Inflammation & Allergy-Drug Targets (Discontinued) - Volume 5, Issue 1, 2006

Type 1 allergic diseases (allergic rhinitis or hay fever, rhinoconjunctivitis, allergic asthma and allergic dermatitis) are a global health problem and are the most common cause of chronic ill health in the western societies. These allergic diseases have increased in prevalence during the past three decades especially in western countries and an upward trend has been forecasted. Current commonly used treatments focus on relief of the clinical symptoms rather than underlying immune mechanisms. Antihistamine and topical corticosteroids are commonly used drugs to relieve symptoms or to alleviate allergic inflammation respectively. Development of cure or vaccine for atopic allergic diseases has not advanced significantly since 1911. Specific immunotherapy remains the only causative approach towards the treatment of such allergic diseases. Conventional immunotherapy involves administration of natural allergen extracts containing mixture of undefined components with potential to induce life-threatening anaphylactic response and new IgE reactivities. Recent advances in molecular biology have led to exponential increase in our understanding of molecular mechanisms involved in manifestation of type 1 allergy symptoms. In addition, molecular approaches have provided tools to resolve structural features of allergen molecules and develop novel therapeutic vaccines for improved and safer form of specific immunotherapy. Moreover, recombinant allergens offer unique possibility for accurate diagnosis and design of patient tailored immunotherapy. Recent clinical trials with engineered birch pollen allergen have demonstrated efficacy of this approach. In this issue, leading researchers in the field of allergy review emerging therapeutic approaches for treatment of allergic diseases. Various strategies and approaches covered include, cellular and immunological mechanisms of immunotherapy, current strategies for genetic modification of allergens, DNA vaccines, anti-IgE therapy, non-injection routes of vaccine delivery, immunotherapy for food allergies, production systems for recombinant allergens and immuno-informatic tools for designing allergy vaccines. Hopefully, this Hot topic issue will provide the readers with emerging perspectives on immunotherapy of type 1 allergic diseases.

Molecular cloning and recombinant production of allergens offered new perspectives for the increasing problem of allergies. A variety of preparations are being developed aiming to increase safety and improve efficacy of specific immunotherapy. Recombinant-based approaches are mostly focused on genetic modification of allergens to produce molecules with reduced allergenic activity and conserved antigenicity, i.e. hypoallergens. Studies dealing with genetic modifications of allergen genes reported the production of site-directed mutants, deletion mutants, allergen fragments and oligomers, and allergen chimeras. An alternative to genetic engineering is the chemical modification of pure recombinant allergens. It has been shown that allergens modified with immunostimulatory DNA sequences (allergen-ISS conjugates), which masks IgE epitopes and adds a desirable Th1-inducing character to the allergen molecule. Other chemical modifications include oligomerization by aldehydes (allergoids) and maleylation, which seems to target allergens to paarticular antigen presenting cells. Several of these modified allergen preparations have been already evaluated for their safety in clinical provocation studies. So far, clinical trials showed the efficacy and safety of immunotherapy with an Amb a 1-ISS conjugate for ragweed pollen-allergic patients. In addition, a preparation consisting of hypoallergenic fragments of Bet v 1 was evaluated for immunotherapy of birch pollen-allergic patients. In parallel, several animal studies have now demonstrated the potential of genetic immunization for allergy treatment in the future.

Allergy is an immunological disorder, which is driven by uncontrolled allergen-activated T cell subsets, leading to immediate type hypersensitivity against otherwise harmless environmental allergens. These allergens are tolerated by healthy individuals as well as by patients, who successfully underwent allergen-specific immunotherapy (SIT). The successful SIT is characterized by the induction of T cell unresponsiveness against the given allergen. Regulatory T cells (Tregs), which are installed or enhanced by SIT and govern the activity of potentially pro-allergic effector T cells, mediate this unresponsiveness. The current article reviews the mechanisms underlying the balance of these cell populations along with suppressive mechanisms of SIT, which may serve as future drug targets.

The past two decades have witnessed an increase in prevalence of food allergy that has been matched with a tremendous progress in research that has led to better understanding of pathogenic mechanisms and development of novel therapies for food allergy. Establishment of murine models of peanut and cow's milk allergy has been extremely useful in investigating food allergy treatments. Diverse strategies for prevention and treatment of established food allergy are being evaluated. Anti-IgE antibody therapy, Chinese herbal medicines, and killed bacteria expressing modified major peanut allergens represent the most promising approaches that will lead to development of therapy for patients for whom no effective treatment is currently available.

