Important insights have recently been gained in our understanding of how host immune responses mediate resistance to parasitic helminths and control associated pathological responses. Although similar cells and cytokines are evoked in response to infection by helminths as diverse as nematodes and schistosomes, the components of the response that mediate protection are dependent on the particular parasite. In this Review, we examine recent findings regarding the mechanisms of protection in helminth infections that have been elucidated in murine models and discuss the implications of these findings in terms of future therapies.More than two billion people are infected with parasitic helminths 1 . Although infections by these pathogens are generally not fatal, they are associated with high rates of morbidity, with chronic infection often leading to anaemia and malnourishment 1 . Developed countries have controlled these infections through primary health-care programmes and effective public sanitation, but helminth diseases are still widespread in developing nations and often drug treatment does not protect against rapid re-infection. The need for effective vaccines to control these infections is compelling and at least a few clinical trials are currently underway 2,3 ; however, one impediment towards development of an effective vaccine is a lack of understanding of the actual components of the immune response that mediate protection against helminths. In this Review, we examine the host protective mechanisms with regard to the cell types and molecules involved in helminth expulsion and in control of pathological inflammation that is associated with infection.Helminth infections and the corresponding host immune responses are products of a prolonged dynamic co-evolution between the host and parasite. For parasites, it is advantageous to trick the host into developing an ineffective immune response, to find a suitable niche for maturation and propagation, and to do so without killing or unduly harming the host. Conversely, the host NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript has to ideally generate an effective immune response to expel the parasite, and minimize its harmful effects, while not sacrificing its ability to effectively respond to other pathogens. The host immune system evolved in the context of a parasite-replete environment, and the balance of immune effector and regulatory cell populations are at least partly a consequence of ongoing responses to infectious organisms that can often simultaneously invade host tissues. Although such dynamic host-pathogen interactions exist throughout much of the world, in industrialized countries infectious diseases are better controlled as a result of increased hygiene, the administration of vaccines at an early age and the widespread use of antibiotics. Although this has resulted in marked reductions in chronic and severe disease, recent studies indicate a possible adverse effect of this enhanced control of infectious diseases that...

C57BL/6 mice infected with the helminth Schistosoma mansoni develop small hepatic granulomas around parasite eggs, but concomitant immunization with soluble schistosome egg Ags (SEA) in CFA (SEA/CFA) causes marked exacerbation of the lesions in a Th1-dominated environment characterized by high levels of IFN-γ. We explored the cause of the severe immunopathology by using IL-12p40−/− and IL-12p35−/− mice. SEA/CFA-immunized IL-12p40−/− mice, incapable of making IL-12 or IL-23, were completely resistant to high pathology, and their SEA-stimulated lymphoid cells failed to secrete significant IFN-γ or IL-17. In contrast, SEA/CFA-immunized IL-12p35−/− mice, able to make IL-23 but not IL-12, developed severe lesions that correlated with high levels of IL-17, low IFN-γ, and an expansion of activated CD4 T cells with a CD44high/CD62Llow memory phenotype. In vivo administration of neutralizing anti-IL-17 mAb markedly inhibited hepatic granulomatous inflammation. Importantly, CBA mice, a naturally high pathology strain, also displayed elevated IL-17 levels comparable to those seen in the SEA/CFA-immunized BL/6 mice, and their lesions were similarly reduced by in vivo treatment with anti-IL-17. Our findings indicate that an IL-17-producing T cell population, likely driven by IL-23, significantly contributes to severe immunopathology in schistosomiasis.

Despite the beneficial therapeutic effects of intravenous immunoglobulin (IVIg) in inflammatory diseases, consistent therapeutic efficacy and potency remain major limitations for patients and physicians using IVIg. These limitations have stimulated a desire to generate therapeutic alternatives that could leverage the broad mechanisms of action of IVIg while improving therapeutic consistency and potency. The identification of the important anti-inflammatory role of fragment crystallizable domain (Fc) sialylation has presented an opportunity to develop more potent Ig therapies. However, translating this concept to potent anti-inflammatory therapeutics has been hampered by the difficulty of generating suitable sialylated products for clinical use. Therefore, we set out to develop the first, to our knowledge, robust and scalable process for generating a well-qualified sialylated IVIg drug candidate with maximum Fc sialylation devoid of unwanted alterations to the IVIg mixture. Here, we describe a controlled enzymatic, scalable process to produce a tetra-Fc-sialylated (s4-IVIg) IVIg drug candidate and its qualification across a wide panel of analytic assays, including physicochemical, pharmacokinetic, biodistribution, and in vivo animal models of inflammation. Our in vivo characterization of this drug candidate revealed consistent, enhanced anti-inflammatory activity up to 10-fold higher than IVIg across different animal models. To our knowledge, this candidate represents the first s4-IVIg suitable for clinical use; it is also a valuable therapeutic alternative with more consistent and potent anti-inflammatory activity.IVIg | sialylation | antibody | inflammation | autoimmune disease

In infection with the trematode helminth Schistosoma mansoni, the severity of CD4 T cell-mediated hepatic granulomatous and fibrosing inflammation against parasite eggs varies considerably in humans and among mouse strains. In mice, either the natural high pathology, or high pathology induced by concomitant immunization with schistosome egg Ags (SEA) in CFA (SEA/CFA), results from a failure to contain a net proinflammatory cytokine environment. We previously demonstrated that the induction of severe immunopathology was dependent on the IL-12/IL-23 common p40 subunit, and correlated with an increase in IL-17, thus implying IL-23 in the pathogenesis. We now show that mice lacking the IL-23-specific subunit p19 are impaired in developing severe immunopathology following immunization with SEA/CFA, which is associated with a marked drop of IL-17 in the granulomas, but not in the draining mesenteric lymph nodes, and with a markedly suppressed SEA-specific IFN-γ response regulated by a striking increase in IL-10. The granulomas are characterized by a significant reduction in Gr-1+ cell recruitment and by alternative macrophage activation. Taken together, these results demonstrate that IL-23 per se is not necessary for the generation of IL-17-producing T cells, but is essential for the development of severe schistosome egg-induced immunopathology, and its absence cannot be overcome with other possible compensatory mechanisms.