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Biomedical subjects

A E Butterworth

Publications and source records attributed to A E Butterworth.

At least 19 recordsLinked to original sources
PubMed1995

A statistical approach to schistosome population dynamics and estimation of the life-span of Schistosoma mansoni in man.

Dynamic models which predict changes in the intensity of schistosome infection with host age are fitted to pre-intervention Schistosoma mansoni data from Kenya. Age-specific post-treatment-reinfection data are used to estimate the force of infection, thus enabling investigation of the rate of worm death. An empirical and statistical approach is taken to the model fitting: where possible, distributional properties and function relationships are obtained from the data rather than assumed from theory. Attempts are made to remove known sources of bias. Maximum likelihood techniques, employed to allow for error in both the pre-intervention and reinfection data, yield confidence intervals for the worm life-span (CI95% = 5.7-10.5 years) and demonstrate that the worm death rate is unlikely to vary with host age. The possibilities and limitations of fitting dynamic models to data are discussed. We conclude that a detailed, quantitative approach will be necessary if progress is to be made with the interpretation of epidemiological data and the models intended to describe them.

Adolescent↗
PubMed1994

A survey of Schistosoma mansoni induced kidney disease in children in an endemic area of Machakos District, Kenya.

The association between Schistosoma mansoni infection and kidney lesions was investigated in school children selected from three primary schools in Machakos District, Kenya, namely Miu (n = 159), Kitengei (n = 160) and Misuuni (n = 99) schools. The children were examined parasitologically for S. mansoni infection, clinically for enlargement of the liver and spleen, and biochemically for proteinuria and serum and urine creatinine. High prevalences of S. mansoni infection, ranging from 84-96%, were seen in all the schools, but the geometric mean intensity of egg excretion varied, being relatively low in Misuuni (31 eggs/g), medium in Miu (182 eggs/g) and high in Kitengei (413 eggs/g). The prevalence of pathological proteinuria (> or = 200 mg/l) in the schools ranged from 10.1% in Miu to 28.8% in Kitengei. No difference in the levels of proteinuria was noted between age or sex groups. No association between intensity of infection and pathological proteinuria was observed in any of the schools, nor was any correlation between organomegaly and proteinuria observed. However, significant correlations between malaria and organomegaly (p < 0.001) and between malaria and proteinuria (p < 0.05) were observed when pooling data from all schools. These findings suggest that S. mansoni induced nephrotic syndromes are not common in children from this highly endemic area of Kenya.

Adolescent↗
PubMed1994

Observations on the effects of different chemotherapy strategies on the transmission of Schistosoma mansoni in Machakos District, Kenya, measured by long-term snail sampling and cercariometry.

Transmission of Schistosoma mansoni was monitored by routine snail sampling for Biomphalaria pfeifferi and by supplementary cercariometric measurements in 4 neighbouring study areas in Machakos District, Kenya. After 1 year, extensive, population-based chemotherapy with a single dose of praziquantel was given in 3 areas, but only minimal treatment in the fourth. In the year preceding treatment, seasonal transmission of S. mansoni and other non-human trematodes occurred in all 4 areas, despite some ecological differences and the effects of earlier treatment campaigns in 1 of the study areas. After treatment of all infected subjects in one area in which there had been earlier chemotherapy campaigns, S. mansoni transmission remained very low. It was reduced for at least 2 years after chemotherapy targeted at either all heavily infected subjects or all infected school children, but it was unaffected in an area where treatment was restricted to those few very heavily infected cases at risk of developing disease. Nowhere was transmission entirely eliminated by chemotherapy and that of non-human trematodes continued unabated. The snail data correspond well with the human, parasitological data. Targeting school children was as effective as more extensive campaigns, but chemotherapy alone never stopped S. mansoni transmission: reinfection was inevitable, at rates determined by ecological factors affecting snail populations.

Animals↗
PubMed1994

Human IgG subclass responses and subclass restriction to Schistosoma mansoni egg antigens.

