Résumé
Background: Helicobacter pylori secretes immunomodulatory proteins to render the human immune system tolerant to its presence and avoid clearance. These proteins can also protect against allergic diseases, as evinced by epidemiological studies in humans, and murine allergic disease models. HpVac-R13 is a recombinant molecule derived from one of these immunomodulatory proteins and is undergoing development as a treatment for allergic diseases. We here demonstrate that HpVac-R13 exerts local and systemic immunomodulatory effects through data obtained in cellular assays and a murine model of allergic asthma.Method: The activity of HpVac-R13 was measured on TGF-β and IL- 10 production by human monocyte-derived dendritic cells (DCs) and M2-macrophages (MΦ) and murine bone-marrow-derived DCs and MΦ. This activity was also followed by Luminex for the expression of other cytokines over time. Phenotypic screens were performed using primary human cells from healthy donors, stimulated to model human disease biology, and used to characterize HpVac-R13 activity in 12 different cell systems. A follow-up study was performed on a panel modeling the adaptive immune cell microenvironment with T and B cell responses. HpVac-R13 was administered p.o. or i.p. post-sensitization in a murine model of house dust mite (HDM)-induced asthma, followed by HDM challenge. Asthma phenotype (lung function, histology, and bronchoalveolar liquid (BAL) cellular composition) and immune parameters (T cell subtypes, DCs, B cells) were monitored.Results: HpVac-R13 induced a 10- and 4-fold increase in IL-10 expression and a 15- and 7-fold increase in TGF-β levels in human MΦ and DCs, respectively. The phenotypic screen, including 148 biomarker readouts, revealed a clear anti-inflammatory (decrease in sTNF-a, increase in IL-10 production), anti-proliferative and anti-remodeling profile (induction of MMP-9 & PAI-1, reduction in tPA levels) and no cytotoxicity. This profile was unique, suggesting an entirely novel mode of action. HpVac-R13 administration to HDM-sensitized mice prior to HDM challenge resulted in decreased airway hyperresponsiveness and 2.5-fold decrease in BAL eosinophils.Conclusion: HpVac-R13 exerts local and systemic immunomodulatory effects and protects against airway hyperresponsiveness and lung inflammation in a mouse model of allergic asthma. These data make HpVac-R13 an attractive candidate for the treatment of patients with allergic asthma and other allergic diseases.