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Biomedical subjects

P Druilhe

Publications and source records attributed to P Druilhe.

At least 73 records · Page 4Linked to original sources
PubMed1994

Immune mechanisms underlying the premunition against Plasmodium falciparum malaria.

The most unique characteristic of a parasite when it is in its normal host is the ability to make itself tolerated, which clearly indicates that it has sophisticated means to ensure the neutrality of its host. This is true also in the case of Plasmodium falciparum, since after numerous malaria attacks an equilibrium is reached with a chronic stage of infection, characterized by a relatively low parasitemia, and low or no disease (Sergent & Parrot 1935). We shall briefly review the main characteristics of this state of "premunition", and present data suggesting that the underlying mechanisms of defense rely on the cooperation between cell and antibodies, leading to an antibody dependent cellular inhibition of the intra-erythrocytic growth of the parasite.

Adult↗
PubMed1994

Aspects of immunity for the AMA-1 family of molecules in humans and non-human primates malarias.

The apical membrane antigen (AMA-1) family of malaria merozoite proteins is characterised by a high degree of inter-species conservation. Evidence that the protein (PK66/AMA-1) from the simian parasite Plasmodium knowlesi was protective in rhesus monkeys suggested that the 83kDa P. falciparum equivalent (PF83/AMA-1) should be investigated for protective effects in humans. Here we briefly review pertinent comparative data, and describe the use of an eukaryotic full length recombinant PF83/AMA-1 molecule to develop a sensitive ELISA for the determination of serological responses in endemic populations. The assay has revealed surprisingly high levels of humoral response to this quantitatively minor antigen. We also show that PK66/AMA-1 inhibitory mAb's are active against merozoites subsequent to release from schizont-infected red cells, further implicating AMA-1 molecules in red cell invasion.

Animals↗
PubMed1994

A novel merozoite surface antigen of Plasmodium falciparum (MSP-3) identified by cellular-antibody cooperative mechanism antigenicity and biological activity of antibodies.

We report the identification of a 48kDa antigen targeted by antibodies which inhibit Plasmodium falciparum in vitro growth by cooperation with blood monocytes in an ADCI assay correlated to the naturally acquired protection. This protein is located on the surface of the merozoite stage of P. falciparum, and is detectable in all isolates tested. Epidemiological studies demonstrated that peptides derived from the amino acid sequence of MSP-3 contain potent B and T-cell epitopes recognized by a majority of individuals living in endemic areas. Moreover human antibodies either purified on the recombinant protein, or on the synthetic peptide MSP-3b, as well as antibodies raised in mice, were all found to promote parasite killing mediated by monocytes.

Amino Acid Sequence↗
PubMed1994

Chimpanzees and supporting models in the study of malaria pre-erythrocytic stages.

Chimpanzees are being used in the study of immune response to Plasmodium falciparum malaria pre-erythrocytic stages (MPES). Responses induced by immunisation with recombinant/synthetic antigens and by irradiated sporozoites are being evaluated in a model system that is phylogenetically close to humans and that is amenable to limited manipulation not possible in humans. The value of chimpanzees for the in-depth study of immunological mechanisms at work in MPES-induced protection are discussed. A total number of 7 chimpanzees have been used to evaluate the immune response to recombinant antigens, and 5 have been challenged with large numbers of sporozoites, followed by surgical liver-wedge resection, in order to generate infected liver tissue for histological and immunological studies. As a complementary model, SCID mice carrying live, transplanted human and primate hepatocytes have been inoculated with sporozoites and infection of transplanted cells has been monitored by histological and immunological methods. In ongoing experiments chimpanzees are being immunised with MPES-derived lipopeptides that have been shown to overcome MHC restriction in mice, and with irradiated sporozoites.

Animals↗
PubMed1993

Culture model for the study of cerebral malaria: antibodies from Plasmodium falciparum-infected comatose patients inhibit the dendritic development of Purkinje cells.

The in vitro development of kitten Purkinje cells was inhibited by sera or IgG from cerebral malaria (CM) patients but not by sera from acute non-complicated malaria (NCM) cases. This inhibitory effect, quantified by computer-assisted methods, concerned the dendritic (though not the axonal) development and was found to be related to the presence of CM sera of self-reactive antibodies of the IgG class. These results suggest that protection acquired against the major complication of Plasmodium falciparum malaria may correspond to the repression of an abnormal stimulation of autoreactive B cells.

