Biomedical subjects
Publications and source records attributed to G Webbe.
Mice vaccinated with ultra violet (u.v.) attenuated cercariae of the Chinese mainland strain of S. japonicum were resistant to homologous challenge, but were not resistant to challenge with the Philippine strain of S. japonicum. Thus vaccination using u.v. attenuated S. japonicum cercariae is strain specific.
Mice can be partially protected against Schistosoma japonicum by prior exposure to ultraviolet (UV)-attenuated infections which fail to survive to the adult stage and produce no overt pathology in the host. Optimum resistance was induced by parasites exposed to 40 seconds of UV, significantly lower levels of resistance being stimulated by both shorter and longer exposures. No consistent relationship between the degree of resistance induced and the number of irradiated cercariae given could be demonstrated and equivocal results were obtained when comparing the efficacy of single and multiple vaccinations. Vaccinations with UV-attenuated cercariae given intraperitoneally (i.p.) were as efficacious as those given percutaneously but mice were as or more resistant to challenges given by the i.p. route, the possible reasons are discussed. There was no observed delay in the migration of the challenge, vaccinated mice being as resistant when perfused 6 or 3.5 weeks after challenge. Vaccination was species specific since mice exposed to either UV-attenuated S. japonicum cercariae or gamma-attenuated S. mansoni cercariae were resistant to homologous but not heterologous challenge.
Two cohorts of Bulinus rohlfsi were reared separately in an outdoor laboratory at Volta Lake, Ghana. One group was kept in lake water with a mud substratum, the other in lake water without mud. Both cohorts were able to tolerate water temperatures ranging from 22.0 to 35.5 degrees C, but growth and survival were significantly greater for the cohort with mud. The overall intrinsic rate of natural increase, r, per fortnight was 1.096 for the snails having the mud substratum and 1.642 for the cohort not having it. The 'r' values were strongly influenced by high early fecundity of the snails in lake water only and low early fecundity of the snails with mud. Oviposition among the latter cohort was suppressed at times of high turbidity in the water above the mud substratum, caused primarily by suspended clay.
Acquired resistance to Schistosoma japonicum was evident after the lung phase of migration of challenge schistosomula. 'Trickle' infections which gave similar primary worm burdens to single infections stimulated similar levels of resistance. There was a strong correlation between the size of the primary worm burden of individual mice and their ability to resist infection 8 weeks after exposure to S. japonicum. However, acquired resistance did not develop until 6 weeks, that is after the primary infection had become patent, and was maximal some 12 weeks after infection; thereafter resistance declined. The numbers of parasite eggs deposited in the tissues increased during acute infection (duration of 12 weeks or less) and tended to stabilize or decrease during chronic infection (longer than 12 weeks). There were good correlations between the resistance of mice to challenge and the numbers of eggs deposited in their livers, guts or lungs during acute infection, but these correlations were not evident during chronic infection. The inflammatory responses to tissue-bound eggs regress during chronic infection and this may influence the relationship between acquired resistance and egg burden. Comparable primary infections of S. japonicum or S. mansoni protected equally well against both heterologous and homologous challenges. However, unisexual infections of S. mansoni, which produced no overt pathology, failed to confer protection against a challenge of S. japonicum.
The skin phase of schistosomular migration was neither essential for the induction or expression of acquired resistance since mice given primary infections by the intraperitoneal route were as resistant to intraperitoneal or percutaneous challenge as were mice given their primary infections percutaneously. Serum taken from resistant donors with acute or chronic infections conferred no ability to resist infection upon recipient mice. In two experiments mice that were deprived of their T-cells were as resistant to infection as intact mice and both types of host had comparable tissue egg loads and liver pathology. In a third experiment the immune-deprived mice had lower tissue egg counts than the intact mice and were less resistant to challenge. It is suggested that specific immune effector mechanisms may not be involved in acquired resistance to reinfection but rather that resistance is affected by the T-cell independent immunopathology induced by tissue-bound Schistosoma japonicum eggs.
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The host-parasite relationship of the Chinese mainland strain of Schistosoma japonicum in CBA mice is described and compared to previous reports on this parasite in mice. S. japonicum took under 2 weeks to complete its migration to the portal system of mice, and peak passage of schistosomula through the lungs occurred 5-6 days after infection. The mean percentage establishment of worms, which was independent of the infecting inoculum, was 46%. The adult worm burdens remained constant over a 28-week period of infection. Male and female worms reached maximum mean lengths of 13 and 19 mm, respectively. Egg laying commenced 30 days after infection. The number of ova deposited in the liver stabilized at some 55 000 by 12 weeks of infection with 30 cercariae, but the intestinal egg burden rose from 132 000 at 12 weeks to 430 000 at 28 weeks. Faecal eggs were first observed 6 weeks after mice were exposed to 100 cercariae and 7 weeks after lighter exposures. Faecal egg output also stabilized 12 weeks after infection. The formation of granulomas in the liver occurred within 2 weeks of egg deposition and encompassed a maximum area 14 weeks after infection. Fifty per cent mortality occurred 15 weeks after exposure, but only in hosts infected with 100 cercariae.
Groups of five baboons were vaccinated three times at approximately six-weekly intervals at a rate of 1,000 organisms per kg of gamma-irradiated Schistosoma haematobium larvae. Five vaccines were tested: 3 and 20 Krad cercariae applied percutaneously; fresh 3 and 20 Krad mechanically transformed schistosomula injected intramuscularly; and cryopreserved 20 Krad schistosomula injected intramuscularly. These five groups and an unvaccinated control group were challenged percutaneously with 7,500 S. haematobium cercariae three months after the last vaccination. The efficacy of the vaccines was judged by faecal egg excretion, and by adult worm and tissue egg recoveries at necropsy 4.5 months after challenge. Significant protection, with 64 to 89% reductions in worm burden and parallel reductions in egg production, was achieved by all but the cryopreserved vaccine, although egg production was not significantly reduced in those female worms which did mature. Cercariae tended to give more protection than schistosomula and 20 Krad more protection than 3 Krad. No significant pathology could be detected in an additional baboon vaccinated with 20 Krad schistosomula but not challenged with cercariae. This is an encouraging result for the development of a live vaccine against S. haematobium.
