Current Drug Targets - Inflammation & Allergy - Volume 4, Issue 5, 2005

The incidence and prevalence of allergic diseases such as asthma, has increased dramatically over the last decades with major socioeconomic consequences. Although enormous efforts have been undertaken to understand the underlying pathomechanism in more detail, asthma is still one of the diseases for which only limited curative therapies are available. As a consequence, identification of appropriate recommendations for prophylaxis and risk management is important. This issue aims to provide an overview on the current state of therapy of asthma and new developments for the prevention of this disease. The first article provides a conceptional point of view on how allergen exposure during early childhood including the prenatal period might trigger the onset of allergy and asthma later in life (Herz et al.). The paper of Strid and Strobel deals with processes of primary sensitization to allergens and provides recent information supporting that epidermal allergen exposure may contribute to systemic allergic sensitization. An overview on the pharmaceutical treatment of asthma in children is given in the article by Carlsen, addressing non-pharmacological and pharmacological aspects of treating allergic airways. Over the last years, a new promising therapeutic agent to treat asthma has been developed. It is well established that there is a close association between IgE antibodies and asthma symptoms. IgE exert their pro-inflammatory effects by binding to receptors expressed on a variety of cell types including mast cells, basophils and antigen presenting cells. Removing IgE from the continuing cycle of allergic inflammation can be considered as an unique anti-inflammatory mode of action of humanized anti-IgE antibodies. Hamelmann et al. summarize the current facts about action, safety and efficacy of anti-IgE therapy. The second part of the issue is targeted on discussions of new developments for therapy and prevention of asthma, starting with two articles providing further insights into antigen processing, presentation and T-cell tolerance induction in the intestinal mucosa. Any antigen/allergen gets in contact with the body defense system through the mucosal immune system present along the respiratory, gastrointestinal and genitourinary tract. Recent data indicate that these first steps are determinative of the later onset of diseases or the development of tolerance. Doganci et al. describe the processes of mucosal immune regulation and the role of transcription factors as possible new therapeutic targets. The article by Wiedermann assesses the potential benefit of recombinant allergens or allergen constructs in combination with mucosal antigen delivery systems, such as lactic acid bacteria in the prophylaxis and therapy of allergy. Another promising approach to induce an anti-allergic immune response in the body is the use of bacterial DNA. The DNA vaccine technique has opened a vast scope of novel approaches for protective and therapeutic treatments of allergies. The article by Weiss et al. presents an overview on the current status of allergy DNA vaccines and present advances in the design of vaccine constructs. The issue is closed by an overview from Björksten on the evidence of probiotics in prevention of allergy and asthma. The intestinal flora is likely to be particularly important in orchestrating host immune responses and thereby affecting the risks of allergy. This has led to several studies of probiotics as therapeutic modulators of inflammatory responses.

The prevalence of asthma and related allergic disorders has increased considerably over the last several decades. Since the genetic makeup of humans has not changed during this time, it is likely that environmental factors may have influenced this rise in allergic diseases. Furthermore, there is increasing evidence to suggest that many aspects of health and disease are determined during the perinatal period and that alterations in lifestyle and diet later in life are secondary to the effects of the immunological programming that occurs during pregnancy and early infancy. This is directly applicable to allergic disease where immune responses at birth implicate intrauterine exposure as a primary sensitization event. Moreover, infants who experience allergy early in life already have an altered immune response at birth and most therapeutic approaches focus on altering the expression of the disease. Therefore, a better understanding of the underlying mechanisms that shapes the immune response towards allergy development is fundamental to strengthening "natural" protective stimuli or developing preventative rather than treatment therapies.

