Current Pharmaceutical Design - Volume 20, Issue 6, 2014

Recent evidence has brought to the spotlight plant-derived polyphenols as a promising tool to prevent allergy. The worldwide increase of allergic disease, probably relying on many factors including immune response to stressors and its loss in complexity, environmental pressure by pollutants and chemical allergens, changes in lifestyle and lifespan, failure of conventional treatments to prevent and treat allergy, has strongly suggested people to refer to healthy promising nature-derived compounds, most of which contained in fruits and vegetables, e.g. in daily diet. Phenolic acids and polyphenols, such as flavonoids, are the best studied natural substances known to possess an anti-inflammatory and anti-allergic potential. Used as nutraceuticals, these compounds are thought to dampen the onset of allergic inflammation, by acting on several immune cells, but concerns still remain about their real employment by the organism who assumes polyphenols through diet, because of their bioavailability, gut transformation and pharmacokinetics. Other issues deal with the wide panoply of actions played by these compounds within cells, which has hampered a clear comprehension of their action on cell molecular signaling and function. In this review, special emphasis is placed on the effects of dietary polyphenols on allergy prevention, the possible mechanism of action of polyphenols-containing food and future perspectives for pharmacology design.

Immune system activation and inflammation are deeply involved in the pathogenesis of a variety of diseases including infections, autoimmunity and malignancy as well as allergy and asthma. The incidence of allergy and asthma has significantly increased during the past decades. Still the background of this phenomenon is not well understood. The contribution of life style and habits are heavily discussed. Among them is a too clean environment which may predispose individuals to an increased sensitivity to allergic responses. Also dietary habits have changed drastically in the Western world, and it appears that especially the increased use of antioxidant food supplements, preservatives and colorants could be of relevance. In vitro experiments show that typical antioxidant compounds like vitamin C and E and the stilbene resveratrol as well as food preservatives such as sulfite, benzoate and sorbic acid and also colorants like curcumin exert significant suppressive effects on the T helper (h)1 immune activation cascade in freshly isolated human peripheral blood mononuclear cells. Obviously, antioxidant compounds interfere with central immunoregulatory pathways such as tryptophan breakdown via indoleamine 2,3-dioxygenase (IDO) and neopterin production by GTP-cyclohydrolase I (GCH). Results show an anti-inflammatory property of antioxidants which could shift the Th1-Th2-type immune balance towards Th2-type immunity that is of utmost importance in allergic responses. Additionally, food preservatives reduce the number of pathogens to which humans are exposed by their diet, so that in agreement with the hygiene hypothesis the likelihood of allergy might increase. This review article discusses the beneficial effects which antioxidants may have to counteract inflammatory diseases, but also their potential in the increase of allergy and asthma in the Western world and their involvement in the obesity epidemic.

Carapa guianensis Aublet (Meliaceae), also known as andiroba, is used in popular medicine in Brazil and other countries encompassing the Amazon rainforest. Virtually all parts of the andiroba tree are utilized, including the seed’s oil, which is employed to treat inflammation and infections. The medicinal properties of C. guianensis have been attributed to the presence of limonoids, which are tetranortriterpenoids. We have previously demonstrated that the oil obtained from C. guianensis seeds contains different tetranortriterpenoids, including 6α-acetoxygedunin, 7-deacetoxy-7-oxogedunin, andirobin, gedunin and methyl-angolensate. The seeds oil and this fraction of tetranortriterpenoids present marked anti-inflammatory and anti-allergic properties, by inhibiting edema formation in different experimental models in rodents, via the impairment of signaling pathways triggered by histamine, bradykinin and platelet-activating factor. Tetranortriterpenoids also impaired the production of inflammatory mediators that trigger leukocyte infiltration into the inflammatory site, including the eosinophilotactic mediators interleukin (IL)-5 and CCL11/eotaxin, as well as the inflammatory cytokines tumor necrosis factor (TNF)-α and IL-1β. This phenomenon seems to depend on the inhibition of nuclear factor κB (NFκB) activation. We have further demonstrated that each one of the five tetranortriterpenoids listed above presented inhibitory effects on the activation of different cell populations, including mast cells, eosinophils and T lymphocytes, through which they impaired allergy and inflammation. This review will discuss the therapeutic effects of C. guianensis oil and its compounds, focusing on the scientific evidences that support its traditional use in inflammatory conditions and its anti-allergic properties.

