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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.

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. It is initiated by autocrine action of IL-10 and/or TGF-Beta, which are increasingly produced by the antigen-specific T Regulatory (T(Reg)) cells. Tolerized T cells can be reactivated to produce either of the distinct Th1 or Th2 cytokine patterns, thus directing allergen-SIT towards successful or unsuccessful treatment. T(Reg) cells directly or indirectly influence effector cells of allergic inflammation, such as mast cells, basophils and eosinophils. In addition, there is accumulating evidence that they may suppress IgE production and induce IgG4 and IgA production against allergens. By the application of the recent knowledge in mechanisms of allergen-SIT, more rational and safer approaches are awaiting in the future for the prevention and cure of allergic diseases.

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. The changes in the immune response brought about by allergen-SIT are slowly being unveiled and explained. Mechanisms underlying allergen-SIT and in particular the role of regulatory T cells will be discussed in this review, based on recent findings and current concepts.

Objective: To evaluate the clinical outcome and changes in allergen-specific antibodies during sublingual immunotherapy (SLIT) in house dust mite (HDM)-allergic asthma patients and to compare levels of allergen-specific antibodies in HDM-allergic patients before and after treatment with that of healthy controls., Method: Thirty-one asthma patients allergic to HDM were studied. Patients in groups I (n=17) and II (n=14) received SLIT with a standardized Dermatophagoides pteronyssinus plus Dermatophagoides farinae 50/50 extract for 6 and 12 months, respectively. A group of healthy children (n=8) were enrolled as controls. Patients in both groups were evaluated at the start and at the end of treatment according to daily symptom and medication scores, lung function and skin prick tests, PC20, blood eosinophil count, and Der-p-1-specific IgE, IgA, IgG1 and IgG4 levels., Results: Drug consumption decreased significantly in both groups. Furthermore, PC20 and forced expiratory flow between 25 and 75% of vital capacity of patients in group II improved significantly. Although specific IgA, IgG1 and IgG4 levels did not change throughout the treatment period, total eosinophil count and specific IgE decreased significantly in both groups. According to baseline measurements, specific IgA levels of patients in groups I and II were significantly lower than that of controls. This difference disappeared at the end of the treatment period in both groups., Conclusion: SLIT seems to be effective in ameliorating clinical symptoms, drug consumption and bronchial hyperreactivity, and results in downregulation of Der-p-1-specific IgE production. Furthermore, at the end of SLIT, specific IgA levels, which were decreased compared to healthy controls initially, did no longer differ between patients and controls., (Copyright (c) 2005 S. Karger AG, Basel.)

Background: Specific immunotherapy is a common treatment of allergic diseases and could potentially be applied to other immunologic disorders. Despite its use in clinical practice, more defined and safer allergy vaccine preparations are required. Differences between epitopes of IgE that recognize the 3-dimensional structure of allergens and T cells that recognize linear amino acid sequences provide a suitable tool for novel vaccine development for specific immunotherapy., Objective: The aim of the study was to delete B-cell epitopes and prevent IgE crosslinking, but to preserve T-cell epitopes by fusion of 2 major allergens of bee venom because of a change in the conformation., Methods: By genetic engineering, we produced a fusion protein composed of the 2 major bee venom allergens: phospholipase A 2 (Api m 1) and hyaluronidase (Api m 2)., Results: The Api m [1/2] fusion protein induced T-cell proliferation and both T H 1-type and T H 2-type cytokine responses. In contrast, IgE reactivity was abolished, and profoundly reduced basophil degranulation and type 1 skin test reactivity was observed. Pretreatment of mice with Api m [1/2] fusion protein significantly suppressed the development of specific IgE as well as other antibody isotypes after immunization with the native allergen., Conclusion: The novel fusion protein of 2 major allergens bypasses IgE binding and mast cell/basophil IgE FcepsilonRI crosslinking and protects from IgE development.

Specific immunotherapy (SIT) represents the only curative treatment of allergy and is, therefore, of particular interest for immunological and pharmacological research. The current understanding of immunological mechanisms underlying SIT focuses on regulatory T cells (T regs), which balance Th1 and Th2 effector functions. This ensures that allergens are recognized, but tolerated by the immune system. There is clear evidence that SIT restores the disturbed balance of T regs and effector cells in allergic patients. Current efforts are focused to improve SIT regimens to make them more applicable in atopy and asthma. The current review provides an overview on the mechanisms of SIT and possible adjuvant treatment strategies on the background of the T reg concept.

