brasiliensis model. The CCR3 receptor would be a logical target for blockade or deletion, because this is the only known receptor for the murine eotaxins. This might be performed in conjunction with inhibition of the C5a receptor, and as previously (75,76), with co-expression of the IL-5 transgene. The cytokines IL-4 and IL-13 and the STAT6 PD-L1 inhibitor signalling pathway through which they work are important for eosinophil recruitment into the skin following N. brasiliensis infection and most importantly, deletion of these genes or the IL-4Rα chain gene, results in higher lung larval burdens during secondary infections (76). IL-4, IL-13 and STAT6 had previously been shown to be important for resistance

at the level of the gut, with gene deletion delaying the clearance of intestinal larvae and adult worms in primary infections (72,85). Our recent findings have now highlighted the importance of these cytokines Protein Tyrosine Kinase inhibitor for early resistance to larvae and this may be a critical result when developing vaccines for helminths such as the hookworms, S. stercoralis and Schistosoma, which enter the host via the skin. In addition to facilitating the recruitment of eosinophils, complement also mediates attachment to N. brasiliensis larvae in vitro and in vivo (78,79). C3 can be detected on infectious-stage larvae incubated with sera from WT, C1qa−/−

and C4−/− mice and these sera facilitate the adherence Niclosamide of eosinophil-rich leucocyte populations (78). In contrast, C3 cannot be detected on L3 incubated with sera from factor B−/− and C3−/− mice, and leucocyte adherence is inhibited in this context. Infective-stage larvae activate murine complement via the alternative pathway, but lung-stage (L4) larvae also activate complement via the lectin pathway (78). Endogenously derived C3 products are readily detectable on larvae recovered from the skin within 30 min of injection, but are found at much lower levels by 150 min pi. Leucocyte adherence to 24- and 48-h lung larvae is also minimal, even when an exogenous source of complement is provided (78). Collectively, these data suggest that late-stage skin and lung-stage larvae upregulate expression of an

inhibitor of complement deposition or a factor capable of rapidly degrading C3, and this may inhibit leucocyte recruitment and adherence to larvae in the lungs up to 48 h pi. Within 30–150 min of injection into skin air pouches, larvae aggregate into very large clumps, and this is largely dependent on the alternative pathway of complement activation (75). Whilst it is difficult to mechanically dissociate these clumps in vitro (75), clearly 80-90% of larvae can escape from the skin during the first few hours of infection in a susceptible WT host (65). In contrast, in IL-5 Tg hosts larvae can be trapped in the skin for up to 24 h and are usually surrounded by a strong inflammatory infiltrate in which eosinophils predominate (65).