Type-1 allergic diseases consist of two phases. An inductive phase comprises IgE formation to allergens based on the immune system being biased to predominant T-helper type 2 responses. In a triggering phase allergic symptoms are triggered due to a robust secretion of mediators from mast cells and other cells after re-exposure to the same allergen. Various polyphenols, found in foods and plant sources, have potent anti-allergic activities that have been shown in different disease models and in human clinical trials. The present review summarizes the recent findings and progress in the research about polyphenols and natural products, and their role in allergic diseases. Intake of representative polyphenols (flavones, flavone-3-ols, catechins, anthocyanidins, flavanones, procyanidins, and resveratrol) can improve a skewed Th1/Th2 balance and suppress antigen-specific IgE antibody formation. Oral administration of fermented grape foods (FGF), one example of natural products fermented by lactic acid bacteria, is effective for decreasing allergic symptoms in the effector phase. Inhibitory mechanisms of polyphenols are also discussed.

Polyphenols contained in FGM from Negroamaro (N) and Koshu (K) Vitis vinifera have been shown to exhibit several immunomodulating activities. For instance, mice affected by experimental colitis when administered with K-FGM showed an attenuation of the inflammatory process. In murine asthma, K-FGM reduced IgE production and eosinophil number in bronchial alveolar lavage fluid. In vitro, both N- and K-FGM were able to induce T regulatory cells in terms of Foxp-3 molecule expression and release of interleukin-10. In another set of experiments both N- and K-FGM were able to balance rate of proliferation/apoptosis/necrosis of normal human peripheral lymphocytes, thus indicating the property of these compounds to maintain immune homeostatic mechanisms in the host. On the other hand, N- and K-FGM inhibited human basophil degranulation, thus, confirming our previous results obtained with rat basophilic leukemia cells. Finally, N- and K-FGM also decreased oxidative burst of human polymorphonuclear cells and monocytes.Taken together, these findings imply the potential clinical usefulness of FGM administration in inflammatory/allergic conditions, such as chronic asthma.

Asthma is an allergy-mediated inflammatory disease characterised by infiltration of the airway with mast cells, lymphocytes, and eosinophils. The disease is induced by co-ordination of T-helper cell type 2 (Th2) cytokines and inflammatory signal molecules. Fruits and vegetables are a rich source of polyphenolic bioactive compounds, which have been observed to have health-promoting properties when consumed by humans. In particular, fruit-derived proanthocyanins and anthocyanins have been found to attenuate lung inflammation. Epidemiological studies have revealed correlations between fruit consumption and a lower prevalence of respiratory symptoms and lower incidence of non-specific lung diseases. In this review we summarise the current understanding of the pathophysiologic mechanism(s) involved in the development of allergic airway disease. We also review evidence of the beneficial effects of plant-derived foods, their components and metabolites in allergic airway inflammation arising from in vitro and rodent studies, epidemiological studies and human intervention trials. The mechanism, biological relevance and functional benefits, such as immune modulation (e.g. reduction in cytokine and eotaxin production), antioxidant ability, tissue remodelling and tight junction function are also discussed.