Induction of specific unresponsiveness (tolerance) in peripheral T cells by IL-10 and/or TGF-beta and recovery by cytokines from the tissue microenvironment represent two key steps in specific immunotherapy of allergy and natural exposure to allergens in healthy individuals. IL-10 and TGF-beta elicit tolerance in T cells and thereby control the suppression and development of antigen-specific immunity. Both cytokines also play an important role on the generation of a non-inflammatory IgG4 and IgA type of allergen--specific antibodies during the course of specific immunotherapy. Histamine plays an important role in upper and lower airway inflammation. In addition to its well-characterized effects in the acute inflammatory and allergic responses, histamine regulates several aspects of antigen-specific immune response development. Histamine affects the maturation of dendritic cells and alters their T cell polarizing capacity. Histamine regulates antigen specific Th1 and Th2 cells as well as related antibody isotype responses. Histamine and four different known histamine receptors (HR) display a very complex system and their expression changes according to the stage of cell differentiation as well as microenvironmental influences.

Background: H1 antihistamines increase safety during allergen-specific immunotherapy and might influence the outcome because of immunoregulatory effects. Objective: We sought to analyze the influence of 5 mg of levocetirizine (LC) on the safety, efficacy, and immunologic effects of ultrarush honeybee venom immunotherapy (BVIT). Method: In a double-blind, placebo-controlled study 54 patients with honeybee venom allergy received LC or placebo from 2 days before BVIT to day 21. Side effects during dose increase and systemic allergic reactions (SARs) to a sting challenge after 120 days were analyzed. Allergen-specific immune response was investigated in skin, serum, and allergen-stimulated T-cell cultures. Results: Side effects were significantly more frequent in patients receiving placebo. Four patients receiving placebo dropped out because of side effects. SARs to the sting challenge occurred in 8 patients (6 in the LC group and 2 in the placebo group). Seven SARs were only cutaneous, and 1 in the placebo group was also respiratory. Difference of SARs caused by the sting challenge was insignificant. Specific IgG levels increased significantly in both groups. Major allergen phospholipase A2-stimulated T cells from both groups showed a slightly decreased proliferation. The decrease in IFN-γ and IL-13 levels with placebo was not prominent with LC, whereas IL-10 levels showed a significant increase in the LC group only. Decreased histamine receptor (HR)1/HR2 ratio in allergen-specific T cells on day 21 in the placebo group was prevented by LC. Conclusions: LC reduces side effects during dose increase without influencing the efficacy of BVIT. LC modulates the natural course of allergen-specific immune response and affects the expression of HRs and cytokine production by allergen-specific T cells. [Copyright &y& Elsevier]

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. In contrast, there is a high frequency of allergen-specific interleukin-4 (IL-4)-secreting T cells in allergic individuals. Allergen-specific immunotherapy can induce specific Tr1 cells that abolish allergen-induced proliferation of Th1 and Th2 cells, as well as their cytokine production. Tr1 cells utilize multiple suppressor mechanisms, such as IL-10 and transforming growth factor-β (TGF-β) as secreted cytokines and various surface molecules, such as cytotoxic T-lymphocyte antigen 4 and programmed death-1. IL-10 only inhibits T cells stimulated by low numbers of triggered T-cell receptors, which depend on CD28 costimulation. IL-10 inhibits CD28 tyrosine phosphorylation, preventing the binding of phosphatidylinositol 3-kinase p85 and consequently inhibiting the CD28 signalling pathway. In addition, IL-10 and TGF-β secreted by Tr1 cells skew the antibody production from immunoglobulin E (IgE) towards the non-inflammatory isotypes IgG4 and IgA, respectively. Induction of antigen-specific Tr1 cells can thus re-direct an inappropriate immune response against allergens or auto-antigens using a broad range of suppressor mechanisms. [ABSTRACT FROM AUTHOR]

