The evolution of allergen and non-specific immunotherapy: past achievements,current applications and future outlook

Recent epidemiological studies estimated that more than 30% of European suffer from allergic rhinitis or conjunctivitis, while up to 20% suffer from asthma and 15% from allergic skin conditions, while for many other regions the prevalence is increasing. Allergen immunotherapy represents the only available treatment that can modify the allergic disease process, and thus is worth considering as a treatment in affected individuals. A beneficial effect of allergen immunotherapy has been shown in both adults and children affected by allergic rhinitis, allergic conjunctivitis, allergic asthma and hymenoptera venom allergy. The present study represents an overview on allergen immunotherapy, focusing on the principal aspects of the use of immunotherapy in the past, its recent clinical applications and future outlook.     

Aspirin-exacerbated respiratory disease: characteristics and management strategies

Aspirin-exacerbated respiratory disease is a clinical entity comprising chronic rhinosinusitis with nasal polyposis, asthma and intolerance to COX-1 inhibiting drugs. The pathogenesis is not completely understood at this point, but abnormal arachidonic acid metabolism is a key feature in this syndrome. The diagnosis is confirmed only by direct drug challenge. Aspirin desensitization followed by daily aspirin therapy is a useful treatment option in these patients. In this review article are discussed the important characteristics and treatment of aspirin-exacerbated respiratory disease.     

Asthma prevalence and exacerbations in children: is there an association with childhood vaccination?

Infections and vaccinations may have a potential role in the normal maturation of the immune system, in the development and balance of regulatory pathways, and in the development and exacerbations of asthma. Asthma exacerbations often result from respiratory viral infections, and, while vaccination towards common viral infections may reduce the occurrence of such exacerbations, there has been concern that vaccinations can increase the risk of asthma. Current studies show that childhood vaccines, including inactivated influenza vaccine, are generally safe. However, there is some concern regarding possible exacerbations in infants or children with frequent wheezing or persistent asthma who are given live-attenuated influenza vaccination. Although severe allergic adverse events attributable to vaccination are extremely rare, all serious allergic reactions should be further assessed to detect the likely causative vaccine component, such as egg protein or gelatin. The risks of not vaccinating children far outweigh the risks of allergy and asthma exacerbations. Therefore, childhood vaccination should remain an essential part of child health programs and should not be withheld, even from children with asthma or those predisposed to allergy.     

Allergen immunotherapy: immunomodulatory treatment for allergic diseases

Allergen immunotherapy is currently the only immune-modifying treatment for allergic disease. At the present time it is indicated for the treatment of allergic rhinitis, asthma and venom hypersensitivity. Efficacy appears to be dose dependent, and the immunological mechanisms responsible for the clinical efficacy of immunotherapy are still being elucidated. Immunological changes associated with immunotherapy include induction of T regulatory cells, increase in allergen-specific immunoglobulin G4, increase in interleukin-10 production and downregulation of the T helper 2 response. The disadvantages of allergen immunotherapy include risk of adverse events and patient time and inconvenience. Risks of immunotherapy range from large local reactions to mild systemic reactions, such as rhinitis. Fatalities from immunotherapy injections have been reported at a rate of approximately one fatality per 2.5 million injections. Conventional subcutaneous immunotherapy build-up schedules involve administration of a single-dose increase each visit and it may take several months before a patient achieves the therapeutic maintenance dose. Accelerated schedules, such as rush and cluster, will allow the patient to achieve the maintenance dose sooner but there may be a greater risk of a systemic reaction. The current focus of immunotherapy research is to develop safer and more effective vaccines. Another approach to enhancing immunotherapy safety is through an alternative delivery method. Sublingual immunotherapy is clearly safer than subcutaneous immunotherapy, but further investigation is needed to determine optimal dose and appropriate patient selection.     

The association between early life antibiotic use and allergic disease in young children: recent insights and their implications

ABSTRACT

Introduction: Greater prescribing of antibiotics to infants has coincided with an epidemic of allergic disease. Through meta-analytic synthesis, accumulating evidence from prospective or database cohorts suggests a link between infant antibiotic treatment and the development of atopy. Stronger associations seen with multiple course and broad-spectrum antibiotic treatment add to biological plausibility. A major bias, confounding by indication, has been addressed in studies on antibiotic treatment of conditions which do not precede allergic disease.

