Identification of immunomodulatory molecules. Both invasive cercariae and eggs release molecules that have important immunoregulatory functions. Cercarial excretory/secretory (ES) products inhibit in vitro proliferation of human PBMCs from schistosome-infected patients stimulated with adult worm antigens. Cercarial ES products released within 3 hrs of transformation (0-3hRP) also activate murine DCs to a ‘modified’ phenotype by expressing low levels of costimulatory molecules. These DCs resemble ones stimulated with soluble egg antigen (SEA) in that they exist in a state of pathogen-induced suppression to other unrelated microbial products. In fact, 0-3hRP inhibits IL-12 production by MΦ stimulated with bacterial LPS, further supporting the immunomodulatory nature of molecules within cercarial ES products. Various glycan structures from schistosomes have immunomodulatory functions (e.g.Lacto-N-fucopentaose III;LNFPIII) that terminate in LewisX, a carbohydrate moiety found on many schistosome glycoproteins and glycolipids. Significantly, murine DCs activated with LNFPIII drive Th2-type responses, although those activated with lacto-neotetraose, a non-fucosylated derivative of LNFPIII, do not. Multivalent LewisX/LNFPIII has a strong propensity to modulate the immune response through the induction of IL-10 by PBMC and B-1 cells, and molecules that express LewisX, α1-3-linked fucose, or difucosylated LDN are present on cercariae and eggs. The ES products of both cercariae and eggs contain an abundance of glycan-rich structures with predicted immunoregulatory function. One approach towards defining the immunomodulatory function of the glycan structures is to chemically deglycosylate parasite proteins that lose their ability to stimulate Th2-type responses.
In humans, DCs co-cultured with schistosome glycolipids mature fully but show impaired IL-12 production. These DCs induce polarization of naïve T cells towards the Th2 subset, as well as towards IL-10- producing Treg cells. Studies indicate that phosphatidylserine molecules (containing two acyl chains) modify DCs such that they are capable of inducing Th2 responses, while lyso-phosphatidylserine (Lyso-PS) molecules (containing one acyl chain) are responsible for interacting with DCs that then induce IL-10-producing Treg cells. These Treg cells are defined by their ability to suppress effector T cell proliferation. Given the central role of DCs in immune activation and polarization, these studies confirm that schistosome-derived molecules (structures not shared by mammalian host) can modify immune responses and may present an, as yet, untapped source of immunomodulatory molecules.