Search PubMed⌕ Search

Biomedical subjects

P Hagan

Publications and source records attributed to P Hagan.

At least 73 records · Page 4Linked to original sources
PubMed1992

Recent advances in immunity to human schistosomiasis.

For many years the epidemiological significance of immunity in human schistosomiasis has been the subject of inconclusive debate. Recently, the results of studies from Brazil and Kenya, on Schistosoma mansoni and from Zimbabwe and The Gambia on S. haematobium have confirmed the importance of protective immunity. In communities in endemic areas the development of immunity to infection only occurs after many years of exposure. In part this is due to the slow development of antibodies which are protective but also to the earlier development of antibody isotypes which lack protective capacity and which are capable of interfering with the functioning of protective antibodies. Protective antibodies appear to be of the IgE class but some IgG subclasses may also be important. Initially, blocking antibodies were thought to be predominantly IgM and IgG2 but IgG4 also seems to possess blocking activity. The early production of blocking antibodies and late production of protective antibodies may be indicative of cytokine induced immunoglobulin class switching caused by the sequential involvement of different lymphokines.

Adult↗
PubMed1991

Human IgE, IgG4 and resistance to reinfection with Schistosoma haematobium.

A well recognized feature of the immune response to parasitic helminth infections, including schistosomiasis, is the production of large amounts of specific and nonspecific IgE1,2. Immunological pathways involving IgE can lead to damage to the developing schistosomulum and it has been suggested that responses involving IgE could have evolved as protection against helminth infections. There has been no epidemiological evidence to support this idea and the only significant IgE responses known in man are those involved in the pathogenesis of allergic disease. Here we measure serological response during reinfection with S. haematobium and demonstrate that IgE antibodies in man can be beneficial. Our results support the hypothesis that the slow build-up of IgE to high levels and the early production of IgG4 antibodies, which may block IgE pathways are responsible for delaying the development of protective immunity to S. haematobium.

Adolescent↗
PubMed1991

Molecular cloning and characterisation of the 22-kilodalton adult Schistosoma mansoni antigen recognised by antibodies from mice protectively vaccinated with isolated tegumental surface membranes.

A cDNA clone from an adult Schistosoma mansoni lambda gt11 expression library (A12) encoding an antigenic polypeptide of 22 kDa is described. A12 is 797 bp long and has one open reading frame encoding a protein of 190 amino acids which does not contain a signal sequence or membrane anchor motif and has no homologies with any sequences on the currently available data bases. Its product (sm22.6) is recognised by antibodies from mice protectively vaccinated with purified adult S. mansoni tegumental membranes and by serum from S. mansoni-infected Brazilians. It is present in all post-snail life cycle stages except the egg, is not sex-specific, and is found in 9 species of Schistosoma, but not in a range of other helminths. Data are presented which suggest that sm22.6 is a soluble, peripheral membrane protein.

Amidohydrolases↗
PubMed1990

Epitopes expressed on very low Mr Schistosoma mansoni adult tegumental antigens conform to a general pattern of life-cycle cross-reactivity.

The relationship between antigens associated with the surface of newly transformed schistosomula of Schistosoma mansoni and the tegumental surface membrane of adult S. mansoni worms has been further explored. Immunoprecipitation of detergent-solubilized 125I-tegumental surface membrane antigens of adult S. mansoni with antibodies from mice vaccinated with highly irradiated S. mansoni cercariae revealed major antigens of Mr 32, 20, 15 and 8K. The Mr 32 and 20K antigens have been previously demonstrated to be antigenically and electrophoretically identical to major antigens on the schistosomulum surface. The Mr 15 and 8K antigens, on the other hand, have not been identified by the immunoprecipitation of 125I-schistosomulum surface antigens, although a distinct schistosomulum surface antigen of Mr 15K is precipitated by antibodies from mice vaccinated with highly irradiated cercariae. Nevertheless, it was shown that antibodies to the Mr 15 and 8K antigens were specifically absorbed from vaccinated mouse serum by intact, live schistosomula, demonstrating that the Mr 15 and 8K antigens are exposed on or released from the schistosomulum surface. In contrast, absorption of the antiserum with eggs failed to remove antibody against any of the four tegumental membrane antigens examined. The Mr 15 and 8K antigens were shown to be recognized via polypeptide epitopes and not periodate-sensitive carbohydrate epitopes, further emphasizing the similarity of these to the well-characterized Mr 32 and 20K tegumental surface membrane antigens. A general relationship between schistosomulum surface, adult tegumental membrane and egg antigens was demonstrated by ELISA, using antibodies raised against the three antigenic fractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Variable species and stage specificity of schistosomulum surface epitopes recognized by mice vaccinated with highly irradiated cercariae.

