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Biomedical subjects

S Jepsen

Publications and source records attributed to S Jepsen.

At least 91 records · Page 5Linked to original sources
PubMed1988

Cell-mediated immunity to Plasmodium falciparum infection: evidence against the involvement of cytotoxic lymphocytes.

Blood mononuclear cells (PBMC) recognizing soluble malaria antigens (SPag) are present in the peripheral blood of individuals clinically immune to malaria, and they proliferate after exposure to such antigens. To test whether these cells have effector activity against Plasmodium falciparum, we stimulated PBMC from malaria-immune donors by SPag and purified protein derivative (PPD) in culture for 7 days. The PBMC were then co-incubated with P. falciparum for 48 h, and parasitaemia was determined by microscopy. Parasite growth was only significantly impaired after incubation with PBMC stimulated by either SPag or PPD in the presence of immune serum. Studies on subpopulations of PBMC indicated that the inhibitory cells resided among the adherent cell fraction. Furthermore we tested PBMC for cytotoxic activity against P. falciparum-infected autologous or heterologous erythrocytes. Experiments were done both in the absence and the presence of immune serum. Neither fresh PBMC nor PBMC activated by SPag or PPD for 7 days prior to assay were cytotoxic, indicating that cytotoxic T cells, natural killer (NK) cells, and K cells did not possess cytotoxic activity directed against parasitized erythrocytes. These data support the hypothesis that activated monocytes are the most important effector cells in the peripheral blood of malaria immune individuals.

Animals↗
PubMed1988

Cell-mediated immune responses to Plasmodium falciparum antigens in adult Gambians.

Peripheral blood mononuclear cells from clinically immune Gambian adults were assayed for in vitro proliferation in response to crude and partially purified Plasmodium falciparum antigens. Lymphoproliferative responses to malaria antigens, lectin mitogens and Candida albicans were compared with those of control donors with no previous exposure to malaria. Cells of malaria-immune individuals were significantly more responsive to conconavalin A, and less responsive to phytohaemagglutinin, than cells from the control donors in both non-immune human serum and autologous serum. Cells from a proportion of immune donors proliferated in response to soluble malaria antigens but a substantial minority did not. Young adults and women were over-represented in the non-responding population. Responses to soluble malaria antigens were depressed in autologous serum compared with normal human serum. Both immune and control cells produced low levels of gamma-IFN when stimulated with crude P. falciparum schizont antigens. Approximately half the immune donors, and none of the controls, produced significant levels of gamma-IFN in response to purified soluble malaria antigen or malaria parasite culture supernatant. There was no direct correlation between lymphoproliferation and gamma-IFN production.

Adolescent↗
PubMed1988

Cellular immune responses to Plasmodium falciparum antigens in Gambian children during and after an acute attack of falciparum malaria.

Peripheral blood mononuclear cells from 63 Gambian children with acute Plasmodium falciparum malaria were examined for lymphoproliferation and interferon-gamma (IFN) production in response to stimulation by mitogens, malaria antigens and other soluble antigens. Mitogen or Candida-induced proliferation was not depressed during acute infection but was enhanced 2 to 4 weeks after treatment. Responses to partially purified soluble P. falciparum antigens were minimal or absent in all children in the acute phase but approximately 50% of the children responded by proliferation or IFN-gamma production during the 2 to 8 week convalescent period. These proliferative responses were severely depressed in the presence of the patient's own serum. Nine children with significant convalescent phase proliferative responses were re-examined several months after acute infection. Of these, four remained responsive for at least 8 months in the probable absence of reinfection.

Acute Disease↗
PubMed1988

Effect of trans(E)-clopenthixol on Plasmodium berghei in vivo.

