Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists

The identification of the antigen recognition receptors for innate immunity, most notably the Toll-like receptors, has sparked great interest in therapeutic manipulation of the innate immune system. Toll-like receptor agonists are being developed for the treatment of cancer, allergies and viral infections, and as adjuvants for potent new vaccines to prevent or treat cancer and infectious diseases. As recognition grows of the role of inappropriate Toll-like receptor stimulation in inflammation and autoimmunity, significant efforts have begun to develop antagonists to Toll-like receptors as well.     

Helminth-modified pulmonary immune response protects mice from allergen-induced airway hyperresponsiveness

It has been shown that the presence of certain helminth infections in humans, including schistosomes, may reduce the propensity to develop allergies in infected populations. Using a mouse model of schistosome worm vs worm + egg infection, our objective was to dissect the mechanisms underlying the inverse relationship between helminth infections and allergies. We have demonstrated that conventional Schistosoma mansoni egg-laying male and female worm infection of mice exacerbates airway hyperresponsiveness. In contrast, mice infected with only schistosome male worms, precluding egg production, were protected from OVA-induced airway hyperresponsiveness. Worm-infected mice developed a novel modified type 2 cytokine response in the lungs, with elevated allergen-specific IL-4 and IL-13 but reduced IL-5, and increased IL-10. Although schistosome worm-only infection is a laboratory model, these data illustrate the complexity of schistosome modulation of host immunity by the worm vs egg stages of this helminth, with the potential of infections to aggravate or suppress allergic pulmonary inflammation. Thus, infection of mice with a human parasitic worm can result in reduced airway inflammation in response to a model allergen.     

Exploring the Determinants of the Perceived Risk of Food Allergies in Canada

Food allergies are emerging health risks in much of the Western world, and some evidence suggests prevalence is increasing. Despite lacking scientific consensus around prevalence and management, policies and regulations are being implemented in public spaces (e.g., schools). These policies have been criticized as extreme in the literature, in the media, and by the non-allergic population. Backlash appears to be resulting from different perceptions of risk between different groups. This article uses a recently assembled national dataset (n = 3,666) to explore how Canadians perceive the risks of food allergy. Analyses revealed that almost 20% self-report having an allergic person in the household, while the average respondent estimated the prevalence of food allergies in Canada to be 30%. Both of these measures overestimate the true clinically defined prevalence (7.5%), indicating an inflated public understanding of the risks of food allergies. Seventy percent reported food allergies to be substantial risks to the Canadian population. Multivariate logistic regression models revealed important determinants of risk perception including demographic, experience-based, attitudinal, and regional predictors. Results are discussed in terms of understanding emerging health risks in the post-industrial era, and implications for both policy and risk communication.     

Genetics of asthma and atopy

The genetics of asthma and atopy has made tremendous progresses over the last couple of years. It has been known for ages that allergies and asthma are concentrating within families. Modern genetics has pinpointed some gene areas such as 5q31.1, 6p21.3, 11q13, 12q15, 14q11.1 and 16p12. Much of the information available today has been fragmentary and not always confirmed. Alleles at multiple loci are likely to be involved and the ultimate picture is most likely determined by many genetic and environmental factors.     

Contact Hypersensitivity to Oxazolone Provokes Vulvar Mechanical Hyperalgesia in Mice

The interplay among pain, allergy and dysregulated inflammation promises to yield significant conceptual advances in immunology and chronic pain. Hapten-mediated contact hypersensitivity reactions are used to model skin allergies in rodents but have not been utilized to study associated changes in pain perception in the affected skin. Here we characterized changes in mechanical hyperalgesia in oxazolone-sensitized female mice challenged with single and repeated labiar skin exposure to oxazolone. Female mice were sensitized with topical oxazolone on their flanks and challenged 1-3 times on the labia. We then measured mechanical sensitivity of the vulvar region with an electronic pressure meter and evaluated expression of inflammatory genes, leukocyte influx and levels of innervation in the labiar tissue. Oxazolone-sensitized mice developed vulvar mechanical hyperalgesia after a single labiar oxazolone challenge. Hyperalgesia lasted up to 24 hours along with local influx of neutrophils, upregulation of inflammatory cytokine gene expression, and increased density of cutaneous labiar nerve fibers. Three daily oxazolone challenges produced vulvar mechanical hyperalgesic responses and increases in nerve density that were detectable up to 5 days post-challenge even after overt inflammation resolved. This persistent vulvar hyperalgesia is resonant with vulvodynia, an understudied chronic pain condition that is remarkably prevalent in 18-60 year-old women. An elevated risk for vulvodynia has been associated with a history of environmental allergies. Our pre-clinical model can be readily adapted to regimens of chronic exposures and long-term assessment of vulvar pain with and without concurrent inflammation to improve our understanding of mechanisms underlying subsets of vulvodynia and to develop new therapeutics for this condition.     

