Article

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

ABSTRACT

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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    • "Currently, allergen-specific immunotherapy (AIT) represents the only disease-modifying treatment, diminishing symptoms , improving quality of life, preventing new sensitisations and reducing the risk of asthma development[2,3]. The golden standard treatment is subcutaneous immunotherapy (SCIT), which shows long-term benefit for the treatment of allergic rhinitis, conjunctivitis and asthma[3,4]. Despite this, only 5 % of patients undergo this therapy, due to frequent injections, risk of adverse effects and the long duration of treatment[2]. "
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    ABSTRACT: Background Allergen-specific immunotherapy represents the only disease-modifying treatment for allergic diseases. We and others have previously demonstrated that intralymphatic immunotherapy (ILIT), a less time-consuming alternative to conventional subcutaneous immunotherapy (SCIT), is safe and effective. However, this has recently been disputed. The aim of this study was therefore to expand our previous trial, further assessing the safety and efficacy of ILIT. Methods Thirty-six patients with pollen-induced rhinoconjunctivitis were randomised to receive three intralymphatic inguinal injections of active allergen (1000 SQ-U birch- or grass-pollen) or placebo. Clinical effects, safety and circulating immunological markers were assessed before, 4 weeks after treatment and at the end of the consecutive pollen season. Results No moderate or severe reactions were recorded following ILIT. Patients receiving active ILIT experienced a significant improvement in self-recorded seasonal allergic symptoms, as compared to placebo (p = 0.05). In a subgroup of these patients (“improved”), a reduction in nasal symptoms following nasal allergen provocation was also demonstrated. No changes in total IgE or IgG4 were found. However, the affinity of allergen specific IgG4 following active treatment was significantly increased, as compared to non-improved patients (p = 0.04). This could be correlated with clinical improvement, on an individual level. Conclusions This double-blinded placebo-controlled study confirms that ILIT is a safe and effective treatment for pollen-induced rhinoconjunctivitis, markedly reducing seasonal allergic symptoms. Trial registration EudraCT: 2009-016815-39 Electronic supplementary material The online version of this article (doi:10.1186/s12931-016-0324-9) contains supplementary material, which is available to authorized users.
    Full-text · Article · Dec 2016 · Respiratory research
    • "In the context of allergy, there are now vaccines developed from a number of allergens that are used for allergenspecific immunotherapy (Akkoc et al., 2011). Recently, a detoxified derivative of LPS from Salmonella minnesota, referred to as monophosphoryl lipid A (MPL), has been used in adjuvanted pollen allergy vaccines (Patel and Salapatek, 2006). "
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    ABSTRACT: Drugs targeting the immune system such as corticosteroids, antihistamines and immunosuppressants have been widely exploited in the treatment of inflammatory, allergic and autoimmune disorders during the second half of the 20th century. The recent advances in immunopharmacological research made available new classes of clinically relevant drugs. These comprise protein kinase inhibitors and biologics, such as monoclonal antibodies that selectively modulate the immune response not only in cancer and autoimmunity but also in a number of additional human pathologies. Likewise, more effective vaccines utilising novel antigens and adjuvants are valuable tools for the prevention of transmissible infectious diseases and for allergen-specific immunotherapy. Consequently, immunopharmacology is presently considered as one of the expanding fields of pharmacology. Immunopharmacology addresses the selective regulation of immune responses and aims to uncover and exploit beneficial therapeutic options for typical and non-typical immune system-driven unmet clinical needs. While in the near future a number of new agents will be introduced, improving effectiveness and safety of those currently in use is imperative for all researchers and clinicians working in the fields of immunology, pharmacology and drug discovery. The newly formed ImmuPhar (http://iuphar.us/index.php/sections-subcoms/immunopharmacology) is the Immunopharmacology Section of the International Union of Basic and Clinical Pharmacology (IUPHAR, http://iuphar.us/). ImmuPhar provides a unique international expert-lead platform aiming to dissect and promote the growing understanding of immune (patho)physiology. Moreover, it challenges the identification and validation of drug targets and lead candidates for the treatment of many forms of debilitating disorders, including, among others, cancer, allergies, autoimmune and metabolic diseases. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2015 · British Journal of Pharmacology
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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.
    Full-text · Article · May 2014 · BMC Immunology
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