The identification of T regulatory (TReg) 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+ TReg cells and inducible populations of allergen-specific IL-10–secreting TR1 cells inhibit allergen-specific effector cells in experimental models. Allergen-specific TReg cell responses contribute to the control of allergic inflammation in several ways. Skewing of allergen-specific effector T cells to a TReg phenotype appears to be a crucial event in the development of a healthy immune response to allergens and successful outcome in allergen-specific immunotherapy. The increased levels of IL-10 and TGF-β produced by TReg cells can potently suppress IgE production while simultaneously increasing the production of the noninflammatory antibody isotypes IgG4 and IgA, respectively. TReg cells directly or indirectly suppress effector cells of allergic inflammation, such as mast cells, basophils, and eosinophils, and contribute to remodeling in asthma and atopic dermatitis. In addition, mediators of allergic inflammation that trigger cyclic AMP–associated G protein–coupled receptors, such as histamine receptor 2, might play a role in peripheral tolerance mechanisms against allergens. Current strategies for drug development and allergen-specific immunotherapy exploit these observations with the potential to provide cure for allergic diseases. [Copyright &y& Elsevier]

Summary Specific immune suppression and induction of anergy are essential processes in the regulation and circumvention of immune defence. Interleukin-10 (IL-10), a suppressor cytokine of T-cell proliferative and cytokine responses, plays a key regulatory role in tolerizing exogenous antigens during specific immunotherapy (SIT) of allergy and natural exposure to antigens. Specific T-cell tolerance is directed against the T-cell epitopes of an antigen and characterized by suppressed proliferative and T helper type 1 (Th1) and type 2 (Th2) cytokine responses. IL-10 elicits tolerance in T cells by selective inhibition of the CD28 co-stimulatory pathway and thereby controls suppression and development of antigen-specific immunity. IL-10 only inhibits T cells stimulated by low numbers of triggered T-cell receptors and which therefore depend on CD28 co-stimulation. T cells receiving a strong signal from the T-cell receptor alone, and thus not requiring CD28 co-stimulation, are not affected by IL-10. IL-10 inhibits CD28 tyrosine phosphorylation, the initial step of the CD28 signalling pathway, and consequently the phosphatidylinositol 3-kinase p85 binding to CD28. Together these results demonstrate that IL-10-induced selective inhibition of the CD28 co-stimulatory pathway acts as a decisive mechanism in determining whether a T cell will contribute to an immune response or become anergic. [ABSTRACT FROM AUTHOR]

Background: Induction of specific unresponsiveness (tolerance/anergy) in peripheral T cells and recovery by cytokines from the tissue microenvironment represent two key steps in specific immunotherapy (SIT) with whole allergen or antigenic T cell peptides. Methods: Antigen-specific T cell responses and molecular mechanisms of T cell inactivation were investigated during conventional SIT, T cell epitope peptide immunotherapy and natural exposure to bee venom in allergic and hyperimmune individuals. Results: T cell unresponsiveness, initiated by autocrine action of IL-10, is characterized by suppressed proliferative and cytokine responses. The unresponsive T cells can be reactivated by different cytokines that may mimic the microenvironmental cytokine influence. IL-10 initiates peripheral tolerance by blocking the CD28 costimulatory signal in T cells. Coprecipitation experiments reveal that upon stimulation CD28 and IL-10 receptor are physically associated in T cells. Accordingly, IL-10 binding to its receptor inhibits CD28 tyrosine phosphorylation, the initial step of the CD28 signaling pathway. This leads to inhibition of phosphatidylinositol 3-kinase p85 binding to CD28. IL-10 only affects T cells that receive a stimulation with low numbers of triggered T cell receptors and that require costimulatory signals by CD28. Conclusion: These data demonstrate the pivotal role of autocrine IL-10 and the interaction of its receptor with CD28 in the induction of T cell tolerance as an immunoregulatory mechanism controlling antigen-specific T cell responses.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Demonstrates that the recombinant Bet v 1 fragments induced proliferation of PBMC from birch pollen-allergic patients comparable to the rBet v 1 wild type, indicating that both fragments contain most of the Bet v 1-specific T cell epitopes. Characteristics of the major birch pollen allergen Bet v 1; Results from the immunization of rabbits and mice with purified rBet v 1 fragments; Effectiveness of hypoallergenic rBet v 1 fragments as vaccines.