The prevalence of allergic diseases has increased worldwide during the past two decades. Change of dietary habit is thought to be one of the environmental factors, which has caused such an increase and worsened allergic symptoms, which suggests that an appropriate dietary habit may substantially prevent the onset of allergic diseases and ameliorate allergic symptoms. Flavonoids, which are polyphenolic plant secondary metabolites ubiquitously present in vegetables, fruits and beverages, possess antioxidant and anti-allergic activities as well as immune-modulating traits. Flavonoids inhibit the activation of mast cells and basophils and therefore suppress the release of chemical mediators, synthesis of Th2 type cytokines such as interleukin (IL)-4 and IL-13, and CD40 ligand expression, They also reportedly inhibit IL-4-induced signal transduction and affect the differentiation process of naïve CD4+ T cells into effector T cell subsets. A cohort epidemiological study in Finland found a significantly low incidence of asthma in a population with a high intake of flavonoids. Moreover, various studies of flavonoids in allergic models such as asthma, atopic dermatitis, anaphylaxis and food allergy demonstrated their beneficial effects, while experience in humans is at the moment limited to respiratory allergy. Although further validation is required, it is anticipated that an appropriate intake of flavonoids may play a role in the prevention and eventually in the management of allergic diseases.

Subcutaneous allergen specific immunotherapy is an effective treatment of IgE-mediated allergies, but it requires repeated allergen injections with a risk of systemic allergic reactions. Other routes of immunization had been explored to improve patient compliance and safety. Skin is not only a physical barrier between the body and outside world, but also an important immune organ eliciting innate and adaptive immune function. Skin has been used as an ideal site for vaccination of infectious diseases. Food allergen topically applied onto disrupted skin can induce sensitization and food allergy would develop subsequently. However, immune tolerance would be induced if the skin barrier is kept intact. Several mice and human studies on epicutaneous immunotherapy showed successful treatment on IgE-induced allergy models or allergic diseases. Migratory Langerhans cells might play a decisive role in the induction of different immune responses. Further research on the underlying mechanism of the crosstalk between skin and gut or airway is helpful for the understanding of many protective or sensitizing immune responses induced via skin, and also is helpful for the development of new strategy for the treatment of allergic disease.

A fundamental means of allergic disease prevention, via the use of functional food factors, is desirable. A number of studies on the role of functional food factors in preventing allergic diseases have been reported. In this review, the preventive effects of polyphenols, carotenoids, polysaccharides, and non-digestible oligosaccharides on allergic diseases are discussed.

Food allergy is an increasingly prevalent problem all over the world and especially in westernized countries, and there is an unmet medical need for an effective form of therapy. During childhood natural tolerance development is frequent, but some children with cow's milk or hen's egg allergy and the majority of children with peanut allergy will remain allergic until adulthood, limiting not only the diet of patients but also their quality of life. Within the last several years, the usefulness of immunotherapy for food allergies has been investigated in food allergic patients. Several food immunotherapies are being developed; these involve oral, sublingual, epicutaneous, or subcutaneous administration of small amounts of native or modified allergens to induce immune tolerance. The approach generally follows the same principles as immunotherapy of other allergic disorders and involves administering small increasing doses of food during an induction phase followed by a maintenance phase with regular intake of a maximum tolerated amount of food. Oral immunotherapy seems to be a promising approach for food allergic patients based on results from small uncontrolled and controlled studies. Diet containing heated milk and egg may represent an alternative approach to oral immunomodulation for cow’s milk and egg allergic subjects. However, oral food immunotherapy remains an investigational treatment to be further studied before advancing into clinical practice. Additional bigger, multicentric and hopefully randomized-controlled studies must answer multiple questions including optimal dose, ideal duration of immunotherapy, degree of protection, efficacy for different ages, severity and type of food allergy responsive to treatment.

Food allergy is on the rise and has become a growing food safety concern. The main treatment is strictly avoiding allergens in the diet. However, this is difficult to do because foods are sometimes contaminated with allergens due to processing of different foods with the same machinery. For this reason, accidental ingestion of trace amount of allergenic proteins is common. For children with severe food allergy, this could be life-threatening. Food products with reduced allergenic proteins, if developed, could be beneficial and may raise the threshold of the amount of allergenic proteins required to trigger an allergic reaction. As a result, the number of serious allergic reactions may decrease. Moreover, such less allergenic products may be useful or replace regular products in studies such as oral tolerance induction or early exposure experiments, where children with severe peanut allergy are usually excluded due to their severe intolerance. This review focuses on recent findings and progress made in approaches to reduce allergenic proteins in foods. Modifying methods may include physical and chemical treatments as well as lifestyle changes and the use of supplements. We discuss the benefits and drawbacks these methods present for production of hypoallergenic food products and food allergy prevention.