In areas endemic for schistosomiasis, there is great heterogeneity in antibody isotype responses to parasite antigens amongst infected individuals. At the population level, the isotype composition of antibody responses undergoes dynamic changes which are associated with the age of infected individuals. Here we examine the IgG subclass responses to Schistosoma mansoni eggs (soluble egg antigens; SEA) of infected individuals by immunoblot and ELISA. By controlled treatment of SEA-coated ELISA plates and immunoblot nitrocellular strips with sodium periodate, in order to oxidize terminal carbohydrate residues selectively, we were able to relate individuals subjects' isotype responses to the different antigens that they responded to, and to the presence of putative carbohydrate and peptide epitopes on those antigens. IgG2 responses were restricted strictly to sodium periodate-sensitive carbohydrate epitopes and antigens of relatively high molecular weight. These antigens were not usually recognized by other isotypes and, therefore, they were only recognized by individuals who had high levels of IgG2. IgG1 and IgG3 responses were directed against both carbohydrate and peptide epitopes, whereas IgG4 responses were restricted to periodate-resistant epitopes. This suggests that the fall in IgG2 responses, and reciprocal rise in IgG4 antibodies, seen in young children as their intensities of schistosome infection increase, is not the result of isotype switching, and that, if these two subclasses are involved in blocking immunity to schistosomiasis, they are operating independently.

Adolescent↗
PubMed1994

Immunity and morbidity in human schistosomiasis mansoni.

This paper reviews the results of a longitudinal, multidisciplinary study on schistosomiasis mansoni that has been in progress in Machakos District, Kenya, since 1980. Different methods of delivering chemotherapy have been compared in a medium scale operational control programme. It is concluded that treatment only of infected children is an effective and feasible means of control, the frequency of treatment depending on the severity of disease. Within the framework of this programme, detailed studies have been undertaken of immunity to reinfection after treatment and of the reasons for differences in observed morbidity between different areas. An apparent resistance to reinfection, especially in older individuals, may be attributable to the protective effect of IgE antibodies against adult worm antigens. Various factors other than intensity of infection may contribute to severe morbidity, including parasite strain differences, interactions with other infections, nutritional status, and abnormalities in the regulation of pathogenic immune responses to egg antigens.

Adolescent↗
PubMed1993

IgA antibodies to a protective antigen in human Schistosomiasis mansoni.

The specific IgA antibody responses to the protective recombinant Schistosoma mansoni 28-kDa glutathione-S-transferase (Sm28GST) Ag and to derived synthetic peptides have been evaluated before and 6 mo after chemotherapy in S. mansoni-infected patients from Kenya. These studies revealed a parallelism between the age-dependent evolution of IgA antibody levels to Sm28GST and to one synthetic peptide (115-131) and the acquisition of resistance to reinfection. Functional analysis revealed that IgA antibodies to Sm28GST displayed a potent neutralizing effect on the enzymatic properties of the molecule, and also markedly impaired schistosome fecundity, by limiting both the egg laying of mature worms and the hatching capacity of schistosome eggs into viable miracidia. These results suggest that, in addition to IgE, IgA antibodies might participate in the protective immune response against schistosomiasis.

Adolescent↗
PubMed1993

The use of mouse/human chimaeric antibodies to investigate the roles of different antibody isotypes, including IgA2, in the killing of Schistosoma mansoni schistosomula by eosinophils.

We report the use of a matched set of mice/human chimaeric antibodies, directed against the 5-iodo-4-hydroxyl-3-nitrophenacetyl (NIP) hapten, to investigate the roles of different human isotypes in antibody-mediated eosinophil-dependent killing of schistosomula. The chimaeric antibodies consist of mouse VH, VL and CL regions with human gamma 1, gamma 2, gamma 3 (2 allotypes), gamma 4, alpha 2, mu or epsilon CH regions and were used in in vitro assays with human eosinophils and NIP-coated S. mansoni schistosomula. Some anti-NIP isotypes mediated high levels of killing, which was specific for NIP-coated larvae, and we suggest that these antibodies will be a valuable tool for studies on the role of antibody isotypes in anti-schistosome immune effector mechanisms. In particular, this method directly demonstrated, for the first time, that IgA is highly effective in mediating the killing of metazoan parasites by human eosinophils.

Animals↗
PubMed1993

Immunity after treatment of human schistosomiasis: association between cellular responses and resistance to reinfection.

