Adjuvants in Allergen-Specific Immunotherapy: Modulating and Enhancing the Immune Response.

Allergen-specific immunotherapy (AIT) is the only treatment that can affect the natural course of allergic diseases such as allergic asthma, allergic rhinitis, and IgE-mediated food allergy. Adjuvants are used to induce a quicker, more potent, and longer-lasting immune response. Only 4 compounds are used as adjuvants in currently marketed AIT products: aluminum hydroxide, calcium phosphate, microcrystalline tyrosine (MCT), and monophosphoryl lipid A (MPL). The first 3 adjuvants are delivery systems with a depot effect, although they may also have immunomodulatory properties. These first-generation adjuvants are still widely used, especially aluminum hydroxide. However, aluminum is subject to limitations. MCT is the depot formulation of L-tyrosine; it enhances IgG production without inducing a significant increase in IgE, is biodegradable, and has good local and systemic tolerability. In turn, MPL is an immunostimulatory agent that is the only second-generation adjuvant currently used for AIT. In addition, multiple adjuvants are currently being studied, including immunostimulatory sequences (ISSs), nanoparticles (liposomes, virus-like particles, and biodegradable polymers), and phosphatidylserine derivatives. In a murine model of allergic bronchial inflammation by sensitization to olive pollen, the specific IgE level was significantly higher in sensitized mice treated with olive pollen and aluminum hydroxide. However, specific IgE levels were significantly reduced and bronchial hyperreactivity significantly improved in sensitized mice treated with olive pollen and bacterial derivatives (MPL or ISSs).

Food protein-induced enterocolitis syndrome by fish: Not necessarily a restricted diet.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food hypersensitivity usually due to cow's milk or soy. Recent researches show that fish is 1 of the most important triggers of FPIES in the Mediterranean countries. Due to the risk of multiple-food FPIES, avoiding foods in the same category or that often occur together may be reasonable. The aim of this study was to evaluate the evolution and follow-up of FPIES related to fish over a period of 20 years. We describe the clinical features of our population, discuss different approaches to oral food challenges, and analyze the possibility of introducing the culprit fish or other nonrelated fish to avoid unnecessary restricted diets.

Social Media as a Tool for the Management of Food Allergy in Children.

BACKGROUND: Food allergy markedly impairs quality of life, and avoiding the offending food requires extensive patient education. Social media have been proven a useful source of information for other chronic conditions. Our aim was to describe how pediatric patients with food allergy and their families are using social media. METHODS: We performed a cross-sectional study in the pediatric allergy unit of a tertiary hospital. Patients with food allergy were questioned about their disease and their use of social media. The survey was completed by the patients themselves in the case of those aged over 13 years and by parents or guardians in the case of younger patients. RESULTS: We included 193 patients (162 guardians, 31 adolescents). Social media were used by 109 guardians (67.3%) and 29 adolescents (90.3%), of whom 30.3% and 6.9%, respectively, used them for food allergy-related purposes. The most popular websites were Facebook for guardians (52.2%) and YouTube for teenagers (80.6%). Having cow's milk and/or egg allergy was the only feature related to using social media for food allergy. Using social media for information on food allergy did not correlate with the frequency of recent reactions, self-scored knowledge about food allergy, or opinion on evidence-based or alternative therapies for the disease. CONCLUSIONS: Most patients and guardians of patients with food allergy used social media. However, only a small portion accessed used them to increase their knowledge of the disease.

Anaphylaxis in Adolescent/Adult Patients Treated in the Emergency Department: Differences Between Initial Impressions and the Definitive Diagnosis.

OBJECTIVES: To contrast the initial suspected etiology of anaphylaxis with the postworkup diagnosis in patients attended at the emergency department (ED) of a tertiary-level hospital in Spain and to investigate the incidence, causes, and management of anaphylaxis. METHODS: We performed an observational study of patients aged more than 15 years who came to the ED with anaphylaxis between 2009 and 2010. All clinical records from the ED were reviewed. We recorded data on clinical management, the etiology proposed by the attending emergency physician, and the cause reported by the patient. The findings were compared with the diagnosis reached after the allergy workup. RESULTS: The incidence of anaphylaxis was 0.08%. The most common manifestation was skin-mucosal symptoms (98.3%). Anaphylaxis was diagnosed in the ED in only 44% of the cases, regardless of severity. Only 39.7% received epinephrine, which was administered more frequently when the ED physician diagnosed anaphylaxis, regardless of severity. A total of 60 patients were subsequently seen at the allergy department. The final etiology differed from the initial suspicion in the ED in 45% of cases. The frequency of anaphylaxis of uncertain origin decreased from 33.3% to 13.3%. After the allergy workup, drugs (41.7%) were considered the main cause of anaphylaxis, followed by food (25%). CONCLUSIONS: The incidence of anaphylaxis (0.08%) was double that estimated in the ED. Anaphylaxis is underdiagnosed. A correct diagnosis conditions the administration of epinephrine, regardless of the severity of symptoms. The real etiology of anaphylaxis should only be proposed after an allergy workup, which is recommended in all cases, as the real cause can differ considerably from the initial impression in the ED.

