However, IL-4, IL-12p40, IL-18, IL-23, and IFN were not detectable in our model. using novel imaging technologies. Subsequently, we studied dermal immune responses and found an enhanced production of regulatory cytokine interleukin (IL)-10, pro-inflammatory cytokine IL-6 and macrophage inflammatory protein (MIP)-1 within 3 days of exposure. Analysis of dermal dendritic cells (DDCs) for their phenotype revealed an increased expression of immune modulators programmed death ligand (PD-L) 1 and 2, and increased IL-10 production. primed DDCs suppress Th1 polarization of na?ve T-cells and increase T-cell IL-10 production, Liquiritigenin indicating their regulatory potential. These immune responses were absent or decreased Rabbit Polyclonal to OR13C4 after exposure to RA parasites. Using transwells, we show that direct contact between APCs and cercariae is required to induce their regulatory phenotype. To the best of our knowledge this is the first study that attempts to provide insight in the human dermal cercariae invasion and subsequent immune responses comparing non-attenuated with RA parasites. We reveal that cercariae induce a predominantly regulatory immune response whereas RA Liquiritigenin cercariae fail to achieve this. This initial understanding of the dermal immune suppressive capacity of cercariae in humans provides a first step toward the development of an effective schistosome vaccine. ((5). Although it is widely accepted that schistosomes are able to direct immune responses via egg-induced immune modulation at late stages of infection, the modulatory effects during the initial stages are less well-defined. Although human dermal immune responses to have not been studied to date, mouse models reveal a mixed immune response to cercariae. In mice, invasion induces inflammation, shown by a dermal infiltrate, which peaks by day 4 post infection (6, 7). From the reports on acute schistosomiasis syndromes it is clear that there is considerable inter-individual variability in the human immune responses to schistosome infection, reflected by variation in cercarial dermatitis and onset of Katayama fever (8C10). Analysis of murine dermal immune responses to larvae revealed an enhanced migration of innate antigen presenting cells (APCs) of such as macrophages (M?) and dendritic cells (DCs), to the skin draining lymph node as well as an increase in their activation markers, MCH class II and CD86 (5, 7, 11C13). Nonetheless, exposure to cercariae does not readily induce protective immunity. This may Liquiritigenin be due to counteracting regulatory cytokine responses in the form of IL-10 and IL-1ra which are mounted in the dermis within 2 days post infection (7, 11, 14). Together these early innate responses in the dermis culminate in a short-lived mixed Th1/Th2 cytokine response in the skin draining lymph node which rapidly declines to baseline (7, 15) resulting in a failure to induce protective immunity against a subsequent infection. One possible way by which cercariae are suggested to achieve immune regulation is by the production of excretory/secretory (ES) products upon transformation into schistosomula, which can suppress (dermal) immune responses (7, 11, 12, 16C20). Proteomic analysis of skin invasion identified a variety of secreted enzymes and factors that are able to degrade host immune defense molecules (20). APCs orchestrate the adaptive immune response to antigens and one molecular mechanism by which APCs are able to inhibit an adaptive immune response is the PD-1/PD-L1 (Programmed Death-1/Programmed Death Ligand-1) interaction. PD-L1 has been described as a regulatory marker on APCs and is linked to the induction of immunological tolerance (21C23). In tumor immunology, PD-L1 up regulation leads to immune-escape and T-cell anergy upon ligation with PD-1 (24C26), and PD-L1 has been shown to play a pivotal role in the polarization of na?ve CD4+ T cells to regulatory T cells (Tregs) (27). The role of PD-L2, the other known PD-1 ligand, is.