To assess the role of osteopontin in the regulation of T helper 2 (TH2)-cell-mediated allergic responses, Xanthou et al. used an established mouse model of ovalbumin (OVA)-induced allergic airway inflammation. In this model, airway inflammation is induced by sensitization with OVA plus alum followed by airway challenges with OVA. The authors show that if mice were given a neutralizing antibody specific for osteopontin before the sensitization phase, the inflammatory response to subsequent OVA challenges was significantly diminished compared with control mice. Thus, the antibody-treated mice showed decreased airway hyper-responsiveness (AHR), a reduced inflammatory-cell infiltrate (including TH2 cells) in the lung-draining lymph nodes and lower levels of TH2-cell-associated cytokines, such as interleukin-4 (IL-4) and IL-13, in lymph-node cultures. By contrast, if osteopontin-specific neutralizing antibody was administered to mice immediately before secondary challenge with OVA, the opposite effect was observed — AHR worsened, the inflammatory-cell infiltrate increased and the levels of TH2-type cytokines were higher. So, neutralization of osteopontin seems to have different effects depending on the stage of the allergic response.
How might this dichotomy be achieved? Plasmacytoid DCs (pDCs) have been shown to have a suppressive effect on TH2-cell responses, so the authors tested whether osteopontin blockade at the sensitization phase might affect pDC recruitment. Indeed, compared with control mice, mice treated with osteopontin-specific antibody before sensitization showed increased numbers of pDCs in the draining lymph nodes. Importantly, the depletion of pDCs before sensitization and antibody treatment restored OVA-driven responses, indicating that the decrease in TH2-cell priming observed after osteopontin blockade was mediated by increased numbers of pDCs that have a regulatory function. Conversely, during secondary challenge, osteopontin blockade caused a more marked increase in the recruitment of conventional DCs than pDCs to the draining lymph nodes. In co-cultures, conventional DCs from these draining lymph nodes promoted the differentiation of OVA-specific CD4+ T cells into TH2 cells. So, the increased recruitment of immunogenic conventional DCs provides an explanation for the enhanced TH2-cell responses observed after osteopontin blockade at the secondary challenge.
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