In Memoriam Siwert Nilsson 1933–2002

Since the beginning of aeropalynology, aerobiologists have tried to develop models able to predict the pollen load of the atmosphere to help physicians and patients suffering pollen allergies to improve the efficiency of pollen allergies prophylaxis. Some models have been developed by aerobiological services and are used for real time predictions, now provided online. They are statistical models and require the pollen load of the previous days as input, as well as statistics on the pollen load of the previous years, daily meteorological data and geographic information on the pollen sources. Here we propose to use process-based phenological models to predict the time course of the pollen load of the atmosphere using solely daily mean temperatures as input. The model proposed has been fitted and validated for 13 major allergenic taxa (Alnus, Artemisia, Betula, Castanea, Corylus, Cupressaceae, Olea, Plantago, Platanus, Populus, Poaceae, Quercus and Tilia) in different areas of France and Spain. The model has been integrated into a freeware called PPF (Positive Pollen Forecast), which will be made available from the 5^th Framework EU project POSITIVE web page at: http://www.forst.tu-muenchen.de/LST/METEOR/positive/.     

Fruit cross-reactive allergens: a theme of uprising interest for consumers' health

Regular consumption of fruits has a positive influence on human health by disease prevention. However parallel to dietetic benefits, IgE-mediated fruit allergies have been shown to be an increasing health risk for children and adults in the Northern hemisphere. The spectrum of food allergies ranges from chronic symptoms to more acute problems and even anaphylaxis. Fruit proteins with high primary sequence similarity display also homologous tertiary structures, resulting in similar epitopes to IgEs and consequently in cross-reactivity. In this review we present the major allergens of stone and pome fruits and discuss the presence of homologous proteins in small fruits. Interestingly these proteins, which might pose an allergenic potential for pre-sensitised individuals are expressed also in strawberry, raspberry and blueberry, otherwise rich in beneficial biofactors.     

Die Genetik atopischer Erkrankungen

Allergic disorders (atopic dermatitis, asthma, hay fever) are common chronic inflammatory diseases of the skin and airways that are often associated with allergies (formation of specific IgE antibodies) to environmental allergens. They are complex genetic diseases, so that both genetic and environmental factors are involved in their causation. Most of the research effort devoted to the search for genes that might be responsible has so far focused on the mechanisms behind the immune response. More recent work on gene identification, however, documents the decisive importance of epithelial barrier defects in the pathogenesis of AD and allergic airways disease. These findings represent an important milestone in unraveling the genetic mechanisms underlying these complex diseases and allow new insight into the molecular mechanisms that lead illnesses to develop. In addition, they might point the way to novel preventive and therapeutic strategies for atopic disorders.     

Design of an Epitope-Based Peptide Vaccine Against the Major Allergen Amb a 11 Using Immunoinformatic Approaches

The Protein Journal - Allergic diseases are a socially significant problem of global importance. The number of people suffering from pollen allergies has increased dramatically in recent decades....     

Focus: Allergic Diseases and Type II Immunity: Allergies and Adaptations: A Perspective on the Need for Culturally Responsive Care to Medically Indicated Dietary Restrictions

In medicine, we tend to think of food as being equivalent to nutrition, and food allergies are understood primarily as a biomedical process. In this piece, I explore how my experience with food allergies intersects with my cultural identity as a second-generation Indian-American. I also offer insights from my experiences in medical training and practice and reflect on the responsibility of health providers to understand the social and cultural context of food allergies.     

The coming-of-age of the hygiene hypothesis

The hygiene hypothesis, as originally proposed, postulated an inverse relation between the incidence of infectious diseases in early life and the subsequent development of allergies and asthma. New evidence from epidemiological, biological and genetic studies has significantly enlarged the scope of the hypothesis. It now appears probable that environmental 'danger' signals regulate the pattern of immune responses in early life. Microbial burden in general, and not any single acute infectious illness, is the main source of these signals. The latter interact with a sensitive and complex receptor system, and genetic variations in this receptor system may be an important determinant of inherited susceptibility to asthma and allergies.     