Microarrays and other large-scale screening technologies produce quantities of increasingly complex allergy data. These data link molecular and clinical measurements and observations and provide fertile ground for improving our understanding of the processes involved in allergic reactions. Information technology is employed in gathering, storage, retrieval and analysis of these data. The increasing proportion of allergy data are generated from genomics and proteomics approaches. The major acivity focuses on characterization of allergens including IgE reactivity, structural properties, and mapping of IgE and T-cell epitopes. Because of the complexity of allergy data, their utilization requires bioinformatics approaches. Allergen data are stored in the general and specialist databases. At least a dosen of important allergen databases and data repositories have been developed to date. These data are analysed using general and specialist bioinformatics tools. The major applications of bioinformatics include support for allergen characterization, assessment of allergenicity, and identification of allergic cross-reactivity. These applications in turn support the development of vaccines and therapies for allergic disease. In this article we review allergen databases and tools for the analysis of allergens, and discuss the new directions in the field supported by large scale screening involving genomics, proteomics, and bioinformatics support.

Allergen specific immunotherapy, together with drugs and allergen avoidance, is a cornerstone in the management of respiratory allergy. The non-injection or local routes were developed with the main goal of improving the safety and minimizing the risk of those side effects, which can accompany the injection route. The pure oral route and the bronchial route showed, in the clinical trials, only a marginal efficacy with not negligible side effects. Therefore, these routes are no longer recommended for clinical use. The nasal route proved effective and safe, but its efficacy is strictly limited to the nose. Moreover, the practical problems with administration have made the use of nasal immunotherapy progressively declining. The efficacy of the sublingual route is confirmed by numerous controlled trials, and a meta analysis (in allergic rhinitis). The safety profile, as derived from clinical trials and post marketing surveillance studies, is satisfactory, with mild gastrointestinal complaints being the more frequent side effect reported. Recent studies have also demonstrated that SLIT has a long-lasting effect and a preventive effect on the onset of new skin sensitizations, and interesting data on adherence and mechanisms of action have become recently available. Based on these experimental data, SLIT is now officially accepted as a viable alternative to the subcutaneous route in adults and children. Several points still need to be elucidated, including: mechanisms of action, optimal dosages, and indications in pediatric patients.

Allergen immunotherapy of future is likely to be based on allergy vaccines that contain engineered allergens modified to abolish or substantially reduce their IgE-binding activity in order to remove the risk of unwanted anaphylactic responses. The development of efficient systems for the production of recombinant allergens in sufficient quantities is requirement for establishing use of engineered allergens as components of allergy vaccines. This review outlines relative advantages and disadvantages of various heterologous systems for production of recombinant allergens. Microbial systems are most convenient and cost effective platforms for the production of recombinant allergens. However, lack of post-translational processing implies that some allergens have to be expressed in eukaryotic systems for proper folding and post-translational modifications such as glycosylation. Yeast systems can yield high levels of recombinant allergens but often are associated with hyper- glycosylation problems. Mammalian cell culture systems offer suitable post -translational modifications but are nearly hundred fold more expensive than microbial systems. The use of plants as bio-factories for production of recombinant allergens is emerging as a very attractive option as plants-based production system offer several advantages over other expression systems such as post translational processing of proteins, low production costs, scale up ability and enhanced safety due to absence of animal or human pathogens.

Patients with mastocytosis have symptoms related to the tissue response to the release of mediators from mast cells (MC), local mast cell burden or associated non-mast cell hematological disorders. MC contain an array of biologically active mediators in their granules, which are preformed and stored. MC are also able to produce newly generated membrane-derived lipid mediators and are a source of multifunctional cytokines. Mediator-related symptoms can include pruritus, flushing, syncope, gastric distress, nausea and vomiting, diarrhea, bone pain and neuropsychiatric disturbances; these symptoms are variably controlled by adequate medications. Management of patients within all categories of mastocytosis includes: a) a careful counseling of patients (parents in pediatric cases) and care providers, b) avoidance of factors triggering acute mediator release, c) treatment of acute and chronic MC-mediator symptoms and, if indicated, d) an attempt for cytoreduction and treatment of organ infiltration by mast cells.