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 IFN-gamma production and downregulated Th2 responses and pulmonary granuloma size. Conversely, anti-IFN-gamma 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 IFN-gamma, TNF-alpha 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 IFN-gamma KO mice but not in B cell KO (microMT) 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.

Pathogenesis of schistosomal 'pipestem' fibrosis: a low-protein diet inhibits the development of 'pipestem' fibrosis in mice.

Mice maintained on a low protein diet for 30 days and then infected with Schistosoma mansoni for 16 weeks completely failed to develop 'pipestem fibrosis' of the liver, whereas 50% of well nourished controls did. Usually mice with relatively mild and prolonged S. mansoni infection develop two different pathological pictures: one consisting of disseminated portal fibrosis caused by periovular granulomas concentrated at the portal spaces (pipestem fibrosis), the other represented by scattered hepatic granulomas. The reason for this dual response is poorly understood. Combined results from parasitological, histopathological, biochemical and morphometric data revealed that peri-ovular granulomas of undernourished mice were smaller, inflammation was less intense and there was minimal fibrosis in comparison with those of controls, which suggest that a vigorous host response is necessary for the pathogenesis of schistosomal portal fibrosis.

Differential regulation of granuloma size and hepatic fibrosis in schistosome infections.

Granuloma size is the variable most frequently used to evaluate the immunopathogenesis of schistosome infections. However, hepatic fibrosis is at the least an equally relevant variable. Hepatic fibrosis and the size of circumoval granulomas are frequently dissociated in experimental murine Schistosoma mansoni and S. japonicum infections. Virtually nothing is known of the immunoregulation of schistosomal hepatic fibrosis. This review notes many of the studies which have found discrepancies in granuloma volume and hepatic fibrosis, attempts to put them in perspective and to evaluate different methods of calculating changes in collagen synthesis or content.

Chronic hepatitis in experimental schistosomiasis.

Histological features of chronic active and chronic persistent hepatitis were observed in mice, rabbits and non-human primates infected with either Schistosoma mansoni and Schistosoma japonicum. In early infection hepatitis appeared as a reactive change due to liver damage caused by the deposition of schistosome eggs, but portal and septal cellular infiltrations tended to remain long after parasite aggression had diminished or disappeared, either spontaneously with time or after chemotherapy. In rabbits, and to a lesser degree in monkeys, a picture of chronic active hepatitis was present, with evolution to cirrhosis in the former. The experimental findings indicate that schistosomiasis has the potential to induce chronic hepatitis and suggest that the current assumption that chronic hepatitis seen in humans with schistosomiasis is always due to concomitant viral infection should be reviewed.

IFN inhibits inflammatory responses and protective immunity in mice infected with the nematode parasite, Nippostrongylus brasiliensis.

Mice infected with the gastrointestinal nematode parasite Nippostrongylus brasiliensis (Nb) develop responses associated with enhanced production of IL-4 (increased serum IgE levels and intestinal mucosal mastocytosis) and IL-5 (tissue and peripheral blood eosinophilia). The antagonistic effects of IFN on IL-4-mediated responses prompted an examination of the effects of IFN on the host response to Nb. Treatment with rIFN-alpha and rIFN-gamma induced a marked increase in parasite egg production (fecundity) in BALB/c mice infected with Nb and delayed intestinal expulsion of adult worms. Treatment with rIFN-alpha or rIFN-gamma also inhibited the rise in peripheral blood eosinophilia that follows inoculation with Nb, and the intensity of pulmonary perivascular tissue eosinophilia. However, Nb-induced increases in serum IgG levels and intestinal mastocytosis were only temporarily delayed by IFN. Induction of endogenous IFN production by injection of fixed Brucella abortus into mice infected with Nb also resulted in an increased worm fecundity and delayed adult worm expulsion. These effects were ablated when mice given Brucella abortus also received injections of neutralizing anti-IFN antibodies. Thus, IFN inhibit host protective immunity to Nb, perhaps by interfering with the production and effects of Th2 cytokines.

Characterization of the murine model of schistosomal hepatic periportal fibrosis ('pipestem' fibrosis).

During mild (one to two pairs of worms) and prolonged (23 weeks or more) mouse infections with Schistosoma mansoni, but not with S. japonicum, periovular granulomas and fibrosis were seen to be preferentially located along periportal tissues. This caused fibrotic expansion of the portal spaces on a background of normal-looking hepatic parenchyma, a picture mimicking 'clay pipestem fibrosis' seen in human patients with advanced schistosomiasis. The model was reproduced in outbred and in several strains of inbred mice, and their main characteristics were studied and compared to the human counterpart. A balanced consideration of the similarities and differences between the murine model and human pipestem fibrosis is needed for the adequate utilization of this simple, reproducible and inexpensive experimental model.

Pathogenesis of Schistosoma mansoni infection.

In this paper a discussion is made on the pathogenesis of schistosomiasis mansoni in mice, presented from the perspectives of "processes", "mediators", "strategies for study" and "disease". These concepts overlap considerably. Regarding "processes", granulomas, fibrosis and vasculitis are discussed. The role of mediators, including cells, antibodies and immune complexes, cytokines and distal mediators is commented as related to the pathological processes occurring in schistosomiasis. Finally, strategies for study are presented, followed by a discussion on the etiopathogenesis of the different clinical stages and pathologic manifestations of schistosomiasis mansoni.

