Jennifer A. Thomas

APCs, including dendritic cells (DC), are central to Ag surveillance in the respiratory tract (RT). Research in this area is dominated by mouse studies on purportedly representative RT-APC populations derived from whole-lung digests, comprising mainly parenchymal tissue. Our recent rat studies identified major functional differences between DC populations from airway mucosal vs parenchymal tissue, thus seriously questioning the validity of this approach. We addressed this issue for the first time in the mouse by separately characterizing RT-APC populations from these two different RT compartments. CD11c(high) myeloid DC (mDC) and B cells were common to both locations, whereas a short-lived CD11c(neg) mDC was unique to airway mucosa and long-lived CD11c(high) macrophage and rapid-turnover multipotential precursor populations were predominantly confined to the lung parenchyma. Airway mucosal mDC were more endocytic and presented peptide to naive CD4+ T cells more efficiently than their lung counterparts. However, mDC from neither site could present whole protein without further maturation in vitro, or following trafficking to lymph nodes in vivo, indicating a novel mechanism whereby RT-DC function is regulated at the level of protein processing but not peptide loading for naive T cell activation.

An increase in the tempo of local dendritic cell (DC)-mediated immune surveillance is a recognized feature of the response to acute inflammation at airway mucosal surfaces, and transient up-regulation of the APC functions of these DC preceding their emigration to regional lymph nodes has recently been identified as an important trigger for T cell-mediated airway tissue damage in diseases such as asthma. In this study, using a rat model, we demonstrate that the kinetics of the airway mucosal DC (AMDC) response to challenge with heat-killed bacteria is considerably more rapid and as a consequence more effectively compartmentalized than that in recall responses to soluble Ag. Notably, Ag-bearing AMDC expressing full APC activity reach regional lymph nodes within 30 min of cessation of microbial exposure, and in contrast to recall responses to nonpathogenic Ags, there is no evidence of local expression of APC activity within the airway mucosa preceding DC emigration. We additionally demonstrate that, analogous to that reported in the gut, a subset of airway intraepithelial DC extend their processes into the airway lumen. This function is constitutively expressed within the AMDC population, providing a mechanism for continuous immune surveillance of the airway luminal surface in the absence of "danger" signals.

The nonselective glucocorticoid receptor (GR) antagonist mifepristone has been approved in the U.S. for the treatment of selected patients with Cushing's syndrome. While this drug is highly effective, lack of selectivity for GR leads to unwanted side effects in some patients. Optimization of the previously described fused azadecalin series of selective GR antagonists led to the identification of CORT125134, which is currently being evaluated in a phase 2 clinical study in patients with Cushing's syndrome.

Airway mucosal dendritic cells (AMDC) and other airway APCs continuously sample inhaled Ags and regulate the nature of any resulting T cell-mediated immune response. Although immunity develops to harmful pathogens, tolerance arises to nonpathogenic Ags in healthy individuals. This homeostasis is thought to be disrupted in allergic respiratory disorders such as allergic asthma, such that a potentially damaging Th2-biased, CD4(+) T cell-mediated inflammatory response develops against intrinsically nonpathogenic allergens. Using a mouse model of experimental allergic airways disease (EAAD), we have investigated the functional changes occurring in AMDC and other airway APC populations during disease onset. Onset of EAAD was characterized by early and transient activation of airway CD4(+) T cells coinciding with up-regulation of CD40 expression exclusively on CD11b(-) AMDC. Concurrent enhanced allergen uptake and processing occurred within all airway APC populations, including B cells, macrophages, and both CD11b(+) and CD11b(-) AMDC subsets. Immune serum transfer into naive animals recapitulated the enhanced allergen uptake observed in airway APC populations and mediated activation of naive allergen-specific, airway CD4(+) T cells following inhaled allergen challenge. These data suggest that the onset of EAAD is initiated by enhanced allergen capture and processing by a number of airway APC populations and that allergen-specific Igs play a role in the conversion of normally quiescent AMDC subsets into those capable of inducing airway CD4(+) T cell activation.