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1.  Inhaled iloprost suppresses the cardinal features of asthma via inhibition of airway dendritic cell function 
Journal of Clinical Investigation  2007;117(2):464-472.
Inhalation of iloprost, a stable prostacyclin (PGI2) analog, is a well-accepted and safe treatment for pulmonary arterial hypertension. Although iloprost mainly acts as a vasodilator by binding to the I prostanoid (IP) receptor, recent evidence suggests that signaling via this receptor also has antiinflammatory effects through unclear mechanisms. Here we show in a murine model of asthma that iloprost inhalation suppressed the cardinal features of asthma when given during the priming or challenge phase. As a mechanism of action, iloprost interfered with the function of lung myeloid DCs, critical antigen-presenting cells of the airways. Iloprost treatment inhibited the maturation and migration of lung DCs to the mediastinal LNs, thereby abolishing the induction of an allergen-specific Th2 response in these nodes. The effect of iloprost was DC autonomous, as iloprost-treated DCs no longer induced Th2 differentiation from naive T cells or boosted effector cytokine production in primed Th2 cells. These data should pave the way for a clinical effectiveness study using inhaled iloprost for the treatment of asthma.
doi:10.1172/JCI28949
PMCID: PMC1783814  PMID: 17273558
2.  Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function 
Journal of Clinical Investigation  2006;116(11):2935-2944.
Airway DCs play a crucial role in the pathogenesis of allergic asthma, and interfering with their function could constitute a novel form of therapy. The sphingosine 1–phosphate receptor agonist FTY720 is an oral immunosuppressant that retains lymphocytes in lymph nodes and spleen, thus preventing lymphocyte migration to inflammatory sites. The accompanying lymphopenia could be a serious side effect that would preclude the use of FTY720 as an antiasthmatic drug. Here we show in a murine asthma model that local application of FTY720 via inhalation prior to or during ongoing allergen challenge suppresses Th2-dependent eosinophilic airway inflammation and bronchial hyperresponsiveness without causing lymphopenia and T cell retention in the lymph nodes. Effectiveness of local treatment was achieved by inhibition of the migration of lung DCs to the mediastinal lymph nodes, which in turn inhibited the formation of allergen-specific Th2 cells in lymph nodes. Also, FTY720-treated DCs were intrinsically less potent in activating naive and effector Th2 cells due to a reduced capacity to form stable interactions with T cells and thus to form an immunological synapse. These data support the concept that targeting the function of airway DCs with locally acting drugs is a powerful new strategy in the treatment of asthma.
doi:10.1172/JCI28295
PMCID: PMC1626118  PMID: 17080194
3.  An unexpected role for the anaphylatoxin C5a receptor in allergic sensitization 
Journal of Clinical Investigation  2006;116(3):628-632.
The anaphylatoxins complement component 3a and 5a (C3a and C5a, respectively) are classically seen as proinflammatory mediators of allergic asthma that recruit inflammatory cells, induce edema, and cause bronchoconstriction. A few years ago, controversy arose when it was shown that C5-deficient mice were more susceptible to experimental asthma compared with C5-sufficient mice. In a study by Köhl et al. in this issue of the JCI, it is shown in a series of truly “complementary” experiments that C5a receptor (C5aR) blockade promotes Th2 sensitization upon first exposure to inhaled allergen, whereas C5aR blockade during established inflammation suppresses the cardinal features of asthma. Blockade of C5aR alters the function of airway DCs, crucial for inducing and maintaining Th2 responses in the lung. Targeting C5aR as a treatment for established asthma could be beneficial, but might be accompanied by sensitization to novel antigens.
doi:10.1172/JCI27876
PMCID: PMC1386114  PMID: 16511597
4.  Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation 
Journal of Clinical Investigation  2000;106(4):551-559.
The aim of this study was to investigate whether dendritic cells (DCs) can induce sensitization to aeroallergen in a mouse model of allergic asthma. Ovalbumin-pulsed (OVA-pulsed) or unpulsed myeloid DCs that were injected into the airways of naive mice migrated into the mediastinal lymph nodes. When challenged 2 weeks later with an aerosol of OVA, activated CD4 and CD8 lymphocytes, eosinophils, and neutrophils were recruited to the lungs of actively immunized mice. These CD4+ lymphocytes produced predominantly IL-4 and IL-5 but also IFN-γ, whereas CD8+ lymphocytes produced predominantly IFN-γ. Histological analysis revealed perivascular and peribronchial eosinophilic infiltrates and goblet cell hyperplasia. Studies in IL-4–/– and CD28–/– mice revealed that production of IL-4 by host cells and provision of costimulation to T cells by DCs were critical for inducing the response. Lung CD4+ T cells strongly expressed the Th2 marker T1/ST2, and signaling through this molecule via a ligand expressed on DCs was essential for the establishment of airway eosinophilia. These data demonstrate that DCs in the airways induce sensitization to inhaled antigen and that molecules expressed on the surface of these cells are critical for the development of Th2-dependent airway eosinophilia.
PMCID: PMC380243  PMID: 10953030

Results 1-4 (4)