Areas covered: Our review provides an up-to-date synthesis of the current literature on associations between infant antibiotic exposure and future allergic disease. We discuss methods that assist in reducing study bias and look at new insights from studies of the infant gut microbiome.

Expert commentary: Large-scale profiling of the gut microbiome provides a new tool for disentangling biases found in observational studies of infant antibiotic use. To date, microbial dysbiosis of the infant gut has been reported to predict allergic disease independent of antibiotic exposure up to 3 months after birth. However, these studies have not accounted for antibiotic treatment in later infancy. Continued study of the infant gut microbiome, mycobiome, or resistome will provide a closer link to antibiotic treatment or refute it as a cause of allergic disease.     

Maternal respiratory sensitization and gestational allergen exposure does not affect subsequent pup responses to homologous or heterologous allergen

Evidence suggests that the predisposition towards atopy begins early in life. Maternal allergy has been associated with an increased risk of the development of allergic disease in offspring. Some studies suggest that the development of childhood atopy may also be influenced by prenatal allergen exposure. In this study, a respiratory allergen exposure model was used to determine the impact of maternal sensitization (with or without additional exposures during pregnancy) on subsequent pup responses to homologous or heterologous allergen. Female BALB/c mice received two intratracheal aspiration (IA) exposures to Metarhizium anisopliae crude antigen (MACA) or Hank’s buffered salt solution (HBSS) prior to breeding. Some mice also received three additional exposures during pregnancy. Control mothers did not receive treatment. Young adult offspring received three IA exposures to MACA, house dust mite extract (HDM) or HBSS. Offspring sensitized as young adults to either HDM or MACA developed an airway inflammatory response, including increased bronchoalveolar lavage fluid lactate dehydrogenase activity, total protein and total and differential cell counts compared to offspring exposed to HBSS. Increased airway responsiveness to methacholine was observed in pups treated with HDM but not with MACA. Maternal sensitization status (with or without gestational allergen exposure) had no effect on offspring response to either MACA or HDM. In conclusion, this study demonstrates that IA administration of MACA or HDM extract to young adult BALB/c mice induces the development of an inflammatory airway response. In contrast to previous reports, neither maternal sensitization nor gestational allergen exposure could be demonstrated to have a clear effect on offspring sensitization. This discrepancy may be a function of the respiratory sensitization and exposure protocol used in this study, which mimics natural sensitization more closely than do parenteral routes of exposure.     

IL4 and IL-17A provide a Th2/Th17-polarized inflammatory milieu in favor of TGF-β1 to induce bronchial epithelial-mesenchymal transition (EMT)

Severe asthma is a chronic airway disease characterized by the Th2/Th17-polarized inflammation along with permanent airway remodeling. Despite past extensive studies, the exact role for Th2 and Th17 cytokines in asthmatic pathoetiology, particularly in the pathogenesis of bronchial epithelial-mesenchymal transition (EMT), is yet to be fully addressed. We herein conducted studies in 16-HBE cells and demonstrated that Th2-derived IL-4 and Th17-derived IL-17A provide a chronic inflammatory milieu that favors TGF-β₁ to induce bronchial EMT. A synergic action was noted between TGF-β₁, IL-4 and IL-17A in terms of induction of EMT. IL-4 and IL-17A synergized with TGF-β₁ to induce epithelial cells re-entering cell cycle, and to promote epithelial to mesenchymal morphological transistion, and by which they enhanced the capacity of TGF-β₁ to suppress E-cadherin expression, and to induce a-SMA expression in epithelial cells. Mechanistic studies revealed that this synergic action is coordinated by the regulation of ERK1/2 activity. Our results not only provide a novel insight into the understanding of the mechanisms underlying airway remodeling in asthmatic condition, but also have the potential for developing more effective therapeutic strategies against severe asthmatics in clinical settings.     

Seasonal Specificity of Seasonal Allergens and Validation of the ARIA Classification in Korea

Purpose

In Korea, tree pollens are known to be prevalent in spring, grass pollens in summer and weed pollens in autumn. However, few studies have revealed their seasonal specificity for allergic rhinitis symptoms. An ARIA (Allergic Rhinitis and its Impact on Asthma) classification of allergic rhinitis was recently introduced and its clinical validation has not been well proved. The aim of this study was to evaluate the seasonal specificity of seasonal allergens and to validate the ARIA classification with the conventional seasonal and perennial allergic rhinitis (SAR/PAR) classification.