Previous studies have demonstrated the development of an age-dependent resistance to reinfection after chemotherapeutic cure of the helminthic parasite Schistosoma mansoni. Here we report on a longitudinal investigation of cell-mediated responses in infected individuals before and after treatment which was designed to outline those parameters important in mediating a protective response. A well-defined study group of 89 individuals with an age range of 9 to 35 years was selected from an area of high S. mansoni transmission in the Machakos district of Kenya. Peripheral blood mononuclear cell proliferation and cytokine production (interleukin-2 [IL-2], gamma interferon IL-5, IL-4, and tumor necrosis factor) in response to different crude life cycle-stage antigens of S. mansoni were assessed longitudinally in vitro before, 3 months after, and 1 year after treatment. Detailed statistical analyses of the results from this study have indicated a clear negative association between the proliferative responses to adult- and schistosomulum-stage antigens and subsequent reinfection intensity in older individuals (14 to 35 years) which was not present in the younger individuals (9 to 13 years). This association was significant even after the effects of age, sex, and exposure had been accounted for in multiple regression analyses. Cytokines were detected predominantly in response to adult worm and egg antigen extracts. An inverse association between the two cytokines gamma interferon and IL-5 was detected in response to all antigens at the three time points investigated, indicating cross-regulation in the production of these two mediators. Differences in antigen-specific cytokine levels between the two age groups were detected, with significantly higher IL-5 levels detected in the older (more resistant) age group. An inverse correlation between this cytokine and reinfection was detected but could not be dissociated from the effects of age and exposure in multiple regression analysis.

Adolescent↗
PubMed1992

Immunity after treatment of human schistosomiasis: association between IgE antibodies to adult worm antigens and resistance to reinfection.

Previous studies in school children have demonstrated the slow development with age of resistance to reinfection after chemotherapy of Schistosoma mansoni infections, and have indicated that inappropriate ("blocking") antibody responses prevent the expression of immunity in young children. The present study was designed to investigate further the nature of the protective responses, by serological studies on a group of 151 S. mansoni-infected individuals resident in an endemic area in Machakos District, Kenya. Antibody levels against various antigens in blood samples before treatment were related to intensity of previous infections; antibodies in blood samples taken 6 months after treatment were related to cumulative reinfection rates over the following 30 months. IgE against an adult-worm antigen preparation correlated positively with age and negatively with reinfection. In contrast, IgE antibodies against other life-cycle stages showed either no relationship or the reverse correlation. Furthermore, antibodies of other isotypes against adult-worm antigens showed no correlations with reinfection. The correlation with IgE could be demonstrated for different preparations of adult worms, including a periodate-treated preparation presumptively depleted of carbohydrate epitopes. For both the intact and the periodate-treated preparations, multiple regression analysis of the results for children less than or equal to 16 years old demonstrated an IgE effect after allowing for age, although this effect was not observed in a previously studied group of school children. Western blot analysis of the adult-worm preparation revealed a limited set of antigens recognized by IgE, among which an antigen of 22 kDa was prominent. The qualitative presence of IgE against this antigen could also be shown to be related to a lack of subsequent reinfection.

Adolescent↗
PubMed1992

On the use of age-intensity data to detect immunity to parasitic infections, with special reference to Schistosoma mansoni in Kenya.

We consider two phenomena, related to the host age-intensity profiles of parasitic infections, which have been suggested to be indicative of acquired immunity: (i) a lower age of peak intensity among more intensely infected hosts; and (ii) a decline with age in the dispersion of the distribution of parasites between hosts. We demonstrate that these phenomena occur among Kenyan schoolchildren infected with Schistosoma mansoni, although the magnitude of both is small. We also examine the mathematical models underlying these predictions and conclude that both phenomena are possible in the absence of acquired immunity or, indeed, in the absence of any density-dependent effect. In our opinion, insufficient attention has been focused upon mathematical models, describing the null hypothesis, i.e. density-independent models. In particular, we regard the usual assumptions made for the two stochastic components of these models, describing the heterogeneity between hosts and the probabilistic nature of infection and death of parasites, as too rigid and unrealistic. We demonstrate that deviation from these assumptions undermines the qualitative distinctions between models which describe acquired immunity or density dependence and those which are density-independent.

Adolescent↗
PubMed1992

Human IgE responses to Schistosoma mansoni and resistance to reinfection.