Known numbers of medium-suspended cercariae of Schistosoma japonicum were injected either intraperitoneally, subcutaneously, intramuscularly or intravenously into mice and were compared for infectivity with S. japonicum cercariae that had been administered percutaneously. The injected cercariae appeared to be no less infective or fecund even after their maintenance in vitro for up to six hours. The intraperitoneal route of inoculation was preferred as it facilitated the rapid infection of mice and furthermore was much safer than conventional percutaneous application of cercariae.
Infections of Schistosoma japonicum were studied in mice which were immunosuppressed either by thymectomy and administration of antithymocyte serum or by treatment with hydrocortisone acetate. The relation of S. japonicum with the immunosuppressed host differed with that reported for Schistosoma mansoni. The pathogenesis of the S. japonicum infection in the immunosuppressed host was less severe than that caused by S. mansoni, with respect to survival of, and hepatocellular damage to, the host. In contrast with S. mansoni, S. japonicum did not have a reduced fecundity in immunosuppressed mice and there was no significant reduction in the numbers of faecal eggs excreted by these hosts.
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The ELISA was used to measure circulating antigen and antibody in four baboons of which three were treated. The circulating antigen appeared earlier after infection than the antibody which eventually, however, reached a higher level. Both antigen and antibody levels increased slightly after treatment and thereafter declined to reach background levels eight weeks later. It is concluded that the ELISA has a potentially useful role in detecting both antibody and circulating antigen and that it may be successfully used in evaluating the efficacy of schistosomicides.
Baboons infected with S. haematobium and vervet monkeys infected with S. japonicum were treated orally with different dosage regimens of 2-cyclohexylcarbonyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-on e(praziquantel, EMBAY 8440, Biltricide) and were autopsied and perfused 3--4 months after treatment. The results suggest that a single oral dose of 75--100 mg/kg body weight is likely to be effective against S. haematobium in the baboon. Female worms of S. haematobium are apparently more susceptible to the compound than male worms. The classic hepatic shift of adult schistosomes was observed in all the primates, but histopathological studies showed that numerous worms also died in situ, only a few being found in the lungs. The results obtained with praziquantel against S. japonicum in the vervet monkey show that a complete cure was obtained in the animal given 50 mg/kg on five consecutive days. A predominant characteristic in the pathology of the animals given a curative dose of praziquantel was the total resolution of cellular reaction and fibrosis in the tissues containing known numbers of dead residual eggs. In the baboons infected with S. haematobium, the ureters and bladders had recovered their functional integrity and in the vervet monkeys infected with S. japonicum, a similar resolution of pathology in the liver and bowel was apparent.
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Effective treatment of mice with six to eight week-old patent S. mansoni infections with any one of five schistosomicidal agents (Oxamniquine, Praziquantel, potassium antimony tartrate, Niridazole and Hycanthone) resulted in a reduction in the degree of resistance to homologous challenge in the treated animals when compared with the level of resistance to reinfection observed in untreated mice with intact primary infections. Mice challenged five to six weeks after treatment with Praziquantel, Niridazole or Hycanthone demonstrated a lower level of resistance than mice challenged within 10 days of the termination of the chemotherapeutic schedules. Direct comparison of Praziquantel with potassium antimony tartrate indicated that treatment with the former drug allowed retention of a greater level of acquired resistance than the antimonial in the immediate post-treatment period. Resistance to reinfection in Hycanthone-treated mice was not restored by intravenous injection of S. mansoni eggs before challenge.
Experiments were conducted to determine whether bladder cancer would develop in primates (Papio sp.) infected with S. haematobium and concurrently exposed to low initiating doses of the bladder carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). To control for the systemic effects of schistosomiasis, 5 baboons were infected with S. mansoni, which does not lay its eggs in the bladder wall; to control for the effect of the carcinogen alone, 5 others were treated with BBN alone at the rate of 5 or 50 mg/kg per week for the duration of the experiment. Five animals were infected with S. haematobium and had no further treatment, and the main experimental group of 10 baboons was infected with S. haematobium and also treated weekly with 5 mg/kg BBN for up to 2½ years. Four of the 10 animals in the last group, but none in the three control groups developed neoplastic disease of the urothelium. Four animals with S. haematobium plus BBN treatment developed in situ carcinoma in the bladder (3 latent adenomatous lesions and 1 more advanced papillary tumour) and 2 of these animals plus 1 other had slightly dysplastic urothelial endophytic papillary growths of the ureter which penetrated the muscle layer. By contrast, none of the control animals developed urothelial carcinomas, though 4/5 of those with S. haematobium infection alone had inflamed bladders with polypoid lesions, and one individual had endophytic papillary hyperplasia of the ureter. The animals were killed after 2½ years while still relatively immature or adolescent, and it is possible that had they been allowed to survive longer some of the BBN-only group would have developed bladder cancer, and more of the latent lesions seen in the BBN + schistosomiasis group would have progressed to invasive carcinoma. It is postulated that, in this model for human bilharzial bladder cancer, schistosomiasis supplies the proliferative stimulus necessary to accelerate cancer growth from latent tumour foci produced by exposure to low doses of the bladder carcinogen. In areas of endemic schistosomiasis, carcinogenesis might be initiated, for example, by low doses of nitrosamines produced in the urinary tract during bouts of bacteriuria.