Food allergies, defined as an immune response to food proteins, affect as many as 8% of young children and 2% of adults in westernized countries, and their prevalence appears to be rising like all allergic diseases. In addition to well-recognized urticaria and anaphylaxis triggered by IgE antibody–mediated immune responses, there is an increasing recognition of cell-mediated disorders such as eosinophilic esophagitis and food protein–induced enterocolitis. New knowledge is being developed on the pathogenesis of both IgE and non-IgE mediated disease. Currently, management of food allergies consists of educating the patient to avoid ingesting the responsible allergen and initiating therapy if ingestion occurs. However, novel strategies are being studied, including sublingual/oral immunotherapy and others with a hope for the future.

There may be a causal relationship between intake of n-6 polyunsaturated fatty acids (PUFAs) and childhood allergic diseases. This can be explained by plausible biological mechanisms involving eicosanoid mediators produced from the n-6 PUFA arachidonic acid. Long chain n-3 PUFAs are found in fish and fish oils. These fatty acids act to oppose the actions of n-6 PUFAs. Thus, it is considered that n-3 PUFAs will lower the risk of developing allergic diseases. In support of this, protective associations have been reported between maternal fish intake during pregnancy and allergic outcomes in infants and children from those pregnancies. However, studies of fish intake during infancy and childhood and allergic outcomes in those infants or children are inconsistent, although some reported a protective association. Supplementing pregnant women with fish oil can induce immunologic changes in cord blood. This supplementation has been reported in some studies to decrease sensitisation to common food allergens and to lower the prevalence and severity of atopic dermatitis in the first year of life. The protective effect of maternal n-3 PUFAs may last until adolescence of the offspring. Fish oil supplementation in infancy may decrease the risk of developing some manifestations of allergic disease, although this benefit may not persist. Whether fish oil is a useful therapy in children with asthma receiving standard therapy is not clear from studies performed to date and this requires further exploration.

IgE-mediated food allergy is a major and increasing health issue with significant impairment of quality of life and significant morbidity and mortality. It affects children, as well as adolescents and adults. This review focuses on novelties in the diagnosis of food allergy. Correct diagnosis relies upon history supplemented by quantification of specific IgE (sIgE) antibodies and/or skin tests. Unfortunately, as these tests do not demonstrate absolute predictive values, controlled oral provocation tests are needed to confirm/exclude diagnosis. To a certain extent, novel in vitro diagnostics in the form of allergen component-based sIgE assays and flow-assisted quantification of in vitro activated basophils might help to discriminate between genuine allergy and merely sensitization. Furthermore they make it possible to establish individual risk profiles, to predict persistence of allergy, and facilitate therapeutic approach.

Currently management of food allergy is mainly based on absolute avoidance of the offending food(s) and the use of rescue medication. However, the risk of severe or life-threatening reactions due to inadvertent exposure, nutritional imbalance and social isolation raises the demand of disease-modifying treatments. The aim of the different treatments is to allow patients to safely ingest the offending food(s). However this unresponsiveness can be transient and requires continued treatment (desensitization) and has to be permanent and sustained also after stopping the treatment (tolerance). This review focuses on non-allergen specific (anti-IgE, Chinese herbal formula, etc..) and allergen specific treatments for food allergy. The anti-IgE treatment is at the moment the only non-allergen-specific therapy, for which some data on a temporarily clinical efficacy have been provided. Regarding allergen-specific treatments, different protocols (oral, sublingual, subcutaneous and epicutaneous) with natural, heat treated or recombinant food allergens have been investigated. Although promising, results of the different clinical trials are heterogeneous. In particular data on long-term effects are lacking. At the moment food specific immunotherapy can be considered an experimental interventional strategy, limited to research, and not yet ready for routine use.