Methods

Two hundred twenty six patients with allergic rhinitis were included in this study. The patients were classified according to the sensitized allergens and the ARIA classifications. A questionnaire survey was performed and the data on the seasonal symptom score, the severity of symptoms and the SNOT (sinonasal outcome test)-20 score was obtained and the data was analyzed and compared between the conventional SAR/PAR classification and the ARIA classification.

Results

Seasonal pollens (tree, grass, weed) were not specific to the pollen peak season and the patients'' symptoms were severe during spring and autumn regardless of the offending pollens. More than 60% of the patients with SAR showed persistent symptoms and 33% of the patients with perennial allergic rhinitis (PAR) had intermittent symptoms, showing the lack of association between the SAR/PAR/PAR+SAR classification and the ARIA classification. The ARIA classification showed better association not only with the symptomatic score, but also with the SNOT-20 score, which showed better validity than the conventional SAR/PAR classifications.

Conclusions

Seasonal pollens were not specific to their season of prevalence in terms of the severity of symptoms, and the ARIA classification showed better representation of allergic symptoms and quality of life (SNOT-20 score) than did the SAR/PAR classification.     

Effects of Interleukin-9 Blockade on Chronic Airway Inflammation in Murine Asthma Models

Purpose

Asthma is a chronic inflammatory disease of the airways associated with structural changes and airway remodeling. Interleukin (IL)-9 has pleiotropic effects on both inflammatory cells and airway structural cells, which are involved in asthma pathogenesis. We evaluated the effects of IL-9 blockade on chronic airway inflammation.

Methods

Acute airway inflammation was induced in Balb/c mice using aerosolized ovalbumin (OVA), whereas chronic asthma was induced by OVA exposure for 5 weeks with anti-IL-9 or isotype-matched antibody (Ab) treatment during the OVA challenge. Inflammatory cells in bronchoalveolar lavage fluid (BALF) were counted and lung tissues were stained to detect cellular infiltration, mucus deposition, and collagen accumulation. The levels of interferon (IFN)-γ, IL-4, IL-5, IL-9, IL-17, and immunoglobulin E (IgE) in BALF were measured using enzyme linked immunosorbent assays, and profiles of inflammatory cells and subsets of T helper (Th) cells were analyzed using flow cytometry.

Results

IL-9, IL-17, and IFN-γ levels were significantly increased in the chronic group compared to the acute asthma group. However, the number of IL-9-positive cells was not affected, with a decrease in Th17 cells in OVA-challenged caspase-1 knockout mice. Numbers of eosinophils, neutrophils, B cells, mast cells, and Th17 cells decreased after administration of anti-IL-9 Ab. Total IgE, IL-5, IL-9, and IL-17 levels were also lower in the anti-IL-9 group.

Conclusions

Our results suggest that anti-IL-9 Ab treatment inhibits pulmonary infiltration of inflammatory cells and cytokine production, especially IL-17. These results provide a basis for the use of an anti-IL-9 Ab to combat IL-17-mediated airway inflammation.     

Immunopathogenesis of Allergic Asthma: More Than the Th2 Hypothesis

Asthma is a chronic obstructive airway disease that involves inflammation of the respiratory tract. Biological contaminants in indoor air can induce innate and adaptive immune responses and inflammation, resulting in asthma pathology. Epidemiologic surveys indicate that the prevalence of asthma is higher in developed countries than in developing countries. The prevalence of asthma in Korea has increased during the last several decades. This increase may be related to changes in housing styles, which result in increased levels of indoor biological contaminants, such as house dust mite-derived allergens and bacterial products such as endotoxin. Different types of inflammation are observed in those suffering from mild-to-moderate asthma compared to those experiencing severe asthma, involving markedly different patterns of inflammatory cells and mediators. As described in this review, these inflammatory profiles are largely determined by the involvement of different T helper cell subsets, which orchestrate the recruitment and activation of inflammatory cells. It is becoming clear that T helper cells other than Th2 cells are involved in the pathogenesis of asthma; specifically, both Th1 and Th17 cells are crucial for the development of neutrophilic inflammation in the airways, which is related to corticosteroid resistance. Development of therapeutics that suppress these immune and inflammatory cells may provide useful asthma treatments in the future.