T-cell tolerance to inhaled allergens: mechanisms and therapeutic approaches.

Background: Specific immune response to allergens is decisive in the development of clinically healthy or allergic states.

Objective: Recent developments in the mechanisms of allergen-specific peripheral tolerance can be used for future treatment modalities.

Methods: This review focuses on recent developments in allergen tolerance.

Increased activation-induced cell death of high IFN-gamma-producing T(H)1 cells as a mechanism of T(H)2 predominance in atopic diseases.

Background: A dysregulated and T(H)2-biased immune response appears to be a key pathogenetic factor in atopic diseases. Increased activation and massive infiltration of T cells in the dermis without any evidence for the expansion of their numbers in peripheral blood characterize atopic dermatitis.

Objective: To investigate differences and mechanisms of T(H)1 and T(H)2 cell activation-induced cell death (AICD) in atopic disease.

Regulatory NK cells suppress antigen-specific T cell responses.

The immune system has a variety of regulatory/suppressive processes, which are decisive for the development of a healthy or an allergic immune response to allergens. NK1 and NK2 subsets have been demonstrated to display counterregulatory and provocative roles in immune responses, similar to Th1 and Th2 cells. T regulatory cells suppressing both Th1 and Th2 responses have been the focus of intensive research during the last decade.

TH17 cells in the big picture of immunology.

The pathogenesis of chronic inflammatory diseases is assumed to depend on activated T cells interacting with resident tissue cells or migratory inflammatory cells. The discovery of new T-cell subsets such as the IL-17-producing T(H)17 and T-regulatory cells innovated our understanding of T-cell biology. Studies on new subsets confirm the important role of T cells in the instruction of tissue cells and also demonstrate the important role of feedback regulation for the polarization toward distinct T-cell subsets.

Comparison of Der p1-specific antibody levels in children with allergic airway disease and healthy controls.

Although children, with allergic airway disease, who are sensitized to house-dust mite (HDM) are known to have increased levels of allergen-specific IgE and IgG, the association between the quantity of those immunoglobulins and the clinical features of disease is not yet well established. The purpose of this study was (i) to evaluate Der p1-specific IgA, IgG1, IgG4, and IgE levels of children with HDM-allergic asthma and allergic rhinitis and to compare it with that of healthy controls (ii) to assess the association with disease duration. A total of 73 patients were included.

IL-10 inhibits CD28 and ICOS costimulations of T cells via src homology 2 domain-containing protein tyrosine phosphatase 1.

Background: Specific T-cell activation requires T-cell receptor stimulation and the generation of costimulatory signals. Major costimulatory signals are delivered to T cells by the interaction of CD28 and inducible costimulator (ICOS).

Objective: To investigate the molecular pathways involved in direct T-cell suppression by IL-10.

Mechanisms of allergen-specific immunotherapy.

Allergen-specific immunotherapy (SIT) has been used for almost a century as a desensitizing therapy for allergic diseases and represents the only curative and specific method of treatment. Administration of appropriate concentrations of allergen extracts has been shown to be reproducibly effective when patients are carefully selected. The mechanisms by which allergen-SIT has its effects include the modulation of T-cell and B-cell responses and related antibody isotypes as well as effector cells of allergic inflammation, such as eosinophils, basophils, and mast cells.

Healthy immune response to allergens: T regulatory cells and more.

The specific immune response to allergens is decisive in the development of clinically healthy or allergic states. In healthy individuals, the B-cell response varies between there being no response and the production of IgG(4)- or IgG(1)-dominating allergen-specific antibodies in the presence or absence of low amounts of IgE. If a detectable immune response is mounted, T regulatory type 1 (Tr1) cells specific for common environmental allergens consistently represent the dominant subset in healthy individuals.

Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report.

There are remarkable differences in the diagnostic and therapeutic management of atopic dermatitis practiced by dermatologists and pediatricians in different countries. Therefore, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology nominated expert teams who were given the task of finding a consensus to serve as a guideline for clinical practice in Europe as well as in North America. The consensus report is part of the PRACTALL initiative, which is endorsed by both academies.

