9 research outputs found
Immune regulation by allergen immunotherapy:lessons learned from experimental approaches
Veel allergische aandoeningen kunnen onderdrukt worden. Er zijn echter nauwelijks medicijnen die de oorzaak van de ziekte aanpakken en die langdurig werkzaam zijn. Dat is ook het geval bij allergische astma. Omdat er over de oorzaak van deze ziekte weinig bekend is, zijn er geen goede medicijnen beschikbaar. Hadi Maazi en Soheila Shirinbak gingen op zoek naar de cellulaire mechanismen die aan allergische astma ten grondslag liggen. De inzichten die dit onderzoek opleverde kunnen wellicht helpen bij de ontwikkeling van een medicijn tegen allergische astma. Maazi en Shirinbak ontdekten dat FoxP3-positieve regulatoire T-cellen belangrijk zijn voor onderdrukking van de luchtwegontsteking die bij allergische astma een rol spelen. B-cellen, plasmacytoide dendritische cellen en CD8-positieve T-cellen daarentegen zijn niet vereist voor de onderdrukking van luchtwegontsteking, luchtweghyperreactiviteit en allergeen-specifiek IgE responsen. Eerder hadden Maazi en Shirinbak al ontdekt dat ook het cytokine IL-10 een belangrijke rol speelt bij de behandeling van allergische astma. In dit proefschrift brengen ze de precieze rol van dit cytokine in kaart. Tenslotte laten ze zien dat CTLA4-Ig en TGFβ de efficiëntie van de SIT behandeling sterk vergroten
Immune regulation by allergen immunotherapy : lessons learned from experimental approaches
Veel allergische aandoeningen kunnen onderdrukt worden. Er zijn echter nauwelijks medicijnen die de oorzaak van de ziekte aanpakken en die langdurig werkzaam zijn. Dat is ook het geval bij allergische astma. Omdat er over de oorzaak van deze ziekte weinig bekend is, zijn er geen goede medicijnen beschikbaar. Hadi Maazi en Soheila Shirinbak gingen op zoek naar de cellulaire mechanismen die aan allergische astma ten grondslag liggen. De inzichten die dit onderzoek opleverde kunnen wellicht helpen bij de ontwikkeling van een medicijn tegen allergische astma.
Maazi en Shirinbak ontdekten dat FoxP3-positieve regulatoire T-cellen belangrijk zijn voor onderdrukking van de luchtwegontsteking die bij allergische astma een rol spelen. B-cellen, plasmacytoide dendritische cellen en CD8-positieve T-cellen daarentegen zijn niet vereist voor de onderdrukking van luchtwegontsteking, luchtweghyperreactiviteit en allergeen-specifiek IgE responsen. Eerder hadden Maazi en Shirinbak al ontdekt dat ook het cytokine IL-10 een belangrijke rol speelt bij de behandeling van allergische astma. In dit proefschrift brengen ze de precieze rol van dit cytokine in kaart. Tenslotte laten ze zien dat CTLA4-Ig en TGFβ de efficiëntie van de SIT behandeling sterk vergroten.
In this PhD thesis we aimed to unravel the mechanism of action of SIT at cellular level on the one hand and find ways to improve the efficacy of SIT in the other hand in a mouse model of allergic asthma. We found that while FOXP3+ regulatory T cells play a role in SIT-induced suppression of airway eosinophilia, CD8+ T cells, B cells and plasmacytoid dendritic cells play dispensable roles in SIT-induced suppression of airway hyperreactivity, airway eosinophilia and allergen-specific IgE levels in the serum.
Airway responsiveness, lung cell infiltration and OVA-specific IgE serum levels.
<p>Mice (n = 8) were sensitized with OVA/Alum and received 3 OVA or PBS inhalation challenges. TLR-2 agonist (20 µg per mouse in PBS) or PBS was administered intranasally 1 hour before each challenge. Asthma manifestations were measured one day after the last challenge. A: Airway responsiveness to increasing doses of methacholine was measured by whole-body plethysmography and is expressed as enhanced pause (PenH) (gray symbols: PBS-challenged groups, white symbols: OVA-challenged groups, squares: Pam3Cys-treated groups, triangles: PBS-treated groups). B, C: total (B) and differential (C) cell counts in the BAL of OVA-challenged mice. D: OVA-specific IgE levels in the serum of OVA-challenged mice. (E) Lung tissue cytokines measured in lung homogenates of PBS or Pam3Cys (P3C) treated mice as indicated. All values are displayed as average ± SEM (panels A–D) or individual values (dots)+mean (bar) (panel E). Significance is indicated (*) when p<0.05.</p
Airway responsiveness, lung cells infiltration and OVA-specific IgE serum levels.
