Abstract
IL-10-differentiated dendritic cells (DC10) can reverse the asthma phenotype in mice, but how they suppress the asthmatic B cell response is unclear. Herein we assessed the mechanism(s) by which DC10 and DC10-induced Treg affect IgG1 production in asthma. We observed a rapid decline in lung-resident OVA-specific IgG1-secreting B cells on cessation of airway allergen challenge, and intraperitoneal DC10 therapy did not amplify that (p>0.05). It did however increase the loss of IgG1-B cells from the bone marrow (by 45+/-7.2%; p≤0.01) and spleen (by 65+/-17.8%; p≤0.05) over 2 wk. Delivery of OVA-loaded DC10 directly into the airways of asthmatic mice decreased the lung IgG1 B cell response assessed 2 dy later by 33+/-9.7% (p≤0.01), while their co-culture with asthmatic lung cell suspensions reduced the numbers of IgG1-secreting cells by 56.5+/-9.7% (p≤0.01). This effect was dependent on the DC10 carrying intact allergen on their cell surface; DC10 that had phagocytosed and fully processed their allergen were unable to suppress B cell responses, although they did suppress asthmatic Th2 cell responses. We had shown that therapeutic delivery of DC10-induced Treg can effectively suppress asthmatic T and B cell (IgE and IgG1) responses; herein CD4+ cells or Treg from the lungs of DC10-treated OVA-asthmatic mice suppressed in vitro B cell IgG1 production by 52.2+/-8.7% (p≤0.001) or 44.6+/-12.2% (p≤0.05), respectively, but delivery of DC10-induced Treg directly into the airways of asthmatic mice had no discernible impact over 2 dy on the numbers of lung IgG1-secreting cells (p≥0.05). In summary, DC10 treatment down-regulates OVA-specific B cell responses of asthmatic mice. While DC10 that carry intact allergen on their cell surface can dampen this response, DC10-induced Treg are critical for full realization of this outcome. This suggests that infectious tolerance is an essential element in regulatory DC control of the B cell response in allergic asthma.
Highlights
Allergic asthma is a chronic immunoinflammatory condition of the airways, wherein allergenspecific type 2 helper T (Th2) cells drive B cell isotype switching to IgE and IgG1 antibodies, and the eosinophilic inflammatory response that is pathognomic of this disease
In order to confirm that our OVA-DC10 were tolerogenic in vivo, we used them to treat mice in which we had induced an asthma phenotype, and here too OVA-presenting DC10 significantly down-regulated 2 dy airway Th2 (i.e., IL-4, IL-5 and IL-13) responses to recall allergen challenges issued at 3 wk after DC10 immunotherapy (Fig 1C)
We examined the conditions under which DC10 can suppress the B cell IgG1 response, co-culturing CD19-/lo asthmatic mouse lung cells with DC10 that had not been exposed to any allergen, or ones that had been loaded with either irrelevant or cognate (OVA) allergen
Summary
Allergic asthma is a chronic immunoinflammatory condition of the airways, wherein allergenspecific type 2 helper T (Th2) cells drive B cell isotype switching to IgE and IgG1 antibodies, and the eosinophilic inflammatory response that is pathognomic of this disease. DC10 treatment reverses airway hyperresponsiveness and airway Th2 recall responses to allergen challenge, and reduces the levels of circulating allergen-specific IgG1 and IgE in ovalbumin (OVA) [8,14,15,16] and house dust mite (HDM) [9] mouse models of asthma. It induces Th2 cells in treated mice to transdifferentiate into CD4+CD25+Foxp3+ regulatory T cells (Treg) [9,11,14]. In a manner analogous to DC10, retinoic acid-differentiated DC can reverse food allergen (e.g., peanut) sensitivity in mouse models, ameliorating anaphylactic responses to allergen challenge and reducing allergen-specific IgE and IgG1 levels in fully hypersensitive mice, albeit via distinct mechanisms [17]
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