kinetics of the clinical response or the role of mast cells and basophils in the food-induced allergic response.
Objective
We sought to determine the kinetics of the clinical response to omalizumab and whether clinical improvement is associated with either mast cell or basophil suppression.
Methods
Subjects with peanut allergy were treated with omalizumab for 6 months and assessed for clinical and cellular responses. At baseline, subjects had a double-blind, placebo-controlled oral food challenge (OFC), skin prick test titration (SPTT), and basophil histamine release (BHR) to peanut. BHR was repeated at week 2 and then weekly until it decreased to less than 20% of baseline values. The OFCs and SPTTs were repeated after the BHR reduction (or at week 8 if BHR did not decrease) and again at 6 months.
Results
Fourteen subjects enrolled in the study. At the second food challenge, there was a significant increase in the threshold dose of peanut inducing allergic symptoms (80 to 6500 mg, P < .01). Peanut-induced BHR was either completely suppressed (n = 5) or 10-fold more allergen was required to induce maximal BHR (n = 9), and SPTT responses were not significantly changed from baseline. After 6 months of omalizumab, further changes in the OFC threshold dose or BHR were not observed, but a significant suppression in SPTTs was identified.
Conclusions
The clinical response to omalizumab occurs early in treatment when the basophil, but not the mast cell, is suppressed, supporting a role for the basophil in acute food reactions.
doi:10.1016/j.jaci.2012.05.039
PMCID: PMC3935509  PMID: 22800401
Omalizumab; peanut allergy; oral food challenge; basophil; mast cell
2.  Suppression of the Basophil Response to Allergen During Treatment with Omalizumab is Dependent on Two Competing Factors 
Background
A recent study of peanut allergic subjects treated with omalizumab generated some results that were concordant with a study of cat allergics being treated with omalizumab. However, there were differences that provided additional insights into the nature of the cellular responses in allergic patients.
Objective
Determine the cause for failure to suppress the allergen-induced basophil response during treatment with omalizumab.
Methods
Peanut allergic patients were treated with omalizumab. Clinical, serological and cellular indices relevant to the response of the patient and their peripheral blood basophils (specific-to-total IgE ratio, cell surface FceRI expression, histamine release responses to anti-IgE Ab or peanut allergen) were obtained at 3 times.
Results
Following treatment, approximately 60% of the subjects’ basophil responses to peanut allergen did not significantly decrease. In 40% of cases, the in vitro basophil response to peanut allergen increased 2–7 fold. The increases were associated with two primary factors, a high (>10%) specific-to-total IgE ratio and an increase in the intrinsic response of the basophil to IgE-mediated stimulation. The extent to which the basophil response to peanut allergen increased was inversely correlated with the improvement in the individual’s ability to tolerate ingestion of peanut.
Conclusion
The basophil response during treatment with omalizumab is a consequence of two competing factors, suppression of allergen-specific IgE on the cell surface vs. increased intrinsic sensitivity to IgE-mediated stimulation. In peanut allergy, the basophil response appears to mitigate against the ability of omalizumab to improve the patients’ tolerance of oral allergen.
doi:10.1016/j.jaci.2012.05.038
PMCID: PMC3488135  PMID: 22800400
basophil; anti-IgE; peanut; syk; IgE receptor
3.  Assessing basophil functional measures during monoclonal anti-IgE therapy 
Journal of immunological methods  2012;383(1-2):60-64.
Several decades of work support that measures of allergen responses of IgE-bearing peripheral blood basophils can reflect clinical expression of allergic disease. Basophils are recognized to respond to allergen exposure with a variety of pro-inflammatory mediators such as histamine, leukotrienes and cytokines such as IL-4 and IL-13. Furthermore, the suppression of established basophil allergen responses has been observed as a consequence of current treatments such as specific allergen immunotherapy (SIT) for allergic airways disease and most recently, in oral immunotherapy for food allergy. In the last decade, an immune-based therapy targeting IgE, omalizumab, has emerged as an adjunct treatment for a variety of allergic diseases. This monoclonal humanized IgG antibody specifically binds circulating IgE at a region in the Fc tail that prevents IgE attachment to high affinity IgE receptor (FcεRI) bearing cell types such as tissue mast cells and blood basophils. As a result of omalizumab capture of IgE, these cells have a significant reduction in surface-bound IgE, FcεRI receptor levels, and their capacity to respond to allergen exposure with mediator release. This review focuses on methods to monitor changes of basophil allergen reactivity with a focus on omalizumab therapy and the implications for clinical disease management.
