Zelluläre Mechanismen der Toleranzinduktion unter spezifischer sublingualer Immuntherapie mit Birkenpollenallergenen

Die Prävalenz allergischer Krankheiten (z.B. allergisches Asthma, allergische Rhinokonjunktivitis, Nahrungsmittelallergien und atopisches Ekzem) hat in einigen Teilen der Welt, besonders der westlichen Welt, innerhalb der letzten Jahrzehnte deutlich zugenommen. Bei einer allergischen Reaktion Typ I...

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Bibliographic Details
Main Author: Ruge, Karolin
Contributors: Pfützner, Wolfgang (PD Dr. med.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2011
Online Access:PDF Full Text
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In some parts of the world, especially in Western industrial countries, the prevalence of allergic diseases (e.g. allergic asthma, allergic rhinoconjunctivitis, food allergy and atopic eczema) has clearly increased over the last decades. During an immediate type allergic reaction, defined by Coombs and Gell, e.g. allergic rhinitis or bronchial asthma, allergen-specific immunoglobulin (Ig)E antibodies against harmless environmental antigens are produced and are bound on effector cells, like mast cells and granolucytes. Anew allergen contact leads to a cell-activation by cross-linking of cell-bound IgE antibodies with a consecutive release of inflammatory mediators. Specific immunotherapy (SIT) is the only causative possibility of treatment for type I hypersensitivity reactions and is conventionally administered per subcutaneous injections (SCIT). Since the middle of the eighties the usage of the sublingual dosage form of SIT has augmented because of an easier application, good efficacy and a greater safety than SCIT referring to the danger of an anaphylactic shock. To determine the optimal dose, length and appropriate beginning of treatment several studies about the identification of cellular mechanisms of sublingual immunotherapy (SLIT) are necessary. In the current longitudinal study blood samples from eight patients with birch pollen allergy were analysed before and during twelve month of SLIT with birch pollen extract in order to detect cellular and humoral changes. The blood samples were taken at different points of time, which implied the phase of induction and maintenance including the birch pollen season, so that not only the effects of SLIT but also the naturally occuring exposition to allergen could be investigated. During the twelve-month course of therapy humoral and cellular changes arose, which led to the development of allergenic tolerance. In the birch pollen season all of the enrolled probands reported reduced clinical symptoms and after one year of treatment they had an attenuated skin prick test against birch pollen allergen. Contrary to observations of other studies, neither an induction of allergen-specific interleukin (IL)-10-producing type 1 regulatory T cells (Tr1) nor an elevated frequency of Foxp3+ regulatory cells (Treg) could be determined in this present investigation. After six month of SLIT there was no typical enlargement of allergen-specific T-helper-2-cells (Th2) during birch pollen season which came along with a subjective as well as an objective clinical improvement of the patients. A rise of interferon (IFN)-γ producing Th1 after twelve month identified the shift from the classical, allergic Th2- to a Th1-dominated immune response. A change of the humoral mechanisms occured after six month of treatment with a mild increase of allergen-specific IgG4 and decrease of the allergen-specific IgE/IgG4-ratio. After one year Bet v 1-specific IgE dropped below the initial values. These findings support the following model of immunological mechanisms of SLIT: Allergen-specific IL-10-producing T-cells cause an elevation of the concentration of blocking IgG4 antibodies in the serum. These antibodies could inhibit the IgE-mediated release of inflammatory mediators through mast cells and basophils, could prevent the IgE-supported allergen presentation of dendritic cells (DC) to T cells and block the IgE-mediated activation of eosinophilic granulocytes. In the late period of SLIT the enhanced production of IFN-γ through Th1 facilitates the inhibition of IL-4 induced IgE-production on the level of transcription. As a consequence allergen-specific IgE antibodies decrease and the induction of allergen tolerance is stabilized. The measurement of IgG4 antibodies in the serum - respectively the quotient of IgE/IgG4 - might provide evidence of the respond to the immunotherapy and in respect of the follow-up. More studies are required to fully analyse the mode of action and identify ideal control parameters of SLIT in order to improve the understanding about the complex, multi-factorial immunoregulatory mechanisms.