Brachypodium distachyon as a model for defining the allergen potential of non-prolamin proteins

Epitope databases and the protein sequences of published plant genomes are suitable to identify some of the proteins causing food allergies and sensitivities. Brachypodium distachyon, a diploid wild grass with a sequenced genome and low prolamin content, is the closest relative of the allergen cereals, such as wheat or barley. Using the Brachypodium genome sequence, a workflow has been developed to identify potentially harmful proteins which may cause either celiac disease or wheat allergy-related symptoms. Seed tissue-specific expression of the potential allergens has been determined, and intact epitopes following an in silico digestion with several endopeptidases have been identified. Molecular function of allergen proteins has been evaluated using Gene Ontology terms. Biologically overrepresented proteins and potentially allergen protein families have been identified.     

Clinical study of peanut and nut allergy in 62 consecutive patients: new features and associations.

OBJECTIVE--To investigate clinical features of acute allergic reactions to peanuts and other nuts. DESIGN--Analysis of data from consecutive patients seen by one doctor over one year in an allergy clinic at a regional referral centre. SUBJECTS--62 patients aged 11 months to 53 years seen between October 1993 and September 1994. MAIN OUTCOME MEASURES--Type and severity of allergic reactions, age at onset of symptoms, type of nut causing allergy, results of skin prick tests, and incidence of other allergic diseases and associated allergies. RESULTS--Peanuts were the commonest cause of allergy (47) followed by Brazil nut (18), almond (14), and hazelnut (13). Onset of allergic symptoms occurred by the age of 2 years in 33/60 and by the age of 7 in 55/60. Peanuts accounted for all allergies in children sensitised in the first year of life and for 82% (27/33) of allergies in children sensitised by the third year of life. Multiple allergies appeared progressively with age. The commonest symptom was facial angioedema, and the major feature accounting for life threatening reactions was laryngeal oedema. Hypotension was uncommon. Of 55 patients, 53 were atopic--that is, had positive skin results of tests to common inhaled allergens--and all 53 had other allergic disorders (asthma, rhinitis, eczema) due to several inhaled allergens and other foods. CONCLUSIONS--Sensitisation, mainly to peanuts, is occurring in very young children, and multiple peanut/nut allergies appear progressively. Peanut and nut allergy is becoming common and can cause life threatening reactions. The main danger is laryngeal oedema. Young atopic children should avoid peanuts and nuts to prevent the development of this allergy.     

Focus: Allergic Diseases and Type II Immunity: Model of Walnut Allergy in CC027/GeniUnc Mice Recapitulates Key Features of Human Disease

Tree nut allergies affect 1% of the United States population, are often severe in nature and rarely outgrown. Despite the severity and prevalence, there are no FDA-approved treatments for tree nut allergy. Development of a therapeutic would be expedited by having a mouse model that mimics the human disease. We utilized the CC027/GeniUnc mouse strain, which was previously identified as an orally reactive model of peanut allergy, to develop a model of walnut allergy. Mice were sensitized with walnut and cholera toxin for 4 weeks and subsequently challenged by oral gavage. Blood samples were collected to measure serum IgE. Walnut-sensitized mice produced high levels of walnut-IgE and were cross-sensitized to pecan. Oral challenges with walnut resulted in severe anaphylaxis and accompanying allergic symptoms. Importantly, pecan challenges also led to severe allergic reactions, indicating cross-reactivity to pecan. Overall, this novel mouse model reproduces key characteristics of human walnut allergy, which provides a platform to develop novel therapies and better understand sensitization mechanisms.     

Enuresis: familial incidence and relationship to allergic disorders

An analysis is made of the incidence of allergic diseases in 105 enuretic boys and girls, in their parents and siblings, and in matched controls. There is an increased incidence of hay fever, urticaria and food and drug allergies in enuretic boys. There is an increased incidence of enuresis in the parents of enuretic children. Enuretic children and their fathers are significantly more prone to develop urinary infections than are controls; there is also an increased incidence in urinary infections in their mothers, but numbers are insufficient to indicate that this is significant.     