Antibodies from mice vaccinated with highly irradiated Schistosoma mansoni or S. haematobium cercariae were used to characterize schistosomulum surface epitopes which were found to be diverse in their species and stage specificities. The epitopes recognized on the Mr greater than 200,000 and 15,000 schistosomulum surface antigens of S. mansoni and the Mr greater than 200,000 schistosomulum surface antigen of S. haematobium were found to be cross-specific whereas those on the Mr 38,000, 32,000 and 20,000 schistosomulum surface antigens of S. mansoni and the Mr 35,000, 30,000 and 24,000 schistosomulum surface antigens of S. haematobium were only immunoprecipitated by homologous antibody and are thus possible targets of the protective species-specific immunity stimulated by highly irradiated cercariae. The epitopes recognized on the Mr greater than 200,000 and 38,000 antigens of S. mansoni were shown to cross-react with both the egg and the adult worm whereas those on the Mr 32,000 and 20,000 antigens only cross-reacted with the adult worm, and those on the Mr 15,000 antigen cross-reacted with neither the adult worm nor the egg. In addition the epitopes on the Mr 38,000 and 32,000 antigens were demonstrated to be polypeptide in nature. Those on the Mr greater than 200,000, 20,000 and 15,000 antigens, on the other hand, could not be conclusively defined.

Animals↗
PubMed1988

Scintigraphy with In-111-labeled monoclonal antitumor antibodies: kinetics, biodistribution, and tumor detection.

The purpose of this study was to evaluate and compare the kinetics, biodistribution, and tumor-depicting properties of three intact indium-111-labeled murine monoclonal antibodies (MoAb) and to determine if use of In-111-labeled F(ab')2 fragments of one of them had advantages over its intact counterpart for immunoscintigraphy. Ten patients with prostate cancer were studied with an anti-prostatic acid phosphatase MoAb (PAY-276), with a resultant tumor detection rate of 15%. Twenty-eight patients with melanoma were studied with ZME-018, a MoAb that targets the KD-240 melanoma antigen. Forty-three percent of the known lesions were detected. Forty patients with carcinoembryonic antigen (CEA)-producing tumors were studied, 24 with intact ZCE-025, and anti-CEA MoAb, and 16 with its F(ab')2 fragment. With use of intact ZCE-025, 34% of known lesions were detected versus 83% with its F(ab')2 fragment. The distribution of each MoAb appears unique unto itself with regard to kinetics, normal tissue distribution, and response to MoAb mass.

Antibodies, Monoclonal↗
PubMed1988

Radioimmunodetection of human melanoma with indium-111-labeled monoclonal antibody.

The purpose of the study was threefold: (1) to evaluate the efficacy of an 111In-labeled murine monoclonal antibody (ZME-018) directed against a heavy molecular weight melanoma associated glycoprotein in localizing metastatic disease; (2) to determine the effect of unlabeled antibody mass (2.5, 5, 10, 20, and 40 mg) on labeled antibody blood clearance, biodistribution and lesion detection; (3) to estimate radiation dosimetry. Twenty-five patients with previously documented disease received an intravenous infusion of 2.5 to 40 mg of monoclonal antibody with 1 mg of the antibody labeled with 5 mCi of 111In. There were no acute reactions. Patients were scanned without computer enhancement or background subtraction techniques at 24 and 72 hr after injection. Imaging detected tumor in 14/18 (78%) patients with active disease, identified 24/44 (77%) of lesions greater than 1 cm and changed or specifically directed patient management in 22% (4/18) patients with tumor. There was a prolongation in blood clearance associated with decreased liver and spleen activity following administration of 20 and 40 mg of antibody compared to the three lower antibody dose levels. Assuming a biodistribution similar to [111In]ZME-018, the radiation dose delivered to normal tissues by [90Y]ZME-018 would restrict its use as a routine vehicle for radioimmunotherapy; however, it may be possible to deliver substantial tumor doses in selected patients.