Animals↗
PubMed1993

Fast immunopurification of small amounts of specific antibodies on peptides bound to ELISA plates.

ELISA is widely used as a means to detect antibodies, but the potential of ELISA plates as an immunosorbent for the purification of specific antibodies does not seem to have been evaluated. In this study, ELISA plates coated with peptides representing short sequences of various antigens from Plasmodium falciparum, the etiologic agent of human malaria, have been successfully used as a means to purify small amounts of the corresponding antibodies. ELISA plates, identical to those used for antibody detection, also permitted the evaluation of various elution conditions for each pairing of peptide and serum; we tested four eluting buffers (0.2 M glycine, pH 2.5; 0.2 M lysine, pH 11.5; 3.0 M MgCl2, 0.075 M Hepes, 25% ethylene glycol, pH 7.1-7.2 and 4 M NH4SCN in 0.1 M NaH2PO4, pH 6.0) with four pairs of peptides and sera. The ELISA plates could also be used to estimate the affinity of the eluted antibodies by the technique of Pullen et al. (1986). The eluted antibodies were compared to those obtained by immunopurification on recombinant proteins adsorbed on nitrocellulose filters. In contrast to the latter, they were not contaminated by antibodies directed against the carrier moiety of the recombinant protein. When used in immunofluorescence assays with various stages of the parasite the antibodies immunopurified on peptides bound to ELISA plates were able to react with the native antigens in the parasite.

Animals↗
PubMed1993

Malaria morbidity among children exposed to low seasonal transmission in Dakar, Senegal and its implications for malaria control in tropical Africa.

To measure morbidity due to malaria and to study its relationship with transmission and parasitemia in children living in an area of low malaria endemicity, a cohort study of 343 schoolchildren was undertaken during a one-year period in Dakar, Senegal. From parallel investigations on transmission and the frequency of malaria as a cause for outpatient visits, three different seasons were chosen for close monitoring of different clinical parasitologic, and sero-immunologic parameters. The daily incidence rates of malaria parasitemia and primary attacks were at a maximum level during the high transmission season (0.00198 and 0.00185 new cases/person/day, respectively) and decreased considerably during the season of low transmission. For each given period, the values of these two rates were close to each other, suggesting that each new infection was followed by a clinical attack. During the period of maximum transmission, clinical malaria prevalence was 1.36% and malaria was responsible for 36% of school absences due to medical reasons. At the end of the period of minimum transmission, clinical malaria prevalence was 0.15% and malaria was responsible for 3% of school absences due to medical reasons. In contrast, parasite prevalence hardly varied with the season (minimum 3.6%, maximum 7.5%). In a one-year period, the total number of new malarial infections was estimated between 173 and 230. Because of the existence of a vector density gradient in the area concerned, the annual malaria incidence varied considerably according to the children's place of residence.(ABSTRACT TRUNCATED AT 250 WORDS)

Absenteeism↗
PubMed1993

[In vivo resistance of Plasmodium falciparum to chloroquine in Anjouan (Comoros)].

An in vivo study of P. falciparum sensitivity to chloroquine was conducted at Anjouan island (République fédérale islamique des Comores) from December 1990 to March 1991. The 27 patients included in the study were given chloroquine at a dose regimen of 25 mg/kg over 3 days and were followed up 7 days. Six patients (22.2%) still harboured parasites up to day 7, thus showing a RII/RIII level of resistance. This is likely related to an increased chloroquine consumption by the inhabitants of this island since 1987.

Adolescent↗
PubMed1992

Plasmodium falciparum malaria: evidence for an isotype imbalance which may be responsible for delayed acquisition of protective immunity.

