Mechanisms of allergen-specific immunotherapy

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
The Journal of allergy and clinical immunology (Impact Factor: 11.48). 01/2011; 127(1):18-27; quiz 28-9. DOI: 10.1016/j.jaci.2010.11.030
Source: PubMed


Allergen-specific immunotherapy has been used for 100 years as a desensitizing therapy for allergic diseases and represents the potentially curative and specific method of treatment. The mechanisms of action of allergen-specific immunotherapy include the very early desensitization effects, modulation of T-and B-cell responses and related antibody isotypes, and migration of eosinophils, basophils, and mast cells to tissues, as well as release of their mediators. Regulatory T (Treg) cells have been identified as key regulators of immunologic processes in peripheral tolerance to allergens. Skewing of allergen-specific effector T cells to a regulatory phenotype appears as a key event in the development of healthy immune response to allergens and successful outcome in patients undergoing allergen-specific immunotherapy. Naturally occurring forkhead box protein 3-positive CD4(+)CD25(+) Treg cells and inducible T(R)1 cells contribute to the control of allergen-specific immune responses in several major ways, which can be summarized as suppression of dendritic cells that support the generation of effector T cells; suppression of effector T(H)1, T(H)2, and T(H)17 cells; suppression of allergen-specific IgE and induction of IgG4; suppression of mast cells, basophils, and eosinophils; and suppression of effector T-cell migration to tissues. New strategies for immune intervention will likely include targeting of the molecular mechanisms of allergen tolerance and reciprocal regulation of effector and Treg cell subsets.

