Etude de l'implication des cellules iNKT dans l'asthme allergique expérimental

Abstract : Asthma is a manifold syndrome consisting in eosinophil-rich airway inflammation, bronchospasm and airway hyperreactivity (AHR), which has recently increased dramatically in prevalence in the industrialized world. In the past few decades it has become clear that the pathogenesis and severity of asthma are mediated through T helper 2 (Th2) lymphocytes. However, the immunological mechanisms that downmodulate or amplify the development of this disease are poorly understood. In our study we highlighted the critical influence of invariant Natural Killer T (iNKT) cells in the severity of experimental allergic asthma. iNKT cells constitute a distinctive population of mature T lymphocytes positively selected by the non-polymorphic MHC class-I-like molecule, CD1d. These lymphocytes coexpress a highly restricted T-cell receptor (TCR) repertoire, composed of a single invariant Va14Ja18 chain in mice and a Va24Ja18 chain in humans, preferentially paired with a limited TCR Vb chain repertoire. iNKT cells specifically recognize glycolipids such as the a-galactosylceramide (a-GalCer). The spectrum of actions attributed to iNKT cells is particularly broad. They are implicated in controlling immune responses against infections, autoimmune diseases, contact sensitivity and tumors.

Here, we found that Th2-type asthma was attenuated in iNKT cell-deficient Ja18-/- mice, which had been immunized and challenged with ovalbumin (OVA) to elicit hyperimmune allergic asthma. OVA airway-challenged iNKT-deficient (Ja18-/-) mice had significantly reduced IL-4 and IL-5 levels in bronchoalveolar lavage fluid (BALF), decreased serum IL-5 and anti-OVA IgE antibodies, inhibited eosinophilic airway inflammation, and reduced airway hyperreactivity (AHR), the major symptom of asthma, compared to wild-type mice. Adoptive transfer of wild-type iNKT-enriched splenic cells into immunized and boosted Ja18-/- mice confirmed the involvement of iNKT cells in this model.

Based on our findings showing the requirement of iNKT cells in the severity of allergic asthma, we further examined whether a-GalCer treatment could influence asthma development. We found that a single i.v. injection of a-GalCer, 1 h before the first airway allergen challenge of OVA-sensitized mice, abrogates elicitation of AHR, airway eosinophilia, IL-4 and IL-5 production in BALF, and specific anti-OVA IgE antibodies. Further, a-GalCer administered intranasally also strongly inhibited the major symptoms of asthma in sensitized and challenged mice. This protection can be transferred to OVA-sensitized recipients mice by splenocytes from OVA-sensitized, a-GalCer treated mice. The role of IFN-g from iNKT cells in protection was shown by adoptive transfer of sorted iNKT cells from OVA-sensitized and a-GalCer-treated mice which protected immunized recipients from manifesting asthma by an IFN-g-dependent pathway.

In conclusion, our findings demonstrate that iNKT cells could either aggravate the symptoms of asthma intrinsically by promoting Th2-type cytokine production or exert a protective pro-Th1 effect when stimulated exogenously by a-GalCer, which induces a preferential production of IFN-g. Therefore, our results raise the possibility that local a-GalCer treatment, acting specifically on iNKT cells, might provide novel therapeutic strategies to reduce allergic asthma.
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Immunology. Université René Descartes - Paris V, 2006. French


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Submitted on : Monday, July 10, 2006 - 12:45:45 PM
Last modification on : Tuesday, July 11, 2006 - 4:07:51 PM

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Patricia Hachem. Etude de l'implication des cellules iNKT dans l'asthme allergique expérimental. Immunology. Université René Descartes - Paris V, 2006. French. <tel-00084723>

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