Allergen immunotherapy.

Department of Respiratory Medicine, Brighton & Sussex Medical School, Brighton, United Kingdom.
The Journal of allergy and clinical immunology (Impact Factor: 12.05). 02/2010; 125(2 Suppl 2):S306-13. DOI: 10.1016/j.jaci.2009.10.064
Source: PubMed

ABSTRACT Specific immunotherapy (SIT) involves the administration of allergen extracts to achieve clinical tolerance of those allergens that cause symptoms in patients with allergic conditions. Immunotherapy is effective in patients with mild forms of allergic disease and also in those who do not respond well to standard drug therapy. Most SIT is given by means of injection, but there is increasing interest in performing SIT through the sublingual route. SIT remains the treatment of choice for patients with systemic allergic reactions to wasp and bee stings and should be considered as an option in patients with allergic rhinitis, asthma, or both. SIT can modify the course of allergic disease by reducing the risk of new allergic sensitizations and inhibiting the development of clinical asthma in children treated for allergic rhinitis. The precise mechanisms responsible for the beneficial effects of SIT remain a matter of research and debate. An effect on regulatory T cells seems most probable and is associated with switching of allergen-specific B cells toward IgG4 production. Few direct comparisons of SIT and drug therapy have been made. Existing data suggest that the effects of SIT take longer to develop, but once established, SIT achieves long-lasting relief of allergic symptoms, whereas the benefits of drugs only last as long as they are continued.