doi:10.1016/j.jim.2012.05.016
PMCID: PMC3411906  PMID: 22664098
Basophils; Activation markers; Omalizumab
4.  Diagnosis and Treatment of Urticaria and Angioedema: A Worldwide Perspective 
Urticaria and angioedema are common clinical conditions representing a major concern for physicians and patients alike. The World Allergy Organization (WAO), recognizing the importance of these diseases, has contributed to previous guidelines for the diagnosis and management of urticaria. The Scientific and Clinical Issues Council of WAO proposed the development of this global Position Paper to further enhance the clinical management of these disorders through the participation of renowned experts from all WAO regions of the world. Sections on definition and classification, prevalence, etiology and pathogenesis, diagnosis, treatment, and prognosis are based on the best scientific evidence presently available. Additional sections devoted to urticaria and angioedema in children and pregnant women, quality of life and patient-reported outcomes, and physical urticarias have been incorporated into this document. It is expected that this article will supplement recent international guidelines with the contribution of an expert panel designated by the WAO, increasing awareness of the importance of urticaria and angioedema in medical practice and will become a useful source of information for optimum patient management worldwide.
doi:10.1097/WOX.0b013e3182758d6c
PMCID: PMC3651155  PMID: 23282382
urticaria; angioedema
5.  Regulation of Syk Kinase and FcRβ Expression in Human Basophils During Treatment with Omalizumab 
Background
In human basophils from different subjects, maximum IgE-mediated histamine release and the level of syk protein expression correlate well. Recent studies suggest that in some patients treated with omalizumab, the response to stimulation with anti-IgE antibody increases. In unrelated studies, there is also evidence that the composition of FcεRI in basophils differs among subjects. This observation raised the possibility that the stoichiometry of FcRβ:FcεRIα is not fixed to 1:1 and might be modifiable during changes in the basophil environment.
Objective
To determine if treatment with omalizumab results in increases in syk expression, anti-IgE-mediated histamine release and disproportionately alters the relative presence of FcRβ and FcεRIα.
Method
Syk, FcεRIα, and FcRβ expression was monitored during the treatment of subjects with omalizumab.
Results
Treatment with omalizumab reduced histamine release from peripheral blood leukocytes stimulated with cat-allergen in vitro, but histamine release stimulated with anti-IgE antibody increased 2 fold. Expression of syk increased 1.86 fold. There was no change in the expression of c-cbl, a signaling element that is sensitive to the presence of IL-3, and no increase in response to FMLP, a response that also increases in the presence of IL-3. There was a 60% decrease in the FcRβ:FcεRIα ratio in patients treated with omalizumab.
Conclusions
In the context of previous studies, these studies provide support for a proposal that syk expression is modulated in vivo by an IgE-dependent mechanism and that the ratio of FcεRI alpha and beta subunits in basophils is influenced by factors extrinsic to the cell.
doi:10.1016/j.jaci.2009.12.996
PMCID: PMC2850964  PMID: 20236696
omalizumab
6.  Effects of Omalizumab on Basophil and Mast Cell Responses using an Intranasal Cat Allergen Challenge 
BACKGROUND
Omalizumab treatment suppresses FcεRI expression faster on blood basophils than skin mast cells.
OBJECTIVE
We utilized omalizumab to elucidate the relative contributions of basophil versus mast cell FcεRI activation in a nasal allergen challenge (NAC) model.
METHODS
Eighteen cat-allergic subjects were enrolled in a 3.5-month, double-blind, randomized (3.5:1), placebo-controlled trial of omalizumab using standard dosing. At baseline, subjects underwent NAC with lavage for PGD2 measurement, skin prick test titration (SPTT), and blood sampling for basophil histamine release (BHR) and basophil IgE/FcεRI measurements. Basophil studies were repeated at day 3 and then weekly until cat allergen-induced BHR was <20% of baseline or until day 45. Baseline visit procedures were repeated after the BHR reduction (mid-study NAC) and at the treatment period’s completion (final NAC).
RESULTS
Subjects treated with omalizumab who completed all NACs (n=12) demonstrated significant mean reduction in BHR to an optimal dose of cat allergen by mid-study NAC as compared to baseline (74% decrease, p=0.001). In addition, these subjects demonstrated significant decreases in mean combined nasal symptom scores (50% decrease, p=0.007) and total sneeze counts (59% decrease, p=0.01) by mid-study NAC relative to baseline NAC. In contrast, measures of mast cell response (SPTT and nasal lavage PGD2) were only significantly reduced by the final NAC. Subjects on placebo (n=4) did not experience a shift in basophil, NAC symptom, or mast cell measures.
CONCLUSIONS
Reduction in nasal symptom scores occurred when the basophil, but not mast cell, response was reduced on omalizumab, implicating a role for basophils in the acute NAC response.
doi:10.1016/j.jaci.2009.09.012
PMCID: PMC2850969  PMID: 19962744
IgE; IgE receptors; omalizumab; basophils; mast cells; basophil histamine release; skin prick test titration; nasal allergen challenge; cat allergy
7.  Effect of in vitro aspirin stimulation on basophils in patients with aspirin-exacerbated respiratory disease 
Background
Basophil activation has been implicated in the pathogenesis of aspirin exacerbated respiratory disease. However, a comprehensive analysis of basophil responses to aspirin in terms of mediator release, cytokine secretion and increased expression of surface activation markers has not been performed.
Objective
To study the in vitro effects of aspirin on the concurrent release of histamine, leukotriene C4 and IL-4 from human basophils and to also evaluate changes in surface activation markers (CD63, CD69 and CD203c) expressed by these cells.