Previous in vitro studies have shown suppression of the growth of Plasmodium falciparum by the neuroleptic agents chlorpromazine and zuclopenthixol (formerly known as cis(Z)-clopenthixol) as well as by the neuroleptic inactive steroisomer trans(E)-clopenthixol. These compounds are chemically related to riboflavin and may act as inhibitors of riboflavin metabolism. As trans(E)-clopenthixol has been found active against chloroquine-resistant strains of P. falciparum in vitro and has been approved for human use, though inactive as a neuroleptic, this drug was selected for the present in vivo study. The dosage of trans(E)-clopenthixol was optimized through a pharmacokinetic study, and the suppression of the growth of Plasmodium berghei in vivo was tested in mice, with chloroquine acting as the positive and saline as the negative control. Trans(E)-clopenthixol did not inhibit the growth of P. berghei, whereas chloroquine almost eradicated the infection. The use of in vitro screening for anti-malarial activity in drugs approved for human use for other indications is discussed in the light of the results. It is concluded that the selection of drugs for further studies in vivo cannot solely be based on positive results in vitro.

Animals↗
PubMed1987

Inhibitory monoclonal antibodies to soluble Plasmodium falciparum antigens.

Several murine monoclonal antibodies were raised against purified soluble Plasmodium falciparum antigens from the asexual blood stage. The monoclonal antibodies were purified from ascites by preparative agarose gel electrophoresis and tested for inhibitory activities against P. falciparum in vitro cultures. One monoclonal antibody, HATR 2-4, showed an isolate-specific growth inhibition of P. falciparum in vitro cultures. The antibody reacted in immunoblotting with bands of 250 and 57 kilo dalton (kdalton). Another monoclonal antibody, HATR 2-8, showed growth inhibition of several geographically distinct P. falciparum isolates. HATR 2-8 reacted in immunoblotting with bands of 250 and 74 kdalton. Heating of the antigens destroyed the reactivity of HATR 2-8. The monoclonal antibodies HATR 2-4 and HATR 2-8 probably recognize different epitopes on the same antigen. This antigen circulates in the plasma of some patients with P. falciparum parasitaemia.

Animals↗
PubMed1987

Generation of reactive oxygen radicals by human phagocytic cells activated by Plasmodium falciparum.

The role of monocytes, macrophages and neutrophils in killing malaria parasites is well documented, and their involvement in malaria pathology has been suggested. However, the underlying mechanisms are not clear. The present study reports on the role of P. falciparum-parasitized erythrocytes, free merozoites, and culture supernatant antigens in the generation of reactive oxygen radicals by human peripheral blood monocytes and neutrophils. Blood neutrophils and monocytes obtained from healthy individuals were isolated by density gradient separation. A human isolate of P. falciparum was grown in continuous culture. Parasitized erythrocytes and free merozoites were prepared from synchronized cultures. Soluble antigens from culture supernatants were purified by affinity chromatography using CNBr-Sepharose 4B columns bound to specific IgG. Oxidative burst response of neutrophils and monocytes were determined by oxygen consumption, superoxide production, and chemiluminescence. It was found that P. falciparum merozoites and the soluble antigens were capable of activating neutrophils and monocytes in vitro and resulting in the production of oxygen radicals by these cells. In conclusion, these findings demonstrate that malaria antigens are able to activate normal human blood phagocytes and result in generation of oxygen radicals by these cells. The released oxygen radicals can then contribute to both the destruction of the parasite and the pathology of malaria.

Antigens, Protozoan↗
PubMed1987

Inhibition of human lymphocyte proliferative response by serum from Plasmodium falciparum infected patients.

Malaria infection has been shown to induce alterations in immune reactivity. This report describes the effect of serum obtained from Plasmodium falciparum infected patients on in vitro proliferation of human blood mononuclear cells (BMNC) isolated from healthy individuals. Serum obtained before initiation of treatment suppressed the in vitro lymphocyte proliferative response to both Plasmodium-derived antigens and an unrelated antigen (PPD-tuberculin). The suppressive effect was lost if the serum was incubated at 56 degrees C for 30 min, and the effect was not HLA-restricted since the inhibition was seen on both autologous and heterologous BMNC. The degree of suppression was not correlated to the duration of the disease, the degree of parasitemia, or the use of chemoprophylaxis. Sera from 7 patients before and from 3 patients 30 days after initiation of treatment were pooled and fractionated. It was found that the strongest suppressive activity was in the serum fraction containing molecules from 30-100 kD.