Most allergic, atopic and hypersensitive reactions are associated with Th2-biased immune responses and allergen-specific IgE antibodies. Pathological allergic disorders are on an alarming increase in the industrialized world. Understanding the mechanism of primary sensitization to allergens is important in elucidating the pathogenesis of these diseases and for possibly preventing their development. In this article, we review recent information supporting that epidermal allergen exposure may contribute to systemic allergic diseases and that atopy may be secondary to skin barrier dysfunction in some dermatoses. The skin is an active immunological organ, which functions as a primary defence and biosensor to the external environment. The critical permeability barrier function is mediated by the outmost layer of the epidermis, the stratum corneum. Perturbation of the stratum corneum initiates a chain of event, which activates homeostatic responses in the underlying epidermis. Repeated barrier-disruption, whether environmentally or genetically determined, may however stimulate signaling cascades that lead to inflammation and epidermal hyperplasia. Skin barrier dysfunction may also allow entry of allergens, which can lead to primary systemic sensitization. The altered epidermal microenvironment in barrier-disrupted skin appears to be particularly well suited for the induction of potent Th2-type responses with production of allergen-specific IgE. Epidermal exposure to food antigens can prevent the normal induction of oral tolerance and also lead to airway eosinophilia following inhalation. Exposure to allergens on barrier-disrupted skin may as such serve as a natural sensitization pathway for food allergy and respiratory allergic disease.

The present review article gives an overview of the present treatment modalities of asthma during childhood and discusses the existing controversies in asthma treatment. Present guidelines of asthma treatment concentrate on treatment for adults and only marginally concern treatment of childhood asthma. The few exceptions are the British Scottish guidelines and the Nordic guidelines, which have separate paragraphs on paediatric asthma management. The main controversy in paediatric asthma treatment is that how early (in age) and how soon (after diagnosis of asthma has been established) should inhaled steroids be instituted. Does treatment with early inhaled steroids influence lung development? Also possible side effects of inhaled steroids as possible impact upon growth and effect upon the hypothalamic adrenal axis are discussed. What is the place of leukotriene antagonists in childhood asthma treatment? Other issues discussed are prevention of asthma (primary, secondary and tertiary) in relationship to treatment of asthma. Primary prevention regards preventive measures to be taken to prevent initial allergic diseases; secondary prevention aims at preventing development of further allergic disease after the initial allergic disorder, as preventing debut of asthma after atopic eczema. Tertiary prevention aims at reducing already existing allergic illness and preventing further progression. For asthma, tertiary prevention regards treatment. During later years, there has been a focus on the respiratory tract as a continuum, and how allergic rhinitis and asthma should be treated when they are coexistent. Treating exercise induced asthma optimally is regarded as an important aim in the general treatment of asthma in childhood. Particularly in childhood asthma, compliance (concordance) with treatment is an important issue. Also some controversial aspects of acute asthma treatment in young children are discussed.

Despite the advanced and increasing understanding of the pathophysiology of asthma and other allergic diseases, current treatment remains unspecific and targets late events within the allergic cascade. Therefore, a novel and promising approach to treat allergic asthma is antagonizing IgE by anti-IgE antibodies. This review analyzes the role of IgE for the pathology of asthma, summarize the current data about action, safety and efficacy of anti-IgE therapy, and tries to give a rational approach for future indications and directions of treatment with anti-IgE antibodies.

Much progress has been recently made with regard to our understanding of the mucosal immune system in health and disease. In particular, it has been shown that uncontrolled mucosal immune responses driven by lymphocytes or non-lymphoid cells may lead to immunological diseases such as allergy, hypersensitivity and inflammation. Thus, a more detailed understanding of mucosal immune regulation and decision making at mucosal surfaces is essential for a better understanding of mucosal immune responses in health and disease. Antigen presenting cells and T lymphocytes play a key role in controlling mucosal immune responses. To deal with this key task, T helper cells differentiate into functionally distinct subsets: TH1 (CD4+ T Helper cells), TH2, TH3, Tr1, and CD4+CD25+ T (Treg) cells. This review summarizes the role of antigen presenting cells, eosinophils, mast cells and T-cell subsets in the pathogenesis of allergic inflammation and intestinal inflammation. Furthermore, we discuss novel immunological treatment modalities for allergic inflammation (e.g. allergic asthma) and chronic intestinal inflammation (e.g. inflammatory bowel diseases (IBD)) such as the control of the expression of transcription factors to redirect pathological immune responses.