Schistosoma mansoni infected Kenyan patients were treated and the intensities of their reinfections were followed over the next two years. In addition, their pre- and six month post-treatment serum levels of IgG1-4, IgM, and IgE, specific for schistosomula, egg and adult worm, were measured in ELISA. No reinfection took place before six months post-treatment. Reinfection intensities varied with age; the younger children becoming reinfected at significantly higher intensities than older individuals. When antibody and reinfection levels were compared, only the six month post-treatment IgE response against adult worm correlated negatively with intensities of reinfection and, therefore, was predictive of resistance or immunity to reinfection. IgE and IgG specific Western Blots were carried out. The adult worm antigens recognized by IgE were restricted compared with the IgG responses of the same patients, although no individual antigen was uniquely recognized by the IgE isotype. A dominant 22 kDa antigen was recognized by most but not all high IgE responders. Patients with IgE responses against this antigen suffered significantly lower subsequent levels of reinfection, compared with non-responders. A monospecific rabbit antiserum against the 22 kDa adult worm antigen showed that this antigen is specifically located in the tegument of the adult worm and of 'lung' and 'liver' stage schistosomula, but is absent from the early 'skin' schistosomula. It is possible that this antigen is a target for human IgE mediated immune effector mechanisms active against the post skin stage schistosomula and that this is boosted by the death of adult worms.

Adult↗
PubMed1992

Human immunity to Schistosoma mansoni: observations on mechanisms, and implications for control.

This review summarizes the personal experiences of the authors and their colleagues during ten years of field and laboratory studies on human immunity to Schistosoma mansoni infections. There is evidence for the very slow development with age of an acquired resistance to reinfection (demonstrable after chemotherapy of the primary infection) distinguishable from a lack of reinfection due to reduced exposure. The implications of this immunity for the design of chemotherapy programs targeted at infected schoolchildren are discussed. Observational studies on the mechanisms of immunity have demonstrated a marked helminthocidal capacity of eosinophils. Subsequent correlative studies have indicated a role of IgM and IgG2 "blocking" antibodies in maintaining the continued susceptibility of young children, and of IgE antibodies in mediating protection in older individuals. Some problems in studying human immunity, and the implications for vaccine development, are also discussed.

Animals↗
PubMed1991

The presence of eosinophil-activating mediators in sera from individuals with Schistosoma mansoni infections.

IgG antibodies and eosinophils kill schistosomula of Schistosoma mansoni in vitro, and there is now evidence to suggest that the main factor that contributes to the expression of purified IgG effector function is the degree of activation of the donor's eosinophils. This study was designed to identify serum-derived activating factors in sera from individuals infected with S. mansoni. Such activating factors may be responsible for enhancing eosinophil cytotoxicity against schistosomula. Serum-borne mediators were prepared by fractionation of sera from infected individuals by gel filtration high-performance liquid chromatography. The eosinophil-stimulating activity of these mediators was assayed by a new method which depends on the increased expression of the CR3 alpha chain (CD11b) on the surface of activated eosinophils. Sera from infected individuals exhibited different levels of eosinophil activation, and activation appeared to be due to several serum factors, including interleukin 5. In conclusion, our results suggest that eosinophil-activating factors present in infection sera may not only be responsible for enhancing eosinophil cytotoxicity but also be necessary for its expression.

Cytotoxicity, Immunologic↗
PubMed1991

Comparison of different chemotherapy strategies against Schistosoma mansoni in Machakos District, Kenya: effects on human infection and morbidity.

A comparison was made of the long-term impact of different methods of administration of chemotherapy (oxamniquine, 30 mg/kg in divided doses; or praziquantel, 40 mg/kg) on prevalence and intensity of Schistosoma mansoni infection in four areas in Kangundo Location, Machakos District, Kenya. In Area A, treatment was offered in October 1983 and again in April 1985 to all infected individuals. In Area H, treatment was offered in April 1985 to individuals excreting greater than or equal to 100 eggs per gram (epg) of faeces. In Area S, treatment was offered in April 1985 to all infected school children, within the framework of the primary schools. In the witness area, Area W, treatment was given in April 1985, for ethical reasons, to a small number of individuals excreting greater than or equal to 800 epg. Prevalence and intensities of infection were subsequently monitored at yearly intervals for three complete post-treatment years. In the Area S schools, clinical examination was also carried out at yearly intervals. Treatment of all infected individuals on two occasions (Area A) was the most effective and long-lasting way of reducing prevalence and intensity of infection. In this area, however, some earlier interventions had been carried out and pre-treatment intensities were lower than in the other areas. Treatment only of infected schoolchildren (Area S) also had a marked and prolonged effect, comparable to or better than treatment of individuals with heavy infections (Area H). Treatment of infected schoolchildren also caused a persistent reduction in the prevalence of hepatomegaly, and there was suggestive evidence from intensities of infection in community stool surveys (but not from incidence rates) of an effect on transmission. In all study areas, reinfection was most rapid and most intense among children. These findings are discussed in the light of theoretical considerations and of results from other studies, both on schistosomiasis and on intestinal helminths. We conclude that, in areas of low morbidity such as Kangundo, chemotherapy of schoolchildren only, at intervals of up to 3 years, is a satisfactory way of producing a long-term reduction in both intensity of infection and morbidity.