Animals↗
PubMed1987

Soluble Plasmodium falciparum antigens contain carbohydrate moieties important for immune reactivity.

The importance of carbohydrate moieties for the antigenicity of purified soluble Plasmodium falciparum antigens from the asexual blood stage was tested. Digestion of the soluble antigens with alpha-D-galactosidase clearly affected the ability of the antigen to react with malaria-immune sera from different geographical origins in crossed immunoelectrophoresis and immunoblotting. Antigens of 220, 180, 80, and 74 kilodaltons were affected by the enzyme treatment. Furthermore, the enzyme digestion reduced the ability of the purified soluble antigen to stimulate lymphocytes from malaria-immune donors. The results might have important implications for the strategy of developing a malaria vaccine.

Animals↗
PubMed1987

Enhancement of human natural cytotoxicity by Plasmodium falciparum antigen activated lymphocytes.

Mononuclear cells (MNC) isolated from malaria immune donors and from donors never exposed to malaria were stimulated in vitro with soluble purified Plasmodium falciparum antigens (SPag) or PPD. After 7 days of culture the proliferative response and the cytotoxic activity against the natural killer cell (NK cell) sensitive cell line, K562, were measured. It was found that SPag stimulation enhanced cytotoxic activity of MNC from donors whose lymphocytes exhibited a strong proliferative response to the antigen. MNC with low proliferative responsiveness showed increased cytotoxic activity if the MNC were preincubated with interleukin 2 (IL-2) for one hour before the start of the cytotoxic assay. SPag activation did not enhance the cytotoxic activity of MNC which did not respond to the antigen in the proliferation assay, and preincubation of these cells with IL-2 did not increase the activity. PPD stimulation enhanced the cytotoxic activity and induced strong proliferative responses in all MNC preparations. The role of NK cells in the protection against malaria is unknown, but they play a role in the protection against virus infection and in the immune surveillance against cancer. Our findings indicate that malaria antigens either directly or through the activation of immunoregulatory cells enhance the NK cell activity.

Animals↗
PubMed1986

Computer controlled affinity chromatographical purification of soluble Plasmodium falciparum antigens from supernatants of in vitro cultures.

Affinity chromatographic procedures are difficult to scale up from the analytical to the preparative level when the ligand used for purification is a limiting factor. A versatile, computer-controlled affinity chromatographic system is described which permits automatic repetition of the purification process and sophisticated control functions based on the ultra-violet absorbance of fluid passing through the affinity column. The system has been used for automation and scaling up of the purification of Plasmodium falciparum exoantigens.

Antigens, Protozoan↗
PubMed1986

Suppression of parasite-specific response in Plasmodium falciparum malaria. A longitudinal study of blood mononuclear cell proliferation and subset composition.

The present longitudinal study was designed to characterize immunosuppression during acute Plasmodium falciparum infection, during the treatment and up to 1 month after the acute stage. The proliferative responses of blood mononuclear cells (BMNC) isolated from non-immune and semi-immune malaria patients and controls to mitogens and two Plasmodium-derived stimulators (merozoites, Meroz, and soluble purified antigen, SPag) and non-related antigens were measured by [3H]thymidine incorporation. BMNC isolated before treatment (day 0) from the non-immune patients did not respond to Meroz, whereas those from controls showed a significantly higher response. The SPag responses were also low in BMNC isolated on day 0 and increased in both the non-immune and the semi-immune patients during the observation period. These findings indicate that during malaria there is a depression of the parasite-specific proliferative response. The subset composition of BMNC isolated from non-immune patients was studied in a FACS analyser. The mean cell volumes of both Leu 2+ and Leu 3+ cells were increased during the acute phase of the infection, indicating that malaria infection results in activation of both T-helper and T-suppressor cells. There was no overall reduction of the response to mitogens on day 0. However, 3 days after initiation of the treatment the mitogen response was decreased. This finding indicates that it is important to distinguish between the effects of malaria infection and of drug treatment.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1986

Proliferation induced by Plasmodium falciparum antigen and interleukin-2 production by lymphocytes isolated from malaria-immune individuals.