The mucosal immune system, present along the respiratory, gastrointestinal and genitourinary tract, has to discriminate between harmful pathogens and innocuous antigens, such as food, airborne antigens or the commensal bacterial flora. Therefore the mucosal immune system has acquired two opposing immunological functions, i.e. the induction of immunity and defence of mucosal pathogens, and the induction and maintenance of tolerance to environmental antigens and bacterial flora. As described for autoimmunity a breakdown or failure of tolerance induction is believed to lead also to allergies and food enteropathies. Based on the physiological role to prevent hypersensitivity reactions, tolerance induction via the mucosa has been proposed as a treatment strategy against inflammatory diseases, such as allergies. The aim of our research is to develop mucosal allergy vaccines based on the induction of mucosal tolerance and/or the induction of counter-regulatory immune responses with or without the use of certain mucosal antigen delivery systems, such as lactic acid bacteria. The use of recombinant allergens instead of allergen extracts with varying allergen content and composition may be essential for improvement of the treatment efficacy. In the present review we give examples of different animal models of type I allergy/asthma. Using these models we demonstrate that recombinant allergens or hypoallergenic variants thereof can be successfully used to induce mucosal tolerance in a prophylactic as well as a therapeutic treatment regime. That the concept of mucosal tolerance induction/mucosal vaccine delivery may in principal also function in humans is supported by recent clinical trials with locally (sublingual) applied immunotherapy.

The DNA vaccine revolution has opened a vast scope of novel approaches for protective and therapeutic treatments of type I allergy. This review gives an overview on the current status of allergy DNA vaccines and presents advances in the design of vaccine constructs. An immense number of concurring studies have proven the stimulation of Th1 cells and the induction of a balanced Th1/Th2 cytokine milieu as the fundamental mechanisms underlying the anti-allergic effects of DNA vaccines. Basic vaccine formulations thus can be optimized by improving the cellular immunogenicity via coadministration of cytokines, co-expression or co-application of immunostimulatory DNA sequences or adapting the codon usage. The latter is a frequent and major reason for impaired vaccine expression (e.g. translation of plant allergen genes in mammal cells). Because of unwanted side effects during conventional specific immunotherapy with allergen extracts, safety is increasingly demanded for both, protein and DNA vaccines for allergy treatment. We discuss the creation of hypoallergenic DNA vaccines based on deliberate allergen gene fragmentation, the use of mutations and the routine production of hypoallergenic DNA vaccines by forced ubiquitination. Furthermore, allergen-expressing DNA replicon vaccines are introduced, which enable a drastic reduction of the vaccine dose without loss of antiallergic efficacy. Finally, the development of DNA multi vaccines and fusion vaccines for protective and therapeutic applications against certain groups of allergens is addressed.

Previous research into the causes of allergic diseases was mostly focussed on potential risk factors in the environment, with little success, however. Over the past 10 years, focus has therefore more been directed against protective factors that could enhance the development of tolerance to allergens which were previously encountered early in life, but are now lost in modern affluent societies. In particular, the role of childhood infections has been discussed, but so far these studies have not been conclusive. Recent epidemiological studies and experimental research suggest that the microbial environment and exposure to microbial products in infancy modifies immune responses and enhances the development of tolerance to ubiquitous allergens. The intestinal microflora may play a particular role in this respect, as it is the major external driving force in the maturation of the immune system after birth and animal experiments have shown it to be a prerequisite for normal development of oral tolerance. The composition of the microflora differs between healthy and allergic infants and in countries with a high and low prevalence of allergies. These differences are apparent within the first week of life, or even in the maternal vaginal flora during pregnancy and thus precede clinical symptoms. The use of live microorganisms that might be beneficial to health has a long tradition and the safety is well documented. Prospective intervention studies, in which the gut flora was modified from birth have yielded encouraging results and may suggest a new mode of primary prevention of allergy in the future.