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    ABSTRACT: Immunization with DNA-based constructs has been shown to be against the antigen and the response is skewed in such a way as to ameliorate the symptoms of allergic disease. This approach is particularly useful in the treatment of allergic inflammatory diseases, such as asthma. The major group 1 allergen from house dust mites is one of the triggers of allergic asthma. This study explores whether a chimeric gene R8, derived from the major group 1 allergen of house dust mite species (Dermatophagoides farinae and Dermatophagoides pteronyssinus), can be expressed in Human Embryonic Kidney 293 cells (HEK 293T) and whether such a construct can be used as a DNA vaccine in asthma therapy. The eukaryotic expression vector pcDNA3.1 was used to express the R8 molecule in HEK 293T cells and successful expression of R8 was confirmed using a fluorescence microscope and western blot analysis. The efficacy of R8 as DNA vaccine was also assessed in a mouse asthma model. The in vivo data showed that R8 rectified the TH1/TH2 imbalance typical of allergic inflammation and stimulated the proliferation of regulatory T (Treg) cells. Immunization with the R8 construct also decreased serum allergen-specific IgE production in this mouse asthma model. Our findings suggest that R8 may be a feasible potential DNA vaccine for specific immunotherapy (SIT) in the treatment of allergic asthma.
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    ABSTRACT: Hintergrund: Die Sensibilisierung von Inzuchtmäusen mit niedrigen Dosen eines Antigens (LD) führt zu einer erheblichen Produktion von antigenspezifischen IgE-Antikörpern, welche bei Applikation von hohen Antigendosen (HD) ausbleibt. Wir haben erstmals gezeigt, dass in HD-Mäusen CD4-CD8--doppelt-negative-T (dnT)-Zellen induziert werden, die regulatorische Funktionen im Rahmen der IgE-Immunantwort ausüben. Methoden: BALB/c-Mäuse wurden repetitiv mit 0,1 µg (LD) oder 100 µg (HD) des Antigens Keyhole Limpet Hemocyanin, adsorbiert an das Adjuvans Aluminiumhydroxid, sensibilisiert. Anschließend wurde der Gehalt an IgE-Antikörpern in den Seren der Mäuse im ELISA bzw. mit Hilfe des Basophilen-Degranulationstests bestimmt. Außerdem wurden die Milzzellen der LD- bzw. HD-Mäuse in vitro mit dem nominellen Antigen restimuliert, und die Proliferation sowie die Zytokinproduktion in den Kulturen gemessen. Die Frequenzen verschiedener Subpopulationen konventioneller regulatorischer T-Zellen (Treg) sowie die Genexpression Treg-assoziierter Moleküle in LD- und HD-Mäusen wurden mittels Durchflusszytometrie bzw. RT-PCR untersucht. Außerdem wurde nach adoptivem Transfer von Milzzellen bzw. separierten Subpopulationen der Milz aus LD- und HD-Spendermäusen der Effekt auf die durch Immunisierung mit niedrigen Dosen ausgelöste IgE-Produktion in den Empfängertieren analysiert. Ergebnisse: Die antigenspezifische Restimulation von Milzzellen aus HD-Mäusen führte zu einer Hypoproliferation sowie einer deutlich verminderten Sekretion der TH2-Zytokine IL-4, IL-5 und IL-13 durch die Splenozyten. Allerdings wurde kein Hinweis auf eine verstärkte Induktion konventioneller Treg oder eine unterschiedliche Genexpression von Treg-assoziierten Molekülen in HD-Mäusen beobachtet. Mit einem adoptiven Transfer von Milzzellen aus HD-Mäusen wurde die Suppression der IgE-Produktion auf naive Empfängertiere übertragen. Eine weitere Eingrenzung der Identität der Suppressorzellen im Rahmen der Transferexperimente ergab, dass nicht etwa CD4+- oder CD8+-T-Zellen, sondern CD4-CD8--dnT-Zellen die Regulation vermitteln. Schlussfolgerung: Die Immunisierung mit hohen Antigendosen induziert CD4-CD8--dnT-Zellen mit inhibitorischer Kapazität für die IgE-Produktion. Summary Background: Sensitization of inbred mice with low doses of antigen (LD mice) leads to substantial production of antigen-specific IgE antibodies, which does not occur after application of high doses of the same antigen (HD mice). We showed for the first time that CD4-CD8- double negative T cells with regulatory capacity for IgE immune responses arise in HD mice. Methods: BALB/c mice were repeatedly sensitized with 0.1 µg (LD) or 100 µg (HD) keyhole limpet hemocyanin, adsorbed to the adjuvant aluminium hydroxide. Subsequently, the content of antigen-specific IgE in the sera of the mice was determined by ELISA and basophil degranulation test, respectively. In addition, splenocytes of LD and HD mice were restimulated in vitro with antigen and proliferation as well as cytokine production by spleen cells were measured. Frequencies of different subsets of conventional regulatory T cells (Treg) as well as gene expression of Treg-associated molecules in LD or HD mice were analyzed using flow cytometry and RT-PCR analysis, respectively. Furthermore, the effect of adoptive transfer of splenocytes or separated subpopulations of spleen cells from LD and HD donor mice on IgE production in recipients, elicited by immunization with low doses, was determined. Results: Antigen-specific restimulation of spleen cells from HD mice results in hypoproliferation as well as considerably lower secretion of Th2 cytokines IL-4, IL-5, and IL-13 by splenocytes. However, we failed to show an increase in conventional Treg induction or upregulation of gene expression of Treg-associated molecules in HD mice. By adoptive transfer of splenocytes from HD mice suppression of IgE production was transferred to naïve recipients. Further analysis of the identity of suppressor cells by transfer experiments showed, that the regulation was mediated neither by CD4+ nor CD8+ T cells, but by CD4-CD8- double negative T cells. Conclusion: Immunization with high antigen doses induces CD4-CD8- double negative T cells with inhibitory capacity for IgE production.
    Allergo Journal: interdisziplinäre Zeitschrift für Allergologie und Umweltmedizin: Organ der Deutschen Gesellschaft für Allergie- und Immunitätsforschung 04/2012; 21(3):160-164. DOI:10.1007/s15007-012-0076-x
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    Journal der Deutschen Dermatologischen Gesellschaft 12/2012; 10(12). DOI:10.1111/j.1610-0387.2012.08017_suppl.x · 1.82 Impact Factor


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