<p>Mice (n = 8) were sensitized with OVA/Alum and received a first series of 3 OVA inhalation challenges, during which TLR-2 agonist (20 µg per mouse in PBS) or PBS was administered intranasally 1 hour before challenge. After 3 weeks, mice received a second series of 3 inhalation challenges (OVA or PBS). Asthma manifestations were measured one day after the last challenge. A: Airway responsiveness to increasing doses of methacholine was measured by whole-body plethysmography and is expressed as enhanced pause (PenH) (gray symbols: PBS-challenged groups, white symbols: OVA-challenged groups, squares: Pam3Cys-treated groups, triangles: PBS-treated groups). B: total cell counts in the BAL of PBS and OVA-challenged mice as indicated. C: differential cell counts in the BAL of OVA-challenged mice only. D: OVA-specific IgE levels in pre-challenge and post-challenge sera of OVA-challenged mice. (E) Lung tissue cytokines measured in lung homogenates of PBS or Pam3Cys (P3C) treated mice after OVA challenge at timepoint 1 (left-hand panel) or at timepoint 2 (right-hand panel) as indicated. All values in panels A–D are displayed as average ± SEM, panel E displays individual values (dots)+mean (bar). Significance is indicated (*) when p<0.05.</p
Airway responsiveness, BAL cell counts and composition, and OVA-specific IgE serum levels.
<p>Mice (n = 8) were sensitized with OVA/Alum and received 4 OVA or PBS inhalation challenges. TLR-2 agonist (20 µg per mouse in PBS) or PBS was administered intranasally 1 hour before the 2 first challenges. Asthma manifestations were measured one day after the last challenge. A: Airway responsiveness to increasing doses of methacholine was measured by whole-body plethysmography and is expressed as enhanced pause (PenH) (gray symbols: PBS-challenged groups, white symbols: OVA-challenged groups, squares: Pam3Cys-treated groups, triangles: PBS-treated groups). B, C: total (B) and differential (C) cell counts in the BAL of PBS and OVA-challenged mice as indicated. D: OVA-specific IgE levels in the serum of PBS and OVA-challenged mice as indicated. All values are displayed as average ± SEM.</p
Time schedule of the experimental procedures.
<p>Days of sensitization, OVA/PBS challenges, Pam3Cys/PBS treatments and lung function measurements/section are indicated for both the short protocol (A) and the long-term protocol (B).</p
Suppression of Th2-driven airway inflammation by allergen immunotherapy is independent of B cell and Ig responses in mice
Allergen-specific immunotherapy (IT) uniquely renders long-term relief from allergic symptoms and is associated with elevated serum levels of allergen-specific IgG and IgA. The allergen-specific IgG response induced by IT treatment was shown to be critical for suppression of the immediate phase of the allergic response in mice, and this suppression was partially dependent on signaling through Fc gamma RIIB. To investigate the relevance of the allergen-specific IgG responses for suppression of the Th2-driven late-phase allergic response, we performed IT in a mouse model of allergic asthma in the absence of FcgRIIB or Fc gamma RI/Fc gamma RIII signaling. We found that suppression of Th2 cell activity, allergic inflammation, and allergen-specific IgE responses is independent of Fc gamma RIIB and Fc gamma RI/Fc gamma RIII signaling. Moreover, we show that the IT-induced allergen-specific systemic IgG or IgA responses and B cell function are dispensable for suppression of the late-phase allergic response by IT treatment. Finally, we found that the secretory mucosal IgA response also is not required for suppression of the Th2-driven allergic inflammation by IT. These data are in contrast to the suppression of the immediate phase of the allergic response, which is critically dependent on the induced allergen-specific serum IgG response. Hence, IT-induced suppression of the immediate and late phases of the allergic response is governed by divergent and independent mechanisms. Our data show that the IT-induced suppression of the Th2 cell-dependent late-phase allergic response is independent of the allergen-specific IgG and IgA responses that are associated with IT treatment
Suppression of Th2-Driven Airway Inflammation by Allergen Immunotherapy Is Independent of B Cell and Ig Responses in Mice
TLR-2 Activation Induces Regulatory T Cells and Long-Term Suppression of Asthma Manifestations in Mice
<p>Asthma is a chronic inflammatory disease of the airways characterized by variable airway obstruction and airway hyperresponsiveness (AHR). The T regulatory (Treg) cell subset is critically important for the regulation of immune responses. Adoptive transfer of Treg cells has been shown to be sufficient for the suppression of airway inflammation in experimental allergic asthma. Intervention strategies aimed at expanding the Treg cell population locally in the airways of sensitized individuals are therefore of high interest as a potential therapeutic treatment for allergic airway disease. Here, we aim to test whether long-term suppression of asthma manifestations can be achieved by locally expanding the Treg cell subset via intranasal administration of a TLR-2 agonist. To model therapeutic intervention aimed at expanding the endogenous Treg population in a sensitized host, we challenged OVA-sensitized mice by OVA inhalation with concomitant intranasal instillation of the TLR-2 agonist Pam3Cys, followed by an additional series of OVA challenges. Pam3Cys treatment induced an acute but transient aggravation of asthma manifestations, followed by a reduction or loss of AHR to methacholine, depending on the time between Pam3Cys treatment and OVA challenges. In addition, Pam3Cys-treatment induced significant reductions of eosinophils and increased numbers of Treg cells in the lung infiltrates. Our data show that, despite having adverse acute effects, TLR2 agonist treatment as a therapeutic intervention induces an expansion of the Treg cell population in the lungs and results in long-term protection against manifestation of allergic asthma upon subsequent allergen provocation. Our data indicate that local expansion of Tregs in allergic airway disease is an interesting therapeutic approach that warrants further investigation.</p>