P. Zaccone et al. Table 3 Infectious agents or their products that prevent T1D in NOD mice Parasite Immunology © 2006 The Authors Journal compilation © 2006 Blackwell Publishing Ltd, Parasite Immunology, 28, 515–523 Agent or product Schistosoma mansoni Schistosoma mansoni eggs Schistosoma mansoni soluble worm antigen (SWA) Schistosoma mansoni soluble egg antigen (SEA) Heligmosomoides polygyrus Trichinella spiralis Mycobacterium bovis Mycobacterium avium Salmonella typhimurium Mouse hepatitis virus (MHV) system, often inducing a long-lasting asymptomatic form of infection (37,38). Parasitic worms can establish and reproduce in mammalian hosts, switching off the inﬂammatory immune response and inducing a tolerant response to parasite antigens. Following encounter with S. mansoni antigens, profound changes are observed in the innate immune system of the host, including modiﬁcation of DC, MΦ, and NKT cells, phenotype and cytokine secretion (39,40). S. mansoni antigens can induce the secretion of regulatory cytokines from these cells as well as B1 B cells (41), resulting in the expansion of Th2 and Treg populations that might be responsible for maintaining self-tolerance (42– 45) (see Figure 3). DC and MΦ are fundamental to directing immune responses along either a tolerating or activating pathway, therefore it is not surprising that helminths have evolved strategies targeting receptors on these cells. Toll like receptors (TLRs) and C- type lectin receptors (CLRs), broadly expressed on DCs and MΦs, are the main parasite targets for evading immuno- surveillance (46). More speciﬁcally, glycosylated molecules (expressed and secreted by S. mansoni) bind to the CLR and antagonize a TLR pro-inﬂammatory pathway (47). Numerous studies have shown that S. mansoni products induce IL-10 production by DCs and have a direct anti-inﬂammatory effect on DCs by controlling TLR ligand-induced DC maturation (48). S. mansoni has also been shown to induce alternatively activated MΦ, which secrete small amounts of inﬂammatory mediators and inhibit T cell proliferation (49). The inﬂuence of helminth products on the innate immune system is not just restricted to DCs. Depending on the nature of the pathogen, NKT cells can direct the immune response in an appropriate direction by secreting a wide variety of pro- and anti-inﬂammatory cytokines (50). Schistosomes are rich in glycosylated molecules, which heavily decorate their integument or are actively secreted, and glycolipids presented by CD1d (a non-classical MHC molecule) on antigen presenting cells (APCs) may thus be able to activate regulatory NKT cells (51). 520 Th1/Th1 bias Reference Th2 Th2 Th2 Th2 Th2 Th2 Th1 Th1 Th1 Th1 (31) (32) (32) (32) C. Lawrence, unpublished data C. Lawrence, unpublished data (33) (34) (35) (36) One of the most obvious and well-documented responses to S. mansoni is the Th2 dominance in the T cell population. Any initial Th1 response to the parasite is quickly redirected to a state of quiescence (52). The cytokine environment is fundamental for this purpose: large amounts of IL-4, IL-5 and IL-13 are secreted from the T cell pool, reinforcing not just T cell polarization, but also the anti-inﬂammatory loop on DC and MΦ (32). The parasite is also capable of containing the side-effects of such a strong Th2 response, inducing the secretion of IL-10 and TGF-β by other T cell subtypes (53,54). For example, animals and humans infected or exposed to S. mansoni antigens do not automatically develop allergies at a higher incidence (see Figure 3). The de novo induction and /or the expansion /recruitment of Treg almost certainly underlies the ability of many parasites to both evade a sterilizing immune response and also suppress both Th1 and Th2 arms of the adaptive immune system (55,56). THERAPEUTIC APPLICATION OF PARASITE PRODUCTS AND FUTURE PROSPECTS Helminths are exquisitely adapted to evading and modulating the mammalian immune response; and interestingly similar evasion mechanisms can be shared among distantly related species (see Table 4). This begs the obvious question of whether this ability can ever be exploited for therapeutic purposes. The growing body of epidemiological and experimental data detailed above strongly suggests that a reduction in helminth infection is linked to rising rates of autoimmunity and atopy. This offers the real possibility that helminths applied in a controllable clinical setting, could relieve inﬂammatory disease yet minimize the adverse effects of the parasite. Indeed, several models of autoimmune disease have validated the potential of such an approach. Although still a very young ﬁeld, limited clinical trials have already been carried out assessing the effects of the porcine whipworm, Trichuris suis, on IBD