Recurrent fixed drug eruption caused by citiolone.

Citiolone (N-acetylhomocysteinethiolactone) is a thiolic-derived medication frequently used in Spain and in other countries as a mucolytic agent for the treatment of certain hepatic disorders. Mucolytic drugs have rarely been implicated in the fixed drug eruption etiology. We report on a patient who presented several episodes of fixed exanthema related to citiolone intake. The patch test with citiolone (10% in dimethyl sulfoxide) was negative. The diagnosis was confirmed by a positive controlled oral challenge test. Other mucolytic thiolic-derivatives (N-acetylcysteine) were tolerated by the patient, thus crossreactivity between these drugs seems to be unlikely.

Fixed drug eruption induced by indapamide. Cross-reactivity with sulfonamides.

Indapamide is a nontiazidic sulfonamide diuretic which has not been previously reported as a cause of fixed drug eruption. We describe a patient who experienced several episodes of fixed drug eruption during treatment with indapamide. The diagnosis was confirmed by positive controlled oral challenge test. The possible existence of cross-reactivity with other sulfonamide derivatives was investigated by controlled oral challenge test with sulfamethoxazole, sulfadiazine and furosemide, with the tests with sulfamethoxazole and sulfadiazine resulting positive.

Bezafibrate-induced anaphylactic shock: unusual clinical presentation.

We report a case of a patient who suffered generalized urticaria, chest tightness, wheezing, nausea, vomiting, hypotension, and loss of consciousness. Two hours earlier she had taken Eulitop Retard following lunch. She had tolerated all the implicated food after the reaction. Allergy evaluation revealed intense positive responses to intradermal tests with bezafibrate active component and Eulitop Retard (skin tests in control subjects were negative). Specific IgE tests (RAST) to Eulitop Retard were negative. An IgE mechanism is suggested to be responsible for this adverse reaction on the basis of the positive skin tets. The delayed onset (two hours) of this anaphylactic shock is unusual. Although infrequent, it may be caused by the specific pharmacokinetic characteristics of this drug, which is a slow releasing agent, mainly absorbed in the gut. The drug was taken just after lunch, and this concomitant food ingestion could also have produced a delay in gastric drainage and a retarded drug absorption. An IgE-mediated accelerated type reaction could also explain this delay. Apparently the patient reacted after the first contact to the drug, and the absence of a sensitization period is not usual in this type of immune reponse. Finally, we recommend the performance of prick and intradermal skin tests prior to any systemic challenge when allergic reactions to fibric acid derivatives are suspected.

Assessment of airway distribution of transnasal solutions in mice by PET/CT imaging.

PURPOSE: Transnasal administration is one of the most common routes for allergen challenge in mouse models of airway diseases. Although this technique is widely used, neither the amount of allergen that reaches the lung nor its airway distribution has been well established. We used positron emission tomography (PET) and computed tomography (CT) to examine the anatomical distribution of a solution containing a tracer immediately after transnasal delivery and to determine the possible influence of age and administered volume. PROCEDURES: Forty-six female BALB/c mice were divided into three groups according to instillation volume and age: (A) 15 microl, 8-10 weeks old (N = 10), (B) 30 microl, 8-10 weeks old (N = 20), and (C) 30 microl, 32 weeks old (N = 16). Anesthetized animals underwent a dynamic scan in a dedicated small-animal PET scanner immediately after transnasal administration of a solution containing (18)FDG. Regions of interest were used to obtain quantitative data. Animals were also imaged with a small-animal CT scanner to obtain complementary anatomical information. RESULTS: Mean +/- SD (5.69 +/- 4.51%) of the solution administered reached the lungs in group A, 41.84 +/- 8.03% in group B, and 36.65 +/- 16.15% in group C. A comparable percentage was delivered to the left and right lungs in all the groups. Analysis of variance revealed a significant difference between the groups in the proportion of the solution that reached the lungs depending on the injection volume (P < 0.001), but not depending on animal age. CONCLUSIONS: In this first report on quantitative imaging by PET and CT in small animals, we confirmed the suitability of the transnasal route with an instilled volume of 30 microl delivering fluids into the lower airways, although only about 40% of the dose reaches the lungs.

Pollen-induced airway inflammation, hyper-responsiveness and apoptosis in a murine model of allergy.

