Inflammation & Allergy-Drug Targets (Discontinued) - Volume 5, Issue 4, 2006

Allergens are proteins capable of raising in predisposed (atopic) individuals an IgE-dependent type I hypersensitivity reaction, supporting allergic symptoms such as anaphylactic shock, asthma and rhinitis. Panallergens are evolutionarily conserved, ubiquitous components of several complex sources of allergens, which usually act as minor allergens, i.e., they do not react with the majority of sera from patients allergic to a given allergen source. However, their presence has important clinical implications in establishing the phenomenon of food-pollen cross-reactivity, in the interpretation of diagnostic tests and in the preparation of immunotherapy extracts. A T-lymphocyte component is necessary to support the panallergen-specific humoral IgE antibody response. While several excellent reviews are available regarding allergen cross-reactivity from the IgE-perspective, data on crossallergenicity from the T-lymphocyte standpoint are quite limited. Indeed, this is a crucial issue in the comprehension of polysensitization, since it is the initial exposure to conserved panallergens that may subsequently drive the allergic immune response towards major allergenic components, which at first proved non-sensitizing to a given patient, through a mechanism of intermolecular epitope spreading. Here, we will discuss data showing that a functionally relevant T-cell response to molecularly defined, conserved regions of panallergens can support cross-allergenicity in allergic patients. This subject is relevant to the comprehension of the natural history and to the clinical management of the majority of allergic patients, who suffer from multiple allergies.

The interest in regulatory T cells (Tregs) has been revived following the discovery of developing multiorgan autoimmune diseases as a result of depleting CD4+CD25+ T cells from mice. The importance of Tregs is being recognized in various clinical fields such as tumor and microbial immunities, transplantation and allergy. Prevalence of allergic diseases such as asthma, atopic dermatitis and rhinitis is significantly increasing worldwide. A better understanding of the mechanisms of T-cell regulation in allergic diseases may help in developing more effective therapeutic strategies. The well-known role of Tregs in preventing autoimmune diseases indicates that these important cells might be involved in prevention of allergy, and allergic diseases are associated with a low frequency and/or an impaired function of Tregs. Recent data show that natural CD4+CD25+ Tregs and interleukin (IL)-10-producing Tregs are normally able to suppress Th2 responses to allergens, while such suppression is diminished in allergic conditions. In this review, I summarize the role of Tregs in allergic diseases and discuss the possibility of manipulating these cells for treating allergic diseases.

Allergic bronchopulmonary aspergillosis (ABPA) is a frequent syndrome in patients with cystic fibrosis (CF) or asthma. Animal models revealed distinct roles for the chemokines CCL2, CCL3, CCL5, CCL6, CCL17 and CCL22 and their receptors in the pathogenesis of allergic aspergillosis. In humans, serum levels of the CCR4 ligand CCL17 identified ABPA in patients with CF or asthma, suggesting CCL17 as novel diagnostic marker and future therapeutical target in ABPA. This review illustrates the manifold role of chemokines in animal models of allergic aspergillosis and translates these findings to human lung diseases.

Adenoviruses (Ads) cause acute and persistent infections. The genome of Ads has five early transcription units that are the first viral genes expressed during an active infection. The Early Region 1A (E1A) gene of the adenovirus genome is crucial for adenovirus transformation of the host cell. Ads E1A block some aspects of the innate immune system to enable viruses to invade the host cell. E1A suppresses nitric oxide (NO) production through transcriptional control of the inducible NO synthase (iNOS) gene. This inhibition of NO production may enable the virus to persist in human tissue because NO is an antiviral effector of the innate immune system. E1A also blocks secretory leukoprotease inhibitor (SLPI) and elafin/skin-derived antileukoproteinase (SKALP) secretion by alveolar epithelial cells. Recent scientific evidence suggests that SLPI and elafin/SKALP have broad-spectrum antibiotic activities that include bactericidal and antifungal properties. The inhibition of inflammation by Ad early region proteins is complex, as certain early region proteins can promote as well as inhibit inflammation depending on the genetic context of the virus. E1A DNA and protein are frequently detected in the lungs of chronic obstructive pulmonary disease (COPD) patients and it is associated with an increased inflammatory response. E1A enhances intercellular adhesion molecule-1 and interleukin-8 mRNA expression with lipopolysaccharide stimulation. Understanding the roles of the Ad gene products in the induction and inhibition of innate inflammatory functions will help us to clarify the pathogenesis of the chronic respiratory illness including COPD.