The role of cytokines in the pathogenesis of hepatic granulomatous disease in Schistosoma mansoni infected mice.

Cytokines are important in the cell-mediated response to Schistosoma mansoni eggs. We have found that Th2 cytokine responses (e.g. IL-4 and IL-5) are augmented after egg laying begins while Th1 responses (IL-2 and IFN-gamma) are down regulated in S. mansoni infected mice. Treatment of mice with anti-IL-5 monoclonal antibodies (Mab) suppressed the eosinophil response almost completely but did not affect granuloma size and slightly increased hepatic fibrosis. Anti-IL-4 treatment abolished IgE responses in infected mice and decreased hepatic fibrosis slightly. Anti-IFN-gamma treatment had no effect on hepatic pathology. Anti-IL-2 treatment decreased granuloma size significantly and decreased hepatic fibrosis markedly. Anti-IL-2 treatment dramatically decreased IL-5 secretion by splenic cells in vitro and decreased peripheral blood and tissue eosinophilia. In contrast IL-4 secretion was unaffected and serum IgE was normal or increased. IL-2 and IFN-gamma secretion by splenic cells of treated mice were slightly but not significantly increased suggesting that anti-IL-2 treatment is affecting Th2 rather than Th1 responses.

Comparison of pathologic changes in mammalian hosts infected with Schistosoma mansoni, S. japonicum and S. haematobium.

The hepatic, intestinal and cardiopulmonary lesions produced by Schistosoma mansoni, S. haematobium and S. japonicum in man and experimental animals often bear striking similarities but usually have distinctive features as well. These are often related to parasitologic differences. Thus S. japonicum and S. haematobium lay their eggs in clusters which elicit the formation of large composite granulomas. The worms of these two species also tend to be sedentary, remaining in a single location for prolonged periods, thus producing large focal lesions in the intestines or urinary tract. Worm pairs of these two species also are gregarious and many worm pairs are often found in a single lesion. The size of circumoval granulomas, and the degree of fibrosis, are T cell dependent. The modulation of granuloma size is largely T cell dependent in mice infected with S. mansoni but is mostly regulated by serum factors in S. japonicum infected mice. In spite of these differences in egg laying and immunoregulation both S. mansoni and S. japonicum produce Symmers' fibrosis in the chimpanzee while S. haematobium does not, despite the presence of numerous eggs in the liver.

Variabilidade de cepas de Schistosoma mansoni na produçäo de cercárias / Variability of Schistosoma mansoni strains in cercaride production

Um estudo preliminar mostrou que Biomphalaria glabrata infectadas com cepas de Schistosoma mansoni isoladas de pacientes com a forma hepatoesplênica da doença produziam proporcionalmente maior número de cercárias e morriam mais precocemente que as infectadas com cepas isoladas da forma intestinal e hepatointestinal, entretanto, em contagens posteriores verificou-se uma grande variabilidade de cercárias no mesmo sistema, independente da forma clínica da origem das amostras

[Variability of Schistosoma mansoni strains in cercariae production]. / Variabilidade de cepas de Schistosoma mansoni na produção de cercárias.

A preliminary study showed that B. glabrata infected with strains of S. mansoni isolated from patients with the hepatosplenic form of the disease produced a higher number of cercariae and died sooner than those infected with strains from the intestinal and hepatointestinal forms. However, further studies showed a great variation of the number of cercariae produced by some of those strains in the same system, without relation with the clinical form of the disease.

Parasitological and pathological findings in capuchin monkeys infected with Schistosoma japonicum or Schistosoma mansoni.

Capuchin monkeys were studied for 7 months after exposure to Schistosoma mansoni or to either a Japanese or a Philippine strain of Schistosoma japonicum. The number of eggs present in the tissues and passed in the feces of S. mansoni-infected monkeys correlated well with the number of worm pairs recovered. Monkeys infected with the Philippine strain of S. japonicum passed large numbers of eggs in the feces and the number of these eggs correlated well with the number of worm pairs present. In monkeys infected with the Japanese strain of S. japonicum, fewer eggs were passed in the feces and there was little correlation with the number of worm pairs. Schistosome eggs were found predominantly in the small intestine in monkeys infected with the Philippine strain and predominantly in the colon in monkeys infected with the Japanese strain. The patterns of egg excretion in the feces and egg distribution in the tissues contrast with the patterns we recently described in rabbits, in which animals infected with the Philippine strain passed few eggs in the feces and showed a high proportion of tissue eggs in the colon. A single host species is thus shown to be inadequate to characterize the behavior of a schistosome strain.

Comparison of geographical strains of Schistosoma mansoni in the mouse.

Mice were killed 7, 11, 19, and 27 weeks after infection with strains of Schistosoma mansoni from Puerto Rico, Brazil, St Lucia, and Tanzania. The percentage recovery of adult worms was variable in different experiments and no consistent strain differences were observed. The prepatent period was prolonged in mice infected with the Mwanza strain. Significant differences were noted in the number of eggs per worm pair in the tissues, in the distribution of eggs in the tissues, and in the weight of the liver of mice infected with different strains. No differences in hepatic histopathology were detected. Although the behaviour of various worm strains in this mammalian host is clearly different, we feel that the observed differences are trivial when considering the effects of the parasite on the host, and that the results in mice probably cannot be used to predict possible differencesin the behaviour of geographical strains of S. mansoni in infected persons.