Tolerogenic Dendritic Cells Reverse Eosinophilic Airway Inflammation And Th2 Cytokine Expression In Experimental Allergic Asthma

Asthma is a kind of disease that harms human seriously. Most cases of the disease are allergic asthma which is characterized by severe infiltration of eosinophils into the lung, enhanced mucus production in respiratory tract and airway hyperresponsiveness(AHR). These changes will lead to a series of clinical manifestation such as repeating expiratory dypnea, cough and expectoration, etc. At present, the major methods to treat allergic asthma are still reducing those symptoms. There is much necessity to seek more effective and safer treatments to inhibit the airway allergic disease.It has been confirmed that airway dendritic cells (DCs) distribute widely in the respiratory tract mucosa and the lung parenchyma, which is the critical factor to determine individuals to respond to some specific kind of antigen or to tolerate it. In the healthy state, airway immature DCs uptake and process the self-antigen (Ag) or innocuous non self-Ag, then migrate to draining lymph nodes and present Ag peptide to Ag-specific T lymphocytes. As a result, such specific clones of T cellspeptide to Ag-specific T lymphocytes. As a result, such specific clones of T cells will be soon deleted or forbidden. However, while some "innocuous" Ag (allergen) inhaled by allergic individuals, after capturing, processing and presenting the allergen by airway DCs, Ag-specific T cell clones will be activated and allergic airway inflammation mediated by T helper 2 cells will be arised.DCs can induce both tolergenic as well as inflammatory immune response in the lung. Studies in mouse models of asthma have revealed a critical role for airway DCs in the induction of Th2 sensitization to allergens. It is known that airway immature DCs (imDC) succeed in establishing tolerance to the innocuous antigen and maintain the steady state of the respiratory system. ImDC can also inhibit inappropriate immune response by induce generation of regulatory T cells. Since imDCs are tolerogenic, they have been considered as potential vaccination to inhibit some autoimmune diseases. It is found that DCs treated in vitro by IL-10 had more potent capacity to induce tolerance. The object of our work is to confirm whether adoptive transferred cognate tolerogenic DCs (including innate imDCs and in vitro IL-10-modified imDCs, named imDC_IL-10 ) can inhibit mice airway allergic inflammation, and to obtain some instructive ideas for treating human asthma.BALB/c mice were sensitized by ovalbumin (OVA) protein. The procedure is shown as followings: On day 0, mice were injected subcutaneously (s.c.) with alum (Al(OH)3)-precipitated OVA at both groins;On day 9, mice were given intraperitoneum (i.p.) injection of alum-precipitated OVA;From day 14 to day 20, mice were challenged intratracheally (i.t) with 1% OVA in saline aerosols daily. Bone marrow-derived imDCs were adoptive transferred into mice models 7 days before the first time of OVA injection. On day 21 (the next day of the last i.t. challenge), the mice were sacrificed and samples were collected. The effect of transferred imDCs on the infiltration of inflammatory cells into the lung, airway goblet cell hyperplasia and cytokine releasing in sensitized mice were studied.Meanwhile, We also investigated the effect of in vitro IL-10-treated imDCs (imDCiL-io) to reduce mice airway allergic inflammation, and compared the efficiencies of the two tolerogenic DC types in the allergic mouse model.Our results showed that bone marrow-derived BALB/c imDCs and imDC il-io expressed lower level of MHC II and co-stimulatory molecules including CD80, CD86, CD40 and CD54 than mDCs. Both imDCs and imDC iL-io were less potent than mDCs to induce T cell proliferation in vitro. So, such imDCs or imDC il-io were considered as tolerogenic DCs. After transferred into the mice models, the two types of tolerogenic DCs showed similar potency to decrease numbers of lung eosinophils and inflammatory cells, to reduce airway mucosa production, and to inhibit overexpression of Th2 type cytokine IL-13 and IL-4 in mice models of asthma. Moreover, the ratio of splenic CD4+CD25+ regulatory T cells were increased after immunization with imDCs or imDC il-io- It is well known that CD4+CD25+ regulatory T cells are the potent inhibitor of immune response and play crucial roles in peripheral tolerance induction. However, there was no significant difference between imDCs and imDCiL-io as far as their efficiency to alleviate airway allergic inflammation is concerned. In conclusion, vaccination of toerogenic DCs is effective to ameliorate mice asthma-like symptoms via the mechanisms of decreasing Th2 cytokine secretion and augmenting CD4+CD25+ T cells expression. Tolergenic DC-based vaccination strategies could be one of the clinical candidates to prevent or treat the development of allergic asthma, however, experimental conditions and effective protocols still have to be improved.