Naturally occurring CD4+CD25+ regulatory T cells (Tregs) play a critical role in the control of periphery tolerance to self-antigens. Interestingly, they also control immune responses to allergens and transplant antigens. Recent studies in animal models have shown that adoptive transfer of CD4+CD25+ Tregs can prevent or even cure allergic and autoimmune diseases, and appear to induce transplantation tolerance. Thus, adoptive cell therapy using patient-specific CD4+CD25+ Tregs has been emerged as individualized medicine for the treatment of inflammatory disease including allergy, autoimmune disease and transplant rejection. Furthermore, strategies to activate and expand antigen-specific CD4+CD25+ Tregs in vivo using pharmacological agents may represent a novel avenue for drug development.

The last decades have shown an increasing incidence of allergic illnesses such as rhinoconjunctivitis, with a prevalence of 20-30% in some industrialised parts of the world. The only treatment that may change the natural course of allergic disease is allergen-specific immunotherapy (SIT), which has been shown to prevent the development of asthma in rhinitic patients and anaphylaxis in insect venom allergic patients. However, the risk-benefit ratio for subcutaneous immunotherapy has changed little from when it was first developed in 1911. Novel developments of adjuvants, and allergens as well as methods of administration, now offer improvements in both the efficacy and safety of SIT. This review describes and discusses these new developments in the context of the many recent advances in our understanding of the mechanisms by which immunotherapy appears to act.

The role of interferon-γ(IFN-γ) in asthma is controversial. However, this cytokine has been proposed to play a role both in acute severe asthma and chronic stable asthma. We have shown that in a chronic low-level challenge model of allergic asthma in mice, which replicates characteristic features of airway inflammation and remodelling, the mechanisms of airway hyperreactivity (AHR) are markedly different to those in short-term high-level challenge models. Notably, AHR is independent of various Th2 cytokines and their signalling pathways. However, administration of a neutralising antibody to IFN-γ suppresses AHR. More recently, we have found that following chronic allergen challenge, but not acute challenge, IFN-γ -producing CD4+ T cells are demonstrable in peribronchial lymph nodes, both in wild-type mice and in STAT6 / mice. Treatment with anti-IFN-γ decreases the number of IFN-γ-producing CD4+ T cells in both wild-type and gene-targeted mice, providing a possible explanation for the ability of anti-IFN-γ to inhibit AHR in the setting of chronic challenge. These data further strengthen the notion that the pathogenesis of the lesions of asthma, and especially of AHR, involves a co-operative interaction between Th2 and Th1 cytokines. This may be particularly relevant to acute exacerbations of asthma, in which setting there may be justification for therapeutic inhibition of IFN-γ.

Hyaluronan (HA) is a variable length, long-chain polysaccharide containing repeating disaccharide units of glucuronic acid and n-acetylglucosamine. Long considered a relatively inert component of the extracellular matrix, HA is now coming under scrutiny as a potential therapeutic agent for a number of different diseases, based on its recently discovered role in modulating inflammation. The effect of HA on the inflammatory response appears to be related to its molecular size, with larger polysaccharide chains having anti-inflammatory activity and smaller ones having proinflammatory properties. This dichotomous behavior presents a challenge to investigators seeking to harness the beneficial effects of this molecule. Rapid breakdown of therapeutically administered HA into smaller fragments may conceivably cause further injury to diseased tissues. With this limitation in mind, the authors discuss their own use of HA to treat experimentally induced lung disease, then suggest possible ways of maximizing the therapeutic potential of this molecule.

Allergic asthma, rhinitis, rhinoconjunctivitis and atopic dermatitis are the most common allergic disorders that are caused by the house dust mite (HDM). Beside pyroglyphid mites, the clinical importance of non-pyroglyphid mites has also been increasingly recognized in the recent years. Blomia tropicalis is the most important and ubiquitous mite species in tropical and subtropical regions of the world. Well-standardized and characterized allergens are essential for the diagnosis and therapy of house dust mite allergy as well as for the study of the pathophysiology of allergic disease. With the introduction of molecular biology, a number of house dust mite allergens were obtained by cloning the genes encoding the allergens. To date, seven allergens from Blomia tropicalis have been identified and characterized. Among these, Blo t 5, with unknown function, is the major allergen of Blomia tropicalis, with up to 92% of allergic patients sensitized to it. Native Blo t 5 has been purified and shown to consist of multiple isoforms. With advancing knowledge of these specific allergens, it is anticipated that targeted, effective, diagnostic, efficacious and safe therapeutic modalities would be developed.