Bacillus Calmette-Guerin, Mycobacterium bovis, as an immunomodulator in atopic diseases.

Based on the hygiene hypothesis association between atopy and bacillus Calmette-Guerin (BCG), purified protein derivative skin test reaction, mycobacterial disease, and environmental mycobacteria are summarized. The role of mycobacterial species in the activation of the innate immune response through Toll-like receptors is mentioned. The implications and perspectives of BCG as a potential therapeutic adjuvant in atopic disease are discussed.

Mechanisms of allergen-specific immunotherapy: T-regulatory cells and more.

Activation-induced cell death, anergy, or immune response modulation by regulatory T cells (Treg cells) are essential mechanisms of peripheral T-cell tolerance. Genetic predisposition and environmental instructions tune thresholds for the activation of T cells, other inflammatory cells, and resident tissue cells in allergic diseases. Skewing allergen-specific effector T cells to a Treg-cell phenotype seems to be crucial in maintaining a healthy immune response to allergens and successful allergen-specific immunotherapy.

T-cell subsets in the pathogenesis of human asthma.

Genetic predisposition and environmental instructions tune thresholds for activation of T cells, other inflammatory cells, and resident tissue cells in asthmatic inflammation. Selective migration of peripheral-blood T cells to the lungs, their survival and reactivation in the submucosa, and their effector functions represent sequential immunologic events. Activation-induced T-cell death and peripheral T-cell tolerance are critical events in disease pathogenesis.

Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells.

Specific immune suppression and induction of tolerance are essential processes in the regulation and circumvention of immune defence. The balance between allergen-specific type 1 regulatory (Tr1) cells and T helper (Th) 2 cells appears to be decisive in the development of allergy. Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals.

Absence of T-regulatory cell expression and function in atopic dermatitis skin.

Background: The role of regulatory T cells has been widely reported in the suppression of T-cell activation. A dysfunction in CD4(+)CD25(+) T-regulatory cell-specific transcription factor FoxP3 leads to immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome, often associated with atopic dermatitis. Increasing the number and activity of regulatory T cells in affected organs has been suggested as a remedy in various inflammatory diseases, including allergy.

Regulation of T cells and cytokines by the interleukin-10 (IL-10)-family cytokines IL-19, IL-20, IL-22, IL-24 and IL-26.

The family of IL-10-related cytokines includes several human members, IL-19, IL-20, IL-22, IL-24 and IL-26, and a series of herpesviral and poxviral paralogs. Some of these cytokines share common receptor subunits. In this study, we investigated the effects of these cytokines on naive T cell differentiation, antigen-specific T cell suppression, survival ad expression of surface markers in comparison to IL-10 and cytomegalovirus (CMV)-IL-10.

Mechanisms of allergen-specific immunotherapy.

Allergen-specific immunotherapy (SIT) is the only treatment, which leads to a life-long tolerance against allergens due to restoration of normal immunity. The induction of a tolerant state in peripheral T cells represents an essential step in allergen-SIT. Peripheral T-cell tolerance is characterized mainly by suppressed proliferative and cytokine responses against the major allergens and its T-cell recognition sites.

T regulatory cells in allergy.

Activation-induced cell death, anergy and/or immune response modulation by T regulatory cells (T(Reg)) are essential mechanisms of peripheral T-cell tolerance. There is growing evidence that anergy, tolerance and active suppression are not entirely distinct, but rather, represent linked mechanisms possibly involving the same cells and multiple suppressor mechanisms. Skewing of allergen-specific effector T cells to T(Reg) cells appears as a crucial event in the control of healthy immune response to allergens and successful allergen-specific immunotherapy.

T regulatory cells in allergen-specific immunotherapy.

A dramatic increase in the prevalence of allergy and asthma has occurred during the past few decades. Although the symptoms of many allergic disorders can be suppressed quite effectively by pharmacological interventions, these do not provide a curative solution and therefore involve lifelong use of medication. Allergen-specific immunotherapy (SIT) on the other hand provides a long-lasting effect on the immune response to common environmental antigens, therefore allowing cessation of the therapy after several years.

T regulatory cells in allergy: novel concepts in the pathogenesis, prevention, and treatment of allergic diseases.