Adult↗
PubMed1987

Resistance to reinfection after treatment of urinary schistosomiasis.

The process of reinfection after treatment was studied in a cohort of subjects in a focus of intense Schistosoma haematobium infection. Detailed observations were made at water contact sites of cercarial densities and of water contact by members of the cohort. Individual values of a cumulative index of exposure to infection were calculated using these observations and assumptions which were made about the effect of different water contact activities on the entry of cercariae into the skin. Among groups of subjects with an apparently similar intensity of exposure to infection, reinfection tended to be much heavier in children under 10 years of age than in 10 to 14-year-olds, while only light infections were found in the few adults who became reinfected. This trend for reinfection to decrease with increasing age, after an allowance for variation in exposure, was highly significant (p less than 0.001). These observations suggest that subjects in this area slowly acquire an increasing degree of immunity to the acquisition of S. haematobium infection which is effective in the absence of a mature egg laying infection.

Adolescent↗
PubMed1987

Resistance to reinfection with Schistosoma haematobium in Gambian children: analysis of their immune responses.

The relationship between reinfection with Schistosoma haematobium and immunological parameters was studied in a group of Gambian children aged from 8 to 13 years. Each individual's exposure to infection was assessed from observations of water contact, cercarial densities and infected snail densities at water contact sites. Eosinophil counts were made and responses to egg antigen (SEA) and adult worm antigen (WWH) measured by ELISA. Low levels of reinfection were associated with a high eosinophil count, high levels of antibodies against WWH and SEA, increased age and low exposure. In a multiple regression analysis of the association of reinfection with eosinophil count, antibody levels, exposure, age and sex, the effects of eosinophil count and exposure were still very significant after allowing for all the other variables. The effects of the antibody levels were close to significance after allowance for exposure and eosinophil count (for WWH: P = 0.09; for SEA: P = 0.07), although the evidence was less clear after additional allowance was made for age and sex. The ability of sera from the children to recognize different parasite antigens was also examined by immunoprecipitation of labelled schistosomulum surface, WWH, SEA and S. haematobium adult worm mRNA in vitro translation products. Schistosomulum surface antigens were recognized by all the sera and there was little variation in this response. There was more variation in their responses to SEA and WWH and a marked heterogeneity in the response to in vitro translation products. However, the pattern of antigen recognition appeared unrelated to susceptibility to reinfection.

Adolescent↗
PubMed1987

Immunity in human schistosomiasis.

Field studies on immunity in human schistosomiasis are expensive, labour-intensive and extremely time-consuming, requiring many years to yield even provisional results. In this review, Anthony Butterworth and Paul Hagan summarize the need for such studies, the evidence for immunity in man, the immunological factors that may govern the expression of immunity, and the implications of such work for the development of new methods of control through vaccination.

Journal Article↗
PubMed1987

Surface and species-specific antigens of Schistosoma haematobium.

Of the surface antigens identified by radio-iodination, two-dimensional gel analyses showed no similarities between those of Schistosoma haematobium and Schistosoma mansoni, thus providing a basis for the species specificity of these antigens described previously (Simpson, Knight, Hagan, Hodgson, Wilkins & Smithers (1985) Parasitology 90, 499-508). The surface antigens of S. haematobium were glycosylated and comprised an acidic polypeptide of Mr 17,000 as well as a complex set of polypeptides of approximate pI 6-7, which resolved in the Mr range 20,000-30,000. At least one of the lower Mr forms of this complex is also present in the adult worm. Limited cross-reaction was observed with S. mansoni infection sera and this may be due to a shared carbohydrate epitope. In contrast, extensive cross-reaction was observed using sera from mice immunized with S. bovis. This pattern parallels the species-specificity of vaccine-induced immunity. Extensive cross-reaction was also observed within cell-free translation products of m-RNA from adult worms of S. haematobium and S. mansoni by use of heterologous human infection sera. The few antigens which were species-specific may represent surface antigens.

Animals↗
PubMed1986

Adult schistosome cDNA libraries as a source of antigens for the study of experimental and human schistosomiasis.