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Available from: Cezmi A Akdis, Nov 06, 2014
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    • "Studies of T cell activity of allergoids in terms of proliferation of primary T cells, lines or clones, have suggested variable degrees of loss of ability to stimulate T cells, either generally or restricted to some epitopes [12-16]. However, the immunological efficacy of SIT most likely relates to induction of tolerance to allergens through interactions with regulatory T cells (Treg) [17]. Studies with unmodified allergen extracts suggest increased numbers and activity of both CD4+CD25hiFoxp3hi T cells and IL-10 producing T cells after SIT treatment, together with induction of the IL-10-dependent antibody IgG4 [17]. "
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    ABSTRACT: Background Allergen immunotherapy (SIT) is the only treatment for allergic disease capable of modifying disease long term. To reduce the risk of anaphylaxis from SIT, allergen-extracts have been modified by polymerisation with glutaraldehyde to reduce IgE binding. It is suggested that these allergoid extracts also have reduced T cell activity, which could compromise clinical efficacy. Effective SIT is thought to act through regulatory T cells (Tregs) rather than activation of effector T cells. There is no published data on the activity of modified extracts on Tregs. Results We compared the capacity of modified (depigmented-polymerised) versus unmodified (native) allergen extracts of grass pollen and house dust mite to stimulate proliferation/cytokine production and to modulate Treg/effector T cell frequency in cultures of peripheral blood mononuclear cells (PBMC), from volunteers sensitised to both allergens in vitro. Depigmented-polymerised allergen extracts stimulated less proliferation of PBMC, and reduced effector cell numbers after 7 days in culture than did native extracts. However, the frequency of Foxp3+ Tregs in cultures were similar to those seen with native extract so that ratios of regulatory to effector T cells were significantly increased in cultures stimulated with depigmented-polymerised extracts. Addition of 1α, 25-dihydroxyvitamin D3 further favoured Treg, and reduced effector cytokine production, but not interleukin-10. Conclusions Depigmented-polymerised allergen extracts appear to favour Treg expansion over activation of effector T cells and this may relate to their demonstrated efficacy and safety in SIT. 1α, 25-dihydroxyvitamin D3 further reduces effector T cell activation by allergen extracts and may be a useful adjuvant for SIT.
    BMC Immunology 05/2014; 15(1):21. DOI:10.1186/1471-2172-15-21 · 2.48 Impact Factor
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    • "Most of research and development on drugs for relieving asthma is at the stage I and II. In recent years, compounds of inhaled glucocorticoid and bronchodilators, desensitization therapy Effect of crude extract of C. elegans on allergic asthma 887 Int J Clin Exp Med 2014;7(4):886-892 for determining sensitinogen of patients, etc. [2] [3] also have gained a rapid development, but due to influences from drug adverse reactions , prices, difficulty in determining allergen, and other factors, it is necessary to strengthen research and development of drugs for relieving asthma. The study explored immunoregulation of natural crude extract of C. elegans to asthma and provided references for research and development of new drugs for relieving asthma. "
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    ABSTRACT: Unlabelled: To explore effects of natural crude extract of C. elegans on treatment of asthma. Method: Obtain crude extract of C. elegans from synchronically incubated C. elegans via centrifugation, washing and ultrasonic emulsification, etc.; measure C. elegans's protein molecular weight via SDS-polyacrylamide gel electrophoresis (SDS-PAG electrophoresis); construct animal models of asthma with 6-8-week-old BALB/c female mice sensitized by chicken ovalbumin (OVA); conduct immunotherapy on animals with asthma with different doses of mixture of C. elegans and OVA (COM) respectively; take PBS buffer group and OVA group as control groups; conduct inspection of cell factors and differential count of cells in serum IgE, IgG1 and IgG2a antibodies and bronchoalveolar lavage fluid (BALF) via enzyme linked immunosorbent assay (ELISA); and incise lung tissue for pathology observation. Result: C. elegans's protein molecular weight is about 50 kd. In bronchoalveolar lavage fluid (BALF) of OVA group, cell factors IL-5 and IL-13 are more than those in PBS buffer group, but IL-2 and IFN-γ are less than those in PBS buffer group; these differences are of statistical significance (P<0.05). Total cellular score and number of eosinophile granulocyte in BALF of OVA group are more than those in PBS buffer group (P<0.05), and the difference in serum IgE, IgG1 and IgG2a between these two groups is of statistical significance (P<0.05). For groups treatment by different doses of COM, cell factors IL-5 and IL-13 in bronchoalveolar lavage fluid (BALF) are less than those in OVA group, but IL-2 and IFN-γ are more than those in OVA group; these differences are of statistical significance (P<0.05). Total cellular score and number of eosinophile granulocyte in BALF of COM treatment groups are less than those in OVA group (P<0.05); serum IgE and IgG1 less than those in OVA group, but IgG2a is more than that in OVA group; these differences are of statistical significance (P<0.05). Conclusion: The natural crude extract of C. elegans has immunoregulation to animals with asthma.
    International Journal of Clinical and Experimental Medicine 04/2014; 7(4):886-92. · 1.28 Impact Factor
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    • "The present study aimed to systemically evaluate the effects of SIT in children. This study was an open clinical observation following the intention-to-treat principle, in which parallel controls and self-controls were established (9). "
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    ABSTRACT: The present study aimed to evaluate the efficacy of three-year subcutaneous SQ-standardized specific immunotherapy (SCIT) in house dust mite (HDM)-allergic children with asthma. Ninety children with allergic asthma to HDMs, with or without allergic rhinitis, were randomly divided into two groups, the treatment group and the control group. The treatment group received SCIT combined with standardized glucocorticoid management and the control group received standardized glucocorticoid management alone for a period of three years. The mean daily dose of inhaled corticosteroids (ICSs), a four-week diary recording the symptom scores of asthma, peak expiratory flow (PEF) measurements, skin prick test results and serum immunoglobulin E (IgE) levels were assessed prior to treatment and following one, two and three years of treatment. The median dose of ICS was reduced in the treatment group after two and three years of treatment compared with that of the control group. After three years of treatment, the discontinuation percentage of ICS in the treatment group was higher than that in the control group. The treatment group demonstrated significantly reduced daytime and night-time asthmatic symptom scores, increased PEF values and reduced serum IgE levels after two and three years of treatment compared with those in the control group (P<0.05). In conclusion, three-year SCIT treatment combined with ICS is an effective immunotherapy for children with allergic asthma and resulted in a reduction of the required ICS dose.
    Experimental and therapeutic medicine 03/2014; 7(3):630-634. DOI:10.3892/etm.2014.1469 · 1.27 Impact Factor
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