Methods
Basophil-enriched cell suspensions from 10 patients with aspirin exacerbated respiratory disease and 10 healthy volunteers were incubated with lysine-aspirin for up to 3 hours. Cells were analysed for expression of CD63, CD69 and CD203c using flow cytometry. Cell-free supernatants were evaluated for histamine, and leukotriene C4 release and for IL-4 secretion.
Results
Aspirin-induced expression of CD63, CD69 and CD203c yielded 30%, 80% and 70% sensitivity, respectively, but with poor specificity. There was no significant difference in leukotriene C4 synthesis between groups. None of the patients with aspirin exacerbated respiratory disease (or controls) released IL-4 in response to aspirin. A higher dose of 5 mg/ml aspirin mediated non-specific effects on basophils.
Conclusion
Basophil responses to in vitro aspirin challenge are poor indicators of clinical sensitivity. Aspirin activates some basophils by means of mechanisms which differ from the classical IgE mediated pathway. Our study also shows that the use of 27 mM of aspirin (5 mg/ml) used by previous investigators causes nonspecific basophil activation, thereby eliminating its usefulness in a cell based diagnostic test for AERD. Evaluation of in vitro basophil activation has low clinical value in identifying aspirin- induced respiratory reactions
doi:10.1111/j.1365-2222.2009.03277.x
PMCID: PMC2788679  PMID: 19486029
Aspirin; asthma; aspirin exacerbated respiratory disease; basophil; CD63; CD69; CD203c; histamine; leukotriene C4; flow cytometry
8.  Cultured Peripheral Blood Mast Cells from Chronic Idiopathic Urticaria Patients Spontaneously Degranulate Upon IgE Sensitization: Relationship to Expression of Syk and SHIP-2 
Clinical immunology (Orlando, Fla.)  2009;132(3):342-348.
Recently, signaling changes in the FcεRI pathway involving inositol lipid phosphatases have been identified in the basophils of chronic idiopathic urticaria (CIU) subjects. Based on the profile of basophil FcεRI-mediated histamine degranulation, we have segregated CIU subjects into two groups, CIU Responder (CIU R) or CIU Nonresponder (CIU NR). In the present study, we compared expression of SHIP-1, SHIP-2, and Syk protein to histamine release (HR) from mast cells (MC) cultured from the peripheral blood of CIU R, CIU NR, and normal subjects. The MC of CIU R donors contained significantly increased Syk and decreased SHIP-2 as compared to CIU NR (Syk: p=0.038: SHIP-2: p=0.038) and normals (Syk: p=0.042: SHIP-2: p=0.027). Spontaneous HR from CIU donors was increased two-fold compared to normals (p=0.04). In summary, our results suggest a possible predilection for urticarial MC to spontaneously degranulate upon IgE sensitization contributing to the increased pruritis associated with CIU.
doi:10.1016/j.clim.2009.05.003
PMCID: PMC2720433  PMID: 19477690
FcεRI; CD34+ stem cell; signal transduction; urticaria; mast cell
9.  New Concepts in Chronic Urticaria 
Current opinion in immunology  2008;20(6):709-716.
Chronic urticaria is a common skin disease without a clear etiology in the vast majority of cases. The similarity of symptoms and lesion pathology to allergen-induced skin reactions supports the idea that skin mast cell and blood basophil IgE receptor activation is involved, however, no exogenous allergen trigger has been identified. The presence of serum IgG autoantibodies targeting IgE or the IgE receptor in ∼40 % of CIU cases supports the theory of an autoimmune basis for the disease. However, issues remain with the assays to detect autoantibodies amongst other serum factors, the relationship of autoantibodies to CIU disease activity, and the occurrence of autoantibodies in healthy subjects. Other studies have identified altered IgE receptor degranulation that reverts in disease remission and is accompanied by changes in signaling molecule expression and function in mast cells and basophils in active CIU subjects. The arrival of therapies targeting IgE and the IgE receptor pathway elements has potential use in CIU.
doi:10.1016/j.coi.2008.09.005
PMCID: PMC2610333  PMID: 18832031
10.  Diagnostic evaluation of food-related allergic diseases 
Food allergy is a serious and potentially life-threatening problem for an estimated 6% of children and 3.7% of adults. This review examines the diagnostic process that begins with a patient's history and physical examination. If the suspicion of IgE-mediated food allergy is compelling based on the history, skin and serology tests are routinely performed to provide confirmation for the presence of food-specific IgE antibody. In selected cases, a provocation challenge may be required as a definitive or gold standard reference test for confirmation of IgE mediated reactions to food. Variables that influence the accuracy of each of the diagnostic algorithm phases are discussed. The clinical significance of food allergen-specific IgE antibody cross-reactivity and IgE antibody epitope mapping of food allergens is overviewed. The advantages and limitations of the various diagnostic procedures are examined with an emphasis on future trends in technology and reagents.
doi:10.1186/1710-1492-5-2
PMCID: PMC2776233  PMID: 19946406

Results 1-10 (10)