Affinity-purified Plasmodium falciparum soluble antigens (SPAg) isolated from in vitro cultures of the parasite were shown to be relatively free of nonspecific polyclonal activators. To determine the presence of lymphocytes with specificity against SPAg in the peripheral blood of malaria-immune individuals, the proliferative response and the interleukin-2 (IL-2) production of SPAg-activated mononuclear cells (MNCs) from individuals unexposed, sensitized, and immune to malaria were measured. It was found that MNC isolated from malaria-immune individuals proliferated in response to SPAg and that this activation resulted in measurable IL-2 production in 5 of 10 MNC cultures. MNC isolates from most unexposed individuals did not respond to SPAg. To establish which cells responded to SPAg, different subpopulations of MNCs were tested. Only T helper cells were found to respond, and they responded only when cocultured with monocytes. The finding of parasite-specific T helper cells in the blood of malaria-immune individuals and the fact that some of these cells were able to produce IL-2 in vitro support the hypothesis that in malaria the cellular part of the protective immune response is initiated by immune T cells. These cells may activate nonspecific effector cells (i.e., macrophages) that eliminate the parasite.

Adult↗
PubMed1986

Cryptosporidium spp., a frequent cause of diarrhea in Liberian children.

This report presents results from a sample survey designed to investigate the possible role of Cryptosporidium spp. in childhood diarrhea in a developing country, Liberia, West Africa. During the four months of January to April 1983, a house-to-house study was carried out in two geographically and socially different communities--an urban slum and three rural villages. Stool samples from 374 children, aged 6 to 59 months, were tested for Cryptosporidium spp. Among the children with diarrhea 8.4% were Cryptosporidium spp. positive compared with a prevalence rate of 5.9% in asymptomatic children. Of the children living in a household with a Cryptosporidium spp.-positive index child, 8.6% had a positive stool sample. Of all children attending a clinic because of diarrhea, 14.6% were Cryptosporidium spp. positive. Cryptosporidiosis was more frequent in younger children; 24 of the total of 29 positive cases (83%) were below 2.5 years old. Actual or previous bottle feeding (formula) was a risk factor, particularly in children below 18 months old. Of the bottle-fed children, 28% were Cryptosporidium spp. positive versus 9.1% of children never bottle fed. Crowding is another possible risk factor. The prevalence of cryptosporidiosis was 13.5% in big urban households with more than 10 children, whereas the prevalence in the small urban households was 6.1%. Ethnic and religious differences were particularly evident in the rural area. No Muslim households had cryptosporidiosis, whereas the prevalence in non-Muslim tribes was 9%. The general belief that cryptosporidiosis is primarily a zoonosis is questioned in this study, partly because many carriers and asymptomatic household contacts were found.

Age Factors↗
PubMed1986

The susceptibility of Plasmodium falciparum to sulfadoxine and pyrimethamine: correlation of in vivo and in vitro results.

In 1982, 2 of 14 Plasmodium falciparum infections acquired in East Africa and diagnosed in Copenhagen were resistant to treatment with sulfadoxine plus pyrimethamine (Fansidar), while in 1983, 6 of 18 were so. The in vivo tests were supplemented by determinations of drug concentrations in serum, and 4 isolates from in vivo-sensitive cases and 6 from in vivo-resistant cases were selected for in vivo tests. These were performed in ordinary RPMI 1640 medium and in a medium with physiological p-aminobenzoic acid and folic acid concentrations. Pharmacokinetic aberrations were found to be of possible importance in only 2 of the in vivo-resistant cases. In vitro susceptibility to sulfadoxine was found to be uniformly low in all isolates. Testing with a combination of sulfadoxine and pyrimethamine in the medium with physiological concentrations of cofactors probably reflects the in vivo situation most accurately, but in all but 1 of the isolates studied in vitro the in vivo susceptibility to Fansidar would be predicted by in vitro susceptibility to pyrimethamine in either medium. The concentration of p-aminobenzoic acid in serum, quantitated by high performance liquid chromatography, was found to be subject to wide variation, and this may have implications for in vitro testing.

Adult↗