Flavonoids are secondary products of plants that include thousands of compounds classified in several classes. Preclinical studies mainly carried out in rodents suggest that they may have a role in the prevention of immunoglobulin E (IgE) synthesis and mast cell degranulation. Interestingly, using animal models with allergic asthma, it can be concluded that preventive treatment with particular flavonoid classes can reduce airway hyperresponsiveness, which is accompanied by lowered inflammatory mediators such as histamine and cytokines, and cell infiltration. In addition, there are some clinical trials in patients with allergic asthma or rhinitis that offer promising results with regard to these natural compounds. On the other hand, the dissection of cellular mechanisms that have interacted with flavonoids allow their effectiveness to be understood. Among these mechanisms there is a lower expression of IgE receptor or other membrane receptors, the modulation of calcium influx, and the downregulation of particular signaling pathways that eventually produces lower primary and secondary mediator release. In conclusion, some particular flavonoids could be an alternative or complementary therapy in the prevention and treatment of some allergies. Nevertheless, an increased number of clinical trials is required in order to confirm the therapeutic role of flavonoids.

The incidence of allergic diseases over the past few decades has shown a significant increase. Many epidemiological studies have shown that dietary factors are involved in the occurrence and development of allergic diseases, especially in early childhood. Hypotheses on the occurrence of a variety of allergic diseases (immunological mechanism) have provided a theoretical basis for dietary interventions for allergic diseases. However, currently, there are still inconsistencies among results of randomized controlled trials (RCTs). Epidemiological and immunological studies have been inconsistent, and in some cases, the results even directly contradict each other. In certain populations, dietary interventions have shown promising signs. Due to the complexity of the pathogenesis of allergic diseases, the issue of whether dietary interventions can prevent the development and progression of allergic disease requires collaborative work among clinicians, epidemiologists, immunologists, and geneticists. Ideally, this will identify population subgroups that would benefit the most from dietary intervention. The individuals in those populations could then be screened. These results may facilitate the development of individualized dietary interventions.

There are a number of atopic conditions that involve mast cells ranging from common allergies to arthritis and chronic pelvic pain syndrome. In addition to the well known allergic triggers, many food substances, drugs, as well as physical and mental stressful conditions could trigger mast cell activation in the absence of any allergic diathesis. The chronicity and morbidity of these conditions and the concern for the “adverse side effects” of the available therapeutic agents has prompted the widespread use of complementary and alternative medicines (CAM). One of the most common CAM interventions in the treatment of allergies is the use of dietary supplements that may contain specific compounds such as chondroitin sulfate, bioflavonoids or various herb extracts including Forsythia, Gingko, and Echinacea. The basis of such use has evolved from clinical anecdotal observations over time, to a growing number of in vitro and some in vivo studies that support the use of some of these compounds, especially select flavonoids.

Asthma is a chronic inflammatory disorder of the airways. The inflammatory response in asthma is heterogeneous. Allergen specific responses lead to activation of the acquired immune system, via a predominantly IL-5 mediated, eosinophilic pathway. Stimuli such as viruses and bacteria activate the innate immune system, via a predominantly IL-8 mediated, neutrophilic pathway. Asthma has also been demonstrated to involve a systemic inflammatory component. Glucocorticoids are the predominant pharmacological treatment used to control inflammation in asthma. However, compliance with medications can be compromised due to patient concerns about side effects. Hence dietary interventions that target the inflammatory response in asthma have great potential. Various aspects of dietary intake are known to modulate inflammation. Saturated fatty acids can induce an inflammatory response via activation of pattern recognition receptors. Omega-3 fatty acids can be anti-inflammatory, via mechanisms such as modification of eicosanoid production. Antioxidants can have anti-inflammatory effects as they scavenge free radicals, preventing activation of transcription factors including NF-κB. Chronic excess energy intake can lead to obesity, which augments inflammation due to the release of inflammatory mediators by adipose tissue. Here we review the role of these dietary components in asthma.