Title: Involvement of the TH1 inflammatory T cells in a mouse model of allergic asthma
Other Titles: Rol van Th1 inflammatoire T cellen in een muismodel van allergisch astma
Authors: Meyts, Isabelle
Issue Date: 5-Jul-2007
Abstract: Asthma is a chronic inflammatory disorder of the respiratory system, characterized by reversible airflow obstruction and by airway hyperresponsiveness, an exaggerated bronchospastic response to non-specific agents such as metacholine or histamine. In general, two subtypes of asthma are distinguished. Extrinsic/allergic asthma affects 60-90% of asthma patients, occurs in the context of sensitization towards environmental allergens and is accompanied by elevated serum IgE levels (total and allergen-specific). The prevalence of allergic asthma has been increasing over thelast decades with approximately 10% of the adult population and 20% of children in Northern America, Europe and Australia suffering from asthma. This rise is up till now ill-explained. Because asthma causes significant morbidity and mortality, further research into the pathophysiological mechanisms of allergic asthma is warranted. This might also leadto new therapeutic and/or preventive strategies. Provocation of an allergic asthmatic individual with allergen results in airway narrowing within 15 minutes after inhalation as a result of mast cell degranulation (the early phase response). In a subset of patients, this airway obstruction persists or recurs after several hours to reach a maximum over 6 to 12 hours, resolving within 24 hours (the late phase response). The LPR is believed to reflect local influx and activation of inflammatory cells (CD4+ T cells, eosinophils, neutrophils) in the airway. Th (T helper) cells are the key players in adaptive immune responses and in inflammation. In the allergic type of asthma, inhaled allergen is taken up and processed by specialized antigen-presenting cells, the dendritic cells into peptides, which are presented to antigen-specific T helper cells (Th) in the context of MHC class II. Activated T cells then secrete cytokines that lead to inflammation. Two subsets of Th cells were identified in mice: murine Th1 cells produce IL-2, IFN-g and TNF-b but noIL-4 or IL-5 whereas Th2 cells produce IL-4, IL-5, IL-13 but no IL-2 orIFN-g. In asthma, the hypothesis is that activated CD4+ Th2 cells and the gamma of cytokines they elaborate (IL-13, IL-4, IL-5, and IL-9) initiate and sustain airway inflammation.In this doctoral research project, we used a murine model of ovalbumin(OVA)-allergic airway inflammation with a biphasic protocol consisting ofsystemic sensitization with adjuvant-free OVA and airway challenges with nebulized OVA. Accordingly treated mice exhibit features reminiscent of clinical asthma and represent a useful research tool to further investigate the immunological background of allergic airway inflammation.In this model, we have elicited an allergen-specific late increase in bronchial tone accompanied by dramatic increases in lymphocyte, eosinophils, neutrophil and macrophage numbers and by a Th2 cytokine pattern bothin the broncho-alveolar lavage and in the lung tissue. Depletion of CD4+ cells but not CD8+ cells prior to allergen provocation is capable of completely abolishing the late response both in terms of bronchial tone and cellular influx. The mechanism behind this finding remains ill-explained, although changes in cytokine (IL-13, IFN-g) and chemokine (MCP-1) and VCAM-1 expression seem to be involved. These data offer more support to the essential role of T cells in allergic asthma and also provide a model that will be suitable for exploring underlying mechanisms.It has been widely believed that the pathological Th2 responses in asthma, can be dampened by enhancing Th1 responses. Here, we show that neutralization of IL-12, a Th1-inducing cytokine, at a late stage, i.e. during the course of the repeated airway challenges in previously sensitized mice attenuated the allergen-induced phenotype of experimental asthma: AHR, Th2 cytokine production and allergen-specific IgE were all profoundly reduced, concomitantly with a reduction of the CD3(+)CD4(+) lymphocytes and of eosinophils in the BAL fluid. These effects of neutralization during the challenge phase were quite unexpected and provide evidence fora crucial role for IL-12 in the effector phase of allergic airway inflammation. This unexpected pro-inflammatory effect of IL-12 in allergic airway disease was not demonstrated in IFN-g-KO mice. These data not only suggest that Th1 and Th2 cells coexist in the pathogenesis of asthma, but also imply that IFN-g, the prototypic Th1 cytokine is a key player in asthma.Recently, the Th17 cells have been accepted to represent a distinct effector cell lineage. Their role in allergic airway inflammation remains elusive. In this thesis, we show a dose-dependent IL-17-induced increased expression of IL-5 by monoclonally stimulated T cells. Moreover, we have shown that both neutrophils and macrophages are increased in theBAL fluid after intra-tracheal administration of IL-17 in both naïve and allergic mice; surprisingly however without any overt effect on the bronchial tone. Finally, neutralization of IL-17 during the sensitization phase led to decreased levels of IgE together with a rise in AHR and cellular airway infiltration, suggestive of enhanced Th2 sensitization in the absence of IL-17 during priming. Our data suggest that the interaction between IL-17/Th17 and naïve T cells and Th2 cells is complex and incompletely understood.Our work certainly demonstrates that the relation between the severity of airway inflammation and the severity of asthma measured as AHR and FEV1 is not clear-cut. Also, the data presented here suggest that asthma pathogenesis is driven by a mixed Th1/Th2/Th17 response. Thisimplies that regulatory mechanisms, distinct from the Th1 immune responses, are involved in the suppression of established inflammation and in the protection against allergic disease. Further research is needed to unravel these regulatory mechanisms and to –hopefully- apply them in the clinical situation. Maybe in this way, asthma will finally become a curable and preventable disease.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Laboratory of Pediatric Immunology
Laboratory of Clinical Immunology
Section Child - Miscellaneous (-)

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