Schistosomiasis (bilharzia) is a parasitic disease caused by several species of schistosome worms (blood flukes). The key pathogenic event in this disease is the formation of granulomas around schistosome eggs trapped in portal venules of the liver. Granulomas are a distinctive form of chronic inflammation characterized by localized aggregation of activated macrophages around an inciting stimulus. Each granuloma evolves to form a fibrous scar; in schistosomiasis, the result is widespread hepatic fibrosis and portal hypertension. To identify the specific immune signal molecules necessary for granuloma formation, we studied schistosome infections in severe combined immunodeficient (SCID) mice, which have normal macrophages but lack functional B or T lymphocytes. Here we report that the immunoregulatory cytokine tumour necrosis factor alpha is necessary and sufficient to reconstitute granuloma formation in schistosome-infected SCID mice. Moreover, we find that the parasitic worms require tumour necrosis factor alpha for egg-laying and for excretion of eggs from the host. The implication of this latter result is that the parasite has adapted so successfully to its host that it uses a host-derived immunoregulatory protein as a signal for replication and transmission.

Tumour necrosis factor α restores granulomas and induces parasite egg-laying in schistosome-infected SCID mice

Praziquantel, (2-cyclohexylcarbonyl)-1,2,3,6,7,11b-hexa-hydro-2H pyrazino[2,1a]isoquinolin-4-one, belongs to a new series of antischistosomal compounds. The results of a detailed study of the efficacy of praziquantel on Schistosoma mansoni in mice, Mastomys and Syrian hamsters are described. Praziquantel is effective after oral and all parenteral routes of administration tested. The amount of praziquantel required to achieve parasite reductions of at least 95% depends on the host species and on the routes and schedules of administration. Total doses range from 200–1,000 mg/kg in mice and from 100–500 mg/kg for Mastomys and hamsters. In all three species, splitting of the total dose into 3 or more fractional doses given within 1 day approximately doubles the efficacy over that achieved after a single oral administration of the same total dose. A single subcutaneous dose is only slightly more effective, whilst a single intramuscular injection in olive oil is about twice as effective as a single oral administration. Praziquantel is very effective against the invading stages and slightly less against schistosomules up to an age of 7 days. It is less effective against 2- to 4-week-old juveniles, but is effective again against 5-week-old and older schistosomes. Praziquantel is equally effective against both sexes of S. mansoni. It is less effective against unpaired and therefore juvenile female worms, but fully effective against single male worms. The efficacy of praziquantel on S. mansoni in mice is not influenced by the strain or the sex of the host, the worm burden or the age of the infection. Considering all data available, praziquantel promises to be a very potent antischistosomal drug.

Praziquantel, a new board-spectrum antischistosomal agent.

Conditions affecting the accuracy of potassium hydroxide digestion techniques for counting Schistosoma mansoni eggs in tissues.

Publisher Summary This chapter discusses the immunology of schistosomiasis. The only developments relating to innate immunity refer to the death of cercariae in the skin. Concomitant immunity has been shown to operate in a number of experimental systems, and there are encouraging reports that it may operate in human infections. A good deal of circumstantial evidence implicates host antigens as playing a role in concomitant immunity, but more direct evidence is needed to show that they indeed serve to protect the mature parasite from immune attack. The use of small animals, particularly those where syngeneic strains are available and in vitro cultivation, has increased the understanding of the immune mechanisms. In particular, a number of in vitro systems have been described in which antibodies and cells combine to damage and kill young schistosomules. It is essential to determine whether the differences described for these several systems truly reflect a multiplicity of host responses or merely represent differences in technical approach to a single system. Much work has concerned the immunopathology of the disease, particularly granuloma formation. Although the granuloma contributes significantly to the pathology, it does seem to protect the host liver from the toxic secretion of the egg. A number of approaches for the immunological control of schistosomiasis are currently under investigation, including the use of live cercariae and schistosomules and the use of more or less purified antigens.

The immunology of schistosomiasis.

Eosinophils are thought to play a major role in the immunobiology of schistosomiasis. To investigate the immunologic basis of the eosinophil response and directly assess the function of eosinophils in egg-induced pathology, mice infected with Schistosoma mansoni were injected with a monoclonal antibody produced against interleukin 5 (IL-5), a cytokine previously shown to stimulate eosinophil differentiation in vitro. This treatment suppressed the generation of eosinophil myelocyte precursors in the bone marrow and reduced to background levels the numbers of mature eosinophils in the marrow, in circulation, and within acute schistosome egg granulomas. Nevertheless, granulomas in the anti-IL-5-treated/eosinophil-depleted mice at 8 weeks of infection were only marginally smaller than those in animals injected with control monoclonal antibody, and hepatic fibrosis was comparable in the two groups. Additional parameters such as worm burden, egg output, and serum IgE levels were unaltered by the anti-IL-5 treatment. In contrast, infected animals injected with monoclonal antibody against gamma interferon (IFN-gamma) displayed circulating eosinophil levels that were elevated with respect to control mice, possibly because of an enhanced release of mature eosinophils from the marrow, and developed egg granulomas that were indistinguishable in size and cellular composition from those in control animals. Immunologic assays revealed that lymphocytes from acutely infected mice produce large quantities of IL-5 but minimal IFN-gamma when stimulated with either egg antigen or mitogen. Taken together, these results indicate that neither IL-5 nor eosinophils are essential for egg-induced pathology but suggest that lymphocytes that belong to the IL-5-producing TH2 subset predominate during acute infection and may induce granuloma formation by the production of other cytokines.

https://www.pnas.org/content/pnas/87/1/61.full.pdf

Interleukin 5 is required for the blood and tissue eosinophilia but not granuloma formation induced by infection with Schistosoma mansoni.

Summary
The technique described is the result of more than 15 years' experience in recovering adult schistosomes from experimentally infected animals. Basically, the method consists in administering intraperitoneally a combined injection of pentobarbital sodium (Nembutal) and heparin to produce a shift of the worms from the mesenteric veins to the liver and to prevent clotting while they are perfused directly into conical sedimentation glasses for collection and counting. The method permits the recovery of almost every live schistosome; it is rapid and simple.

An improved perfusion technique for recovering adult schistosomes from laboratory animals.

Hepato-Splenic Schistosomiasis in Mice

SummaryA useful technic for producing portal hypertension and esophageal varices in the laboratory animal has been described. Ten weeks following infection of mice with S. mansoni, there was a significant increase in portal pressure in 51% of our animals, and the development of esophageal varices in 43%.

Production of Portal Hypertension and Esophageal Varices in the Mouse

Repeated infection and treatment of mice with Schistosoma mansoni: functional, anatomic and immunologic observations.

Summary
The percentage of Schistosoma mansoni cercariae that successfully penetrated and matured in mice was found to be strongly influenced by environmental temperature The optimal temperature for penetration was between 30° and 35°C; however, penetration took place at all temperatures tested between 10° and 40°C

Effects of Temperature on Penetration of Mice by Cercariae of Schistosoma mansoni.

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