Protective immunity has been demonstrated in experimental schistosomiasis and is also believed to occur in man. It can be mediated by antibodies from infected animals or animals immunized with attenuated organisms. Recombinant Escherichia coli synthesizing antigenic polypeptides from the three principal species of schistosome that infect man, Schistosoma mansoni, S. japonicum and S. haematobium, have been constructed. Libraries of adult worm cDNA were prepared from each species in the expression vector lambda gt 11 and directly screened with antibodies from animals experimentally immunized with S. mansoni and S. japonicum and from humans infected with S. haematobium. The S. mansoni clones have been analysed in greatest detail. At least four different types of clones were identified. All the detected recombinant polypeptide antigens were recognised by antibodies from chronically infected mice and most were also recognised by antibodies from mice immunized with attenuated cercariae and anti-surface membrane antibodies. Clones synthesizing species-specific antigens for both S. mansoni and S. japonicum were identified by simultaneous screening of both libraries. At least three types of S. haematobium clones were identified by screening with human infection serum, most of which were species-specific. All the antigens were in the form of fusion peptides with E. coli beta-galactosidase and their expression was induced by isopropylthiogalactopyranoside. Since known protective monoclonal antibodies recognise highly glycosylated membrane proteins which cannot be identified in the form of nascent polypeptides, the direct identification of polypeptide antigens defined by their reactivity, as reported here, is an essential step in producing reagents by recombinant DNA technology, suitable for vaccination and diagnosis.

Animals↗
PubMed1985

Hymenolepis citelli (Cestoda) and Nematospiroides dubius (Nematoda): interspecific interaction in mice.

In mice concurrently infected with Hymenolepis citelli and Nematospiroides dubius, survival of the tapeworm was prolonged, and there was an impairment of the efferent arm of the response to the cestode. The immunological rejection of a six cysticercoid primary H. citelli infection was delayed by the N. dubius infection. The growth of the cestode was poorer in concurrently infected mice, and this effect was rapid, being evident within 4 days of the N. dubius infection. Maximum biomass in the controls was reached on Day 20, whereas in the concurrently infected mice it was reached on Day 25. The induction of acquired immunity to homologous H. citelli infection was suppressed, although the expression of a secondary response against homologous challenge was not abrogated in doubly infected mice. The results are discussed with reference to the immunodepressive effects the nematode is known to have on heterologous antigenic stimulation.

Animals↗
PubMed1985

The schistosomulum surface antigens of Schistosoma haematobium.

Surface antigens of Schistosoma haematobium were identified by 125I-surface labelling of schistosomula followed by immunoprecipitation of the solubilized, labelled surfaces. The major antigens, after electrophoresis, formed a continuous smear corresponding to a molecular weight in the range 35-24 000; in addition, a 17 000 antigen was also identified. These surface antigens, in contrast to somatic antigens, were species-specific, as judged by immunoprecipitation with human anti-S. mansoni serum and serum from mice vaccinated with highly irradiated S. mansoni cercariae. S. haematobium surface antigens, however, were recognized to some extent by serum from mice chronically infected with S. mansoni. It is suggested that this cross-reactivity may reflect the heterologous immunity demonstrated experimentally between these two species, whilst the species-specificity of vaccine sera to surface antigens may mirror the highly specific immunity induced by vaccination.

Animals↗
PubMed1985

In-vitro antibody-dependent killing of schistosomula of Schistosoma haematobium by human eosinophils.

Schistosomula of S. haematobium have been shown to be susceptible to in vitro killing by eosinophils in the presence of serum from an infected individual. The highest level of killing was found after 48 h in culture. Killing was related to the eosinophil to schistosomula ratio, being highest at 5000: 1. Killing was also related to serum concentration, being highest at a 1/10 final dilution, falling to background levels at a 1/120 final dilution. At a cell: target ratio of 2000: 1 and at a serum dilution of 1/10 eosinophils from subjects with high peripheral blood eosinophil counts were, cell for cell, more active in killing S. haematobium schistosomula than were eosinophils from subjects with lower counts. Sera taken from adults resident in an endemic area gave higher levels of killing in the presence of eosinophils than did sera taken from adults with no history of exposure.

Adolescent↗