BACKGROUND: Previous studies indicate that murine models are useful tools for studying the allergic diseases, including certain aspects of bronchial asthma such as cellular tissue inflammation and pulmonary function. OBJECTIVE: To develop an experimental model of allergic lung inflammation based on a relevant human allergen, olive pollen, and to establish the immunological, cellular and functional airway features of the allergic response in this model. METHODS: Induction of systemic allergic response was achieved by the subcutaneous administration of Olea europaea extract in BALB/c mice. Olea-specific Igs (IgG1, IgG2a and IgE) and cytokines from splenocyte cultures IL-4, IL-5 IL-10, IL-13 and IFN-gamma were measured. Allergic airway response was generated by transnasal instillation of the allergens. Airway responsiveness was monitored by non-invasive methacholine inhalation challenge. Lungs were paraffin embedded and histologically analysed. Apoptosis was studied by the TUNEL technique in the lung tissue and through cell cycle analysis by flow cytometry in splenocytes. RESULTS: Our results demonstrate that Olea-sensitized mice develop a specific allergic antibody (IgG1 and IgE) and cytokine (IL-4, IL-5, IL-10 and IL-13) response. After transnasal Olea instillation, they show inflammatory infiltration of lung tissue, mucus secretion and non-specific hyper-responsiveness in the airway. Concomitantly, differences in the rate of apoptosis are observed in the lung cells as well as a significant reduction of spontaneous apoptosis in the splenocytes of allergic mice. CONCLUSION: We present a novel animal model of olive pollen-allergic disease. This model presents traits associated with human allergic asthma and could be an interesting tool in the study of underlying molecular mechanisms and in exploring the therapeutic approaches to this disease.

Anisakis simplex allergy: a murine model of anaphylaxis induced by parasitic proteins displays a mixed Th1/Th2 pattern.

The study of the singular hypersensitivity reactions to Anisakis simplex (A.s) proteins, may help us to undestand many of the unknown immune interactions between helmiths infections and allergy. We have developed a murine model of allergy to A. simplex, that mimics human A. simplex allergy to study the specific aspects of anaphylaxis induced by parasites. Male C3H/HeJ mice were intraperitoneally sensitized to A. simplex. Mice were then intravenous or orally challenged with A. simplex. Antigen-specific immunoglobulins, polyclonal IgE, anaphylactic symptoms, plasma histamine levels and cytokine profiles were determined. Comparative IgE immunoblot analyses were also performed. Specific IgE, IgG(1) and IgG(2a) were detected in sensitized mice since week 3. Polyclonal IgE raised and peaked with different kinetics. Intravenous A. simplex challenge produced anaphylaxis in mice, accompanied by plasma histamine release. Oral A. simplex challenge in similarly sensitized mice did not caused symptoms nor histamine release. Numerous A. simplex allergens were recognized by sensitized mouse sera, some of them similar to human serum. The A. simplex stimulated splenocytes released IL-10, IFN-gamma, IL-4, IL-13 and IL-5. We describe a new animal model of anaphylaxis. It exhibits characteristics of type I hypersensitivity reactions to Anisakis simplex similar to those observed in allergic humans. Different responses to i.v. or oral A. simplex challenges emerged, which did not reflect a window tolerization period. The cytokine profile developed (mixed Th(1)/Th(2) pattern) differed from the observed in classical models of anaphylaxis or allergy to food antigens. This model may permit to investigate the peculiar allergic reactions to parasitic proteins.

DNA-based immunotherapeutics for the treatment of allergic disease.

Allergic diseases are a growing health concern in industrialized countries. Despite a number of effective therapeutic options for the prevention and treatment of the pathophysiologic responses which characterize allergic diseases, the induction of true allergen desensitization remains an elusive therapeutic goal. Only immunotherapy (IT) has been shown to have any effect on the underlying hypersensitivities which mediate allergic reactions, and traditional protein-based allergen IT has a limited scope of efficacy However, a number of reagents collectively termed DNA-based immunotherapeutics have proven highly effective in both the prevention and reversal of Th2-mediated hypersensitivity states in mouse models of allergic disease. Four basic DNA-based immunotherapeutic modalities have been used for these studies. These include immunization with gene vaccines, allergen mixed with immunostimulatory oligodeoxynucleotide (ISS-ODN), and physical allergen-ISS-ODN conjugates (AIC), as well as immunomodulation with ISS-ODN alone. Results from many laboratories have generated guarded optimism that DNA-based immunotherapeutics may be effective for the reversal of allergic hypersensitivity states in humans, and several clinical trials have already been initiated. This review will focus on our present understanding of the biological activities of DNA-based immunotherapeutics and their application to the treatment of allergic diseases.

Immunostimulatory DNA-based therapeutics for experimental and clinical allergy.

Although allergen immunotherapy (IT) has been shown to modulate allergic hypersensitivities, its efficacy is limited. Recently, in various models of experimental allergy, a number of reagents which we have termed immunostimulatory DNA-based therapeutics have proven highly effective in both the prevention and reversal of Th2 mediated hypersensitivity states. These include immunization with gene vaccines, allergen mixed with immunostimulatory oligodeoxynucleotide (ISS-ODN), and physical allergen: ISS-conjugates (AIC), and immunomodulation with ISS-ODN alone. Results from our laboratory have shown that immunostimulatory DNA-based therapeutics may be effective for the reversal of allergic hypersensitivity states in humans and several clinical trials have already been initiated. This review will focus on our laboratory's experience with immunostimulatory DNA-based therapeutics in various murine models of allergy and their potential utility in the treatment of allergic patients.