The immunomodulatory properties of helminth-derived products on dendritic cell maturation and function
Dowling, David J. (2009) The immunomodulatory properties of helminth-derived products on dendritic cell maturation and function. PhD thesis, Dublin City University.
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Parasitic worms and molecules derived from them drive Th2/Treg immune responses in mammalian hosts and have powerful anti-inflammatory properties which are shown to
have therapeutic effects on inflammatory diseases. Using products derived from the helminth parasites Fasciola hepatica and Ascaris lumbricoides we investigated the
mechanism by which these responses are induced. Dendritic cells (DC’s) play a crucial role in linking the innate to adaptive arms of the immune system and directing the
subsequent immune responses. Here, we report that Fasciola hepatica tegumental antigens (FhTeg) can suppress DC maturation and function. While FhTeg alone did not
induce cytokine production or cell surface marker expression on DCs, it can maintain the DCs in an immature state, suppressing their function to Toll-Like-Receptor (TLR) stimulation and impairing the subsequent development of adaptive immunity. Furthermore, we selected recombinant forms of two major F. hepatica secreted molecules, the protease cathepsin L (rFhCL1) and anti-oxidant, sigma class glutathione S-transferase (rFhGST-si), to examine their interactions with DCs. Despite enzymatic and functional differences between these antigens they both induced IL-6, IL-12p40 and chemokine secretion from DCs in a TLR4 dependent manner. While neither helminth enzyme induced Th2/Treg immune responses both could instruct DCs that suppress IL-17 secretion in vivo. This study also demonstrates that another helminth-derived heterogeneous extract, Ascaris lumbricoides pseudocoelomic fluid (AlPCF), induced partial maturated of DCs as characterised by the increased production of IL-6, IL-12p40 and MIP-2. These DCs were capable of inducing Th2 responses. Overall the data
suggests that helminth parasites secrete multiple molecules each possessing a unique mechanism of modulation, which can either suppress inflammatory Th1/Th17 responses or induce/permit the uninhibited development of modified Th2 responses.
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