The identification of T regulatory (T(Reg)) cells as key regulators of immunologic processes in peripheral tolerance to allergens has opened an important era in the prevention and treatment of allergic diseases. Both naturally occurring CD4(+)CD25(+) T(Reg) cells and inducible populations of allergen-specific IL-10-secreting T(R)1 cells inhibit allergen-specific effector cells in experimental models. Allergen-specific T(Reg) cell responses contribute to the control of allergic inflammation in several ways.

Role of bacillus Calmette-Guérin as an immunomodulator for the prevention and treatment of allergy and asthma.

Purpose Of Review: As an essential part of the hygiene hypothesis, the association between exposure to mycobacterial components and the prevention, development and severity of atopic diseases has not been fully understood. The current status on the causal-effect link of this relationship and the potential use of mycobacterial adjuvants as a preventive or disease-modifying modality in allergic diseases is reviewed in this article.

Recent Findings: Data obtained from human and animal models indicate a discrepancy regarding the preventive and therapeutic effect of bacillus Calmette-Guérin in atopic diseases.

Prevention of allergy by a recombinant multi-allergen vaccine with reduced IgE binding and preserved T cell epitopes.

Novel approaches for the prevention of allergy are required, because of the inevitably increasing prevalence of allergic diseases during the last 30 years. Here, a recombinant chimeric protein, which comprises the whole amino acid sequences of three bee venom major allergens has been engineered and used in prevention of bee venom sensitization in mice. Phospholipase A2 (Api m 1), hyaluronidase (Api m 2) and melittin (Api m 3) fragments with overlapping amino acids were assembled in a different order in the Api m (1/2/3) chimeric protein, which preserved entire T cell epitopes, whereas B cell epitopes of all three allergens were abrogated.

Apoptosis and loss of adhesion of bronchial epithelial cells in asthma.

Background: Asthma is an inflammatory airway disease associated with infiltration of T cells and eosinophils, increased levels of pro-inflammatory cytokines, and shedding of bronchial epithelial cells (EC). We have recently shown that T cells and eosinophils cooperate in inducing bronchial EC apoptosis in asthma through secretion of IFN-gamma and TNF-alpha. Since EC shedding is a histologic hallmark of asthma, the intercellular junction of EC may be a target of pro-inflammatory cytokines.

Cytokine and antibody responses in birch-pollen-allergic patients treated with genetically modified derivatives of the major birch pollen allergen Bet v 1.

Background: Recently, recombinant hypoallergenic derivatives of the major birch pollen allergen, Bet v 1, were used to treat birch-pollen-allergic patients in a double-blind, placebo-controlled, multi-centre immunotherapy study. The aim of this study was to evaluate the effects of vaccination with aluminium-hydroxide-adsorbed recombinant Bet v 1 derivatives versus placebo on T-cell, cytokine and antibody responses in a subgroup of patients.

Methods: Blood was drawn from patients of the Swedish centre (n = 27; rBet v 1 fragments: n = 10; rBet v 1 trimer: n = 8, and placebo-aluminium hydroxide: n = 9) before the start and after completion of the treatment.

Are regulatory T cells the target of venom immunotherapy?

Purpose Of Review: Allergen-specific immunotherapy is the only treatment that leads to lifelong tolerance to previously disease-causing allergens by restoring normal immunity against allergens. T-regulatory (TReg) cells are involved in preventing sensitization to allergens and represent a major target for venom- or other allergen-specific immunotherapy.

Recent Findings: Induction of peripheral tolerance in T cells, which is characterized mainly by suppressed proliferative and cytokine responses against the T-cell epitopes of major allergens, is an essential step in specific immunotherapy.

Targets in allergy-directed immunotherapy.

Allergic diseases such as asthma, atopic dermatitis, rhinitis and urticaria are immunological disorders affecting almost one third of the population in industrialised countries. Therapeutic or prophylactic approaches to turn around the increasing prevalence of these diseases have been intensively investigated. Allergen-specific immunotherapy has been applied in clinical practice for many decades, although varying results and occasional severe side effects have called for more effective and safer vaccines.