IL-10 Blocks the Development of Resistance to Re-Infection with Schistosoma mansoni

Despite effective chemotherapy to treat schistosome infections, re-infection rates are extremely high. Resistance to reinfection can develop, however it typically takes several years following numerous rounds of treatment and re-infection, and often develops in only a small cohort of individuals. Using a well-established and highly permissive mouse model, we investigated whether immunoregulatory mechanisms influence the development of resistance. Following Praziquantel (PZQ) treatment of S. mansoni infected mice we observed a significant and mixed anti-worm response, characterized by Th1, Th2 and Th17 responses. Despite the elevated anti-worm response in PBMC's, liver, spleen and mesenteric lymph nodes, this did not confer any protection from a secondary challenge infection. Because a significant increase in IL-10-producing CD4+CD44+CD25+GITR+ lymphocytes was observed, we hypothesised that IL-10 was obstructing the development of resistance. Blockade of IL-10 combined with PZQ treatment afforded a greater than 50% reduction in parasite establishment during reinfection, compared to PZQ treatment alone, indicating that IL-10 obstructs the development of acquired resistance. Markedly enhanced Th1, Th2 and Th17 responses, worm-specific IgG1, IgG2b and IgE and circulating eosinophils characterized the protection. This study demonstrates that blocking IL-10 signalling during PZQ treatment can facilitate the development of protective immunity and provide a highly effective strategy to protect against reinfection with S. mansoni

IL-10R Blockade during Chronic Schistosomiasis Mansoni Results in the Loss of B Cells from the Liver and the Development of Severe Pulmonary Disease

In schistosomiasis patients, parasite eggs trapped in hepatic sinusoids become foci for CD4+ T cell-orchestrated granulomatous cellular infiltrates. Since the immune response is unable to clear the infection, the liver is subjected to ongoing cycles of focal inflammation and healing that lead to vascular obstruction and tissue fibrosis. This is mitigated by regulatory mechanisms that develop over time and which minimize the inflammatory response to newly deposited eggs. Exploring changes in the hepatic inflammatory infiltrate over time in infected mice, we found an accumulation of schistosome egg antigen-specific IgG1-secreting plasma cells during chronic infection. This population was significantly diminished by blockade of the receptor for IL-10, a cytokine implicated in plasma cell development. Strikingly, IL-10R blockade precipitated the development of portal hypertension and the accumulation of parasite eggs in the lungs and heart. This did not reflect more aggressive Th2 cell responsiveness, increased hepatic fibrosis, or the emergence of Th1 or Th17 responses. Rather, a role for antibody in the prevention of severe disease was suggested by the finding that pulmonary involvement was also apparent in mice unable to secrete class switched antibody. A major effect of anti-IL-10R treatment was the loss of a myeloid population that stained positively for surface IgG1, and which exhibited characteristics of regulatory/anti-inflammatory macrophages. This finding suggests that antibody may promote protective effects within the liver through local interactions with macrophages. In summary, our data describe a role for IL-10-dependent B cell responses in the regulation of tissue damage during a chronic helminth infection

Periodontal Ligament, Cementum, and Alveolar Bone in the Oldest Herbivorous Tetrapods, and Their Evolutionary Significance

Tooth implantation provides important phylogenetic and functional information about the dentitions of amniotes. Traditionally, only mammals and crocodilians have been considered truly thecodont, because their tooth roots are coated in layers of cementum for anchorage of the periodontal ligament, which is in turn attached to the bone lining the alveolus, the alveolar bone. The histological properties and developmental origins of these three periodontal tissues have been studied extensively in mammals and crocodilians, but the identities of the periodontal tissues in other amniotes remain poorly studied. Early work on dental histology of basal amniotes concluded that most possess a simplified tooth attachment in which the tooth root is ankylosed to a pedestal composed of “bone of attachment”, which is in turn fused to the jaw. More recent studies have concluded that stereotypically thecodont tissues are also present in non-mammalian, non-crocodilian amniotes, but these studies were limited to crown groups or secondarily aquatic reptiles. As the sister group to Amniota, and the first tetrapods to exhibit dental occlusion, diadectids are the ideal candidates for studies of dental evolution among terrestrial vertebrates because they can be used to test hypotheses of development and homology in deep time. Our study of Permo-Carboniferous diadectid tetrapod teeth and dental tissues reveal the presence of two types of cementum, periodontal ligament, and alveolar bone, and therefore the earliest record of true thecodonty in a tetrapod. These discoveries in a stem amniote allow us to hypothesize that the ability to produce the tissues that characterize thecodonty in mammals and crocodilians is very ancient and plesiomorphic for Amniota. Consequently, all other forms of tooth implantation in crown amniotes are derived arrangements of one or more of these periodontal tissues and not simply ankylosis of teeth to the jaw by plesiomorphically retaining “bone of attachment”, as previously suggested

Role of cytokines in the formation and downregulation of hepatic circumoval granulomas and hepatic fibrosis in Schistosoma mansoni-infected mice

Schistosoma mansoni infections are associated with a strong Th2 cytokine response. Treatment of mice with IL-12 or anti-IL-2 or anti-IL-4 before i.v. injection of eggs increased IFNγ production and downregulated Th2 responses and pulmonary granuloma size. Conversely, anti-IFN-γ antibody treatment increased Th2 responses and granuloma size. Similar manipulation produced less dramatic results in infected mice. However, sensitization of mice with eggs + IL-12 before infection augmented the Th1 response and decreased Th2 cytokines, granuloma size and fibrosis. Antisera to IFNγ, TNFα or IL-12 during IL-12-egg immunization partly restored granuloma size and fibrosis following infection. Variations in the size of granulomas in acute (8 week) infections may be influenced primarily by the number and state of activation of T cells. In chronic (12-16 week) infections immunologic downmodulation proceeded normally in mice without functional CD8+ cells and in IFNγ KO mice but not in B cell KO (mMT) mice or in mice deficient in FcR expression in spite of the fact that these mice downregulated their T cell and cytokine responses. It is evident that the participation of cytokines in granuloma formation and regulation is complicated and that the mechanisms controlling both these phenomena are likely to involve both T cells and antibody/FcR interactions