Meteorological phenomena affecting the presence of solid particles suspended in the air during winter

Winter is not traditionally considered to be a risky season for people who suffer from pollen allergies. However, increasing numbers of people are showing symptoms in winter. This prompted our investigation into the levels of solid material in the air, and some of the meteorological phenomena that allow their accumulation. This study showed a possible relationship between the phenomenon of thermal inversion, which occurs when very low temperatures, cloudless skies and atmospheric calms coincide, and an increase in the concentration of solid material in the atmosphere. Frequently, this situation is associated with other predictable phenomena such as fog, dew and frost. This may allow a warning system to be derived for urban pollution episodes. The effect caused by parameters such as wind and rainfall was also analysed. Solid material was differentiated into non-biological material from natural and non-natural sources (e.g. soot, dust, sand, diesel exhaust particles, partially burnt residues) and biological material. The latter mainly comprises pollen grains and fungal spores. Owing to its abundance and importance as a causal agent of winter allergies, Cupressaceae pollen was considered separately. Received: 28 April 1999 / Revised: 16 November 1999 / Accepted: 17 November 1999     

New allergies after cord blood transplantation

Background aimsUmbilical cord blood transplantation (CBT) is an effective treatment for benign and malignant diseases. Late effects of CBT are not well described in the literature. In the present study, we present our experience of new-onset allergies in long-term survivors after CBT.MethodsAfter an initial patient had a severe peanut allergic reaction after CBT, all CBT patients were prospectively followed for new allergy development. Fifty patients received CBT between March 2006 and June 2011.ResultsThe median follow-up after CBT was 447 days (range, 12–2022). At the time of analysis, 30 patients were alive, with 3-year survival of 55.5%; median follow-up of surviving patients was 910 days (range, 68–2022). The allergic syndrome developed in five patients, with the cumulative incidence of new allergies at 2 years of 18.4% (95% confidence interval, 10.8–26). The median time to onset of new allergy after transplantation was 298 days (range, 250–809).ConclusionsAllergy development has been linked to a delayed maturation of the immune system in several studies. We present the first case series of patients who had new allergies after CBT. Further study of this novel complication as well as counseling of patients after CBT would be important.     

Development of a rice-based peptide vaccine for Japanese cedar and cypress pollen allergies

Peptide immunotherapy using dominant T-cell epitopes is a safe treatment alternative to conventional subcutaneous injection of natural crude allergen extract, which is sometimes accompanied by anaphylactic shock. For Japanese cedar pollinosis (JCP), hybrid peptides composed of six to seven major T-cell epitopes (7Crp peptide) from the causative allergens Cry j 1 and Cry j 2 have been developed on the basis of different human leukemia antigen class II restrictions, because of the diversity of patients’ genetic backgrounds. However, other dominant T-cell epitopes that are produced in some patients are not covered by these peptides. To develop a more universal peptide vaccine for JCP, we generated transgenic rice seeds containing seven new T-cell epitopes (Crp3) in addition to the T-cell epitopes used in the 7Crp peptide. Next, we co-expressed unique T-cell epitopes (6Chao) from the Japanese cypress pollen allergens Cha o 1 and Cha o 2 in transgenic rice seeds, with 7Crp and Crp3. These transgenic rice seeds, containing many highly homologous T-cell epitopes derived from cedar and cypress allergens, are expected to be applicable to a wide range of patients suffering from these pollen allergies.     

Suppression of TH2-type allergic reactions by helminth infection

There is no immunological mechanism to adequately explain the sudden epidemic in allergies noted in the last 30 years in developed countries. The reduction in the development of allergic disorders observed in individuals infected with parasitic helminths, however, supports a possible role for worms in suppressing allergies. Helminths regulate the immunity of the host to ensure a mutually beneficial environment for the survival of both the parasite and the host. This interplay between helminths and allergic responses raises fundamental questions in immunobiology. Harnessing current mechanistic studies for translational research into helminth infections and atopy might have potential for the identification of novel biomarkers, and even therapeutics, in allergic diseases.     

Induction of pulmonary allergen-specific IgA responses or airway hyperresponsiveness in the absence of allergic lung disease following sensitization with limiting doses of ovalbumin-alum.

Respiratory allergies represent a failure to generate nonpathogenic responses to innocuous foreign materials. Herein we assessed the role of the sensitizing dose of allergen in this response/nonresponse paradigm, sensitizing BALB/c mice with 5 ng-2 microg of OVA-alum and assessing their responses to repeated OVA aerosol challenge. Mice sensitized with < or = 25 ng of OVA-alum did not develop atopic antibodies, airway hyperresponsiveness (AHR), eosinophilia, or pulmonary Th2 responses, but the 25-ng group animals did develop significant IgA responses. The mice sensitized with 100 ng of OVA-alum developed AHR in the absence of detectable allergic disease, while the mice sensitized with 250 ng-2 microg of OVA/alum developed full-spectrum allergic disease (i.e., eosinophilia, IgE, IgG1, pulmonary Th2 cytokine responses, and AHR). These data indicate that limiting doses of allergen can differentially induce IgA or AHR in the absence of atopic disease in mice.