Immunologische Pathomechanismen bei Spättypallergie auf Betalactamantibiotika

Die Entwicklung von Allergien ist auf das komplexe Zusammenspiel zwischen genetischen Faktoren und bestimmten Umwelteinflüssen zurückzuführen. Bei etwa 25% der Menschen entwickeln sich überschießende Immunantworten, die durch harmlose Umweltstoffe wie Pollen oder Nahrungsmittel aber auch Arzneimitte...

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Bibliographic Details
Main Author: Schäfer, Carolin
Contributors: Pfützner, W. (Prof. Dr. med.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2016
Online Access:PDF Full Text
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The development of allergies is a complex interaction between genetic factors and environ-mental influences. About 25% of the population acquires an immune-mediated hypersensitivi-ty reaction to harmless environmental antigens like pollen, food or drugs during lifetime. In the last years the impact of drug allergies has increased gradually. The immune-mediated hypersensitivity response to drugs can be classified into an immediate and a non-immediate type according to Coombs and Gell. The pathomechanism of the immediate hypersensitivity reaction is mediated by specific IgE antibodies. In case of delayed-type hypersensitivity reac-tions, drug-specific T cells are activated and secretion of proinflammatory cytokines leads to the respective skin responses like occurrence of exanthema. Among drug-allergies beta-lactam antibiotics are one of the most common triggers. In the present study different antibiotics (penicillin G, amoxicillin, ampicillin and cefuroxime) were tested on four distinct subject cohorts. Since this study mainly focused on the delayed-type of drug reactions, patients with non-immediate type reactions were compared to a cohort of patients with immediate-type hypersensitivity and to two cohorts of non-allergic individu-als, one of them was exposed to beta-lactams. For this purpose different in-vivo-skin tests like intracutaneous, skin prick and epicutaneous tests as well as oral provocation tests were per-formed. On the basis of these test results and the anamneses, subjects were clinically charac-terized and categorized into the four different cohorts. Subsequently, in-vitro-diagnostic methods were performed to analyze the allergen-specific serum antibodies and the frequencies of allergen-specific T cell populations depending on their effector cytokines (IFN-γ, IL-5 and IL-10) in the peripheral blood of the patients. In addition, regulatory T (Treg) cells were quantified according to the surface marker profile CD4+CD25+CD127low. Finally, all of the immunological parameters obtained for the patients with delayed-type drug reactions were compared to the other three cohorts. The results of the study showed no substantial differences in the humoral response between all four tested cohorts. Although an increase of drug-specific IFN-γ+ T cells could not be de-tected in delayed-type, there was an increase of IL-5+ Th2 cells in the cohort of patients with immediate-type drug allergy. Additionally, there were no differences in IL-10-secreting type-1-Treg (Tr1) cells detectable after beta-lactam stimulation of peripheral blood mononuclear cells (PBMC) comparing the four cohorts. However, the cohort of healthy individuals showed an increase of drug-specific IFN-γ+ and IL-10+ T cells by trend. This could indicate a protec-tive immune mechanism in healthy individuals after exposure to beta-lactam antibiotics. On the other hand, a decrease of the CD4+CD25+CD127low Treg population could be observed in the non-allergic control cohort during the three days of systemic beta-lactam treatment. These findings highlight the complexity of immunological mechanisms after drug exposure. Thus, the results of this study might provide both novel insights and new starting points for future research in the field of drug allergy.