Adolescent↗
PubMed1990

A new method for measuring eosinophil activating factors, based on the increased expression of CR3 alpha chain (CD11b) on the surface of activated eosinophils.

The observation that activation of eosinophils in vitro with PAF increases the surface expression of the alpha chain of the complement receptor CR3 (CD11b) has been extended to other eosinophil activating factors. CD11b may be detected on activated eosinophils by reaction with mouse monoclonal anti-human CD11b IgG, following the addition of urease-conjugated sheep anti-mouse IgG. CD11b levels were increased on eosinophils after incubation with (a) recombinant colony stimulating factors, IL-3, GM-CSF and IL-5, at concentrations of 100 U/ml, or (b) with eosinophil activating factors, recombinant TNF alpha (1000 U/ml), EAF purified from mononuclear cell supernatants and PAF (10(-6) M). CD11b levels were not affected by IL-1 alpha, IL-2 or IFN-gamma. Unstimulated neutrophils had higher levels of CD11b than unstimulated eosinophils, but neutrophil CD11b was unaffected by IL-3, GM-CSF and IL-5 and was only slightly affected by TNF, EAF and PAF. Polyclonal rabbit antibodies to IL-3 and TNF neutralised their CD11b enhancing activities. The PAF antagonists WEB 2086 and WEB 2170 neutralised the CD11b enhancing activity of PAF. We conclude that measurement of CD11b expression on eosinophils is a convenient method for the assay of eosinophil activating activity.

Animals↗
PubMed1990

Studies on human schistosomiasis: chemotherapy, immunity and morbidity.

At present, chemotherapy is the mainstay of schistosomiasis control programmes, but the most appropriate method of drug delivery frequently remains uncertain. In a six-year study in Machakos District, Kenya, designed to compare different drug delivery protocols, we have found that treatment only of infected primary school children is an effective, inexpensive and logistically practicable method of achieving a long-term reduction in intensity of infection in an area of high transmission but low morbidity. However, it is argued that even this simple approach to drug delivery is still not ideal--especially in areas of high morbidity in which intensity of infection may not be the only determinant of severe disease--and that a long-term approach to alternative control measures, especially vaccination, is desirable. Extensive studies have shown that a range of experimental hosts can be substantially protected against a challenge infection by immunisation not only with live attenuated larvae but also with individual recombinant antigens. The demonstration that an age-dependent acquired resistance to reinfection after chemotherapy also occurs in man offers encouragement that immunisation should theoretically be feasible: and attempts have been made to relate an observed resistance to reinfection in older individuals to various immune responses both to whole parasite antigens and to individual recombinant peptides. However, many questions remain unanswered, especially in the context of understanding what factors, other than intensity of infection, contribute to the development of severe morbidity in particular geographical foci, and some possibilities are discussed.

Humans↗
PubMed1990

Antibody isotype responses to the Schistosoma mansoni schistosomulum in the CBA/N mouse induced by different stages of the parasite life cycle.

During infection with Schistosoma mansoni the extent and nature of immune reactions against schistosomula may be influenced by responses to cross-reactive antigens in eggs or adult worms, and there is now extensive evidence for cross-reactivity between the different stages of the parasite life cycle. In this study IgM and IgG subclass antibodies produced in (CBA/N x Balb/c) F1 male and female mice were measured over a period of time following exposure to a chronic infection, to unisexual male cercariae or to irradiated larvae. Antibody levels were also measured following immunization with antigen preparations derived from adult worms, schistosomula or eggs. (CBA/N x Balb/c) F1 male mice exhibit an X-linked immune deficiency which results in an inability to respond to T-independent (TI) type 2 polysaccharides. Isotype levels were measured by ELISA to detergent-soluble schistosomulum antigen. Results showed that antigens on the different stages of the parasite life cycle have a qualitative influence on the antibody response to the larval surface, and that T-independent type 2 polysaccharides, particularly abundant in egg, exhibit antigen-directed isotype restriction in the form of IgM and IgG3 antibodies.

Animals↗