In view of the recent demonstration that antibodies that are protective against Plasmodium falciparum malaria may act in collaboration with blood monocytes, we investigated the isotype content of sera from individuals with defined clinical states of resistance or susceptibility to malaria. Profound differences in the distribution of each immunoglobulin subclass were found. Immunoglobulin G1 (IgG1) and IgG3, two cytophilic isotypes, predominated in protected subjects. In nonprotected subjects, i.e., children and adults that have sustained a primary malarial attack, four different situations were encountered: (i) an imbalance in which IgG2, a noncytophilic class, predominated (mostly seen in primary attacks), (ii) an imbalance also concerning IgG2 but only of a given antigenic specificity, (iii) an imbalance in which mostly IgM antibodies predominated (a frequent event in children), and, less frequently, (iv) an overall low level of antimalarial antibodies. Of 33 nonimmune subjects studied, all but one had one of the above defects. The function of total immunoglobulin presenting such an isotype imbalance was studied in vitro in antibody-dependent cellular inhibition assays. IgG from protected subjects cooperated efficiently with blood monocytes, whereas IgG from nonprotected groups did not. Also, the latter could inhibit the in vitro effect of the former: in competition assays whole IgG from primary-attack cases with increased IgG2 content and IgG or IgM from children from endemic areas competed with IgG from immune adults. This led us to formulate the hypothesis that nonprotected subjects have antibodies to epitopes critical for protection, but that these antibodies are nonfunctional. These results bring some clues to the very long delay required to reach protection against malaria and clearly stress the need to investigate immune responses in both quantitative and qualitative terms.

Adolescent↗
PubMed1992

Antibodies in falciparum malaria: what matters most, quantity or quality?

In view of the recent demonstration that antibodies that are protective against Plasmodium falciparum malaria may act in collaboration with blood monocytes, we have investigated the isotype content of sera from individuals with defined clinical states of resistance or susceptibility to malaria. Profound differences in the distribution of each Ig subclass and particularly in the ratio of cytophilic versus noncytophilic antibodies were found. In protected subjects, two cytophilic isotypes, IgG1 and IgG3 were found to predominate. In non-protected subjects, i.e. children and primary attack adults, three different situations were encountered: a) an imbalance in which IgG2, a non-cytophilic class, predominated (mostly seen in primary attacks); b) an imbalance in which mostly IgM antibodies predominated (a frequent event in children) or c) less frequently, an overall low level of antimalarial antibodies. Of 33 non immune subjects studied all, except one, had one of the above defects. The function of total Ig presenting such an isotype imbalance was studied in vitro in Antibody-Dependent-Cellular-Inhibition assays. Not only did IgG from protected subjects cooperate efficiently with blood monocytes, whilst IgG from non-protected groups did not, but moreover the latter inhibit the in vitro effect of the former: in competition assays whole IgG from primary attack cases with increased IgG2 content, competed with IgG from immune adults, thus suggesting that non-protected subjects had antibodies to epitopes critical for protection, but that these antibodies are non functional.

Adolescent↗
PubMed1992

Mefloquine resistant malaria in Cameroon and correlation with resistance to quinine.

Based on the results of in vitro sensitivity of Plasmodium falciparum to chloroquine, quinine and mefloquine, and evaluation of drug consumption conducted in 1987-1988 in four areas in the north and south-west of Cameroon, two opposite situations were encountered in this country. In northern Cameroon where mefloquine resistance is prevalent a close correlation was found between the responses of P. falciparum to mefloquine and to quinine, but not between mefloquine and chloroquine. In the south, where chloroquine resistance is highly prevalent, no correlation was found neither between mefloquine and chloroquine nor mefloquine and quinine, but the responses to quinine and chloroquine appear partly correlated. These results lead to formulate the hypothesis of a "southern" type of P. falciparum submitted to a high chloroquine drug pressure inducing a secondary cross resistance, whilst a "northern" type submitted to a relatively high and abortive quinine drug pressure inducing a primary quinine resistance and a secondary cross resistance with mefloquine.

Animals↗
PubMed1992

Multi-drug resistant falciparum malaria in Cameroon in 1987-1988. I. Stable figures of prevalence of chloroquine- and quinine-resistant isolates in the original foci.

The status of drug-resistant Plasmodium falciparum in Cameroon was determined in 1987-1988 in 221 children who were selected for chloroquine and quinine in vitro microtests. Resistance to quinine was found in 17% of 72 isolates from the southern part of the country, and in 7% of 87 isolates from the northern part of the country. The effective concentrations of 50% and 90% (EC50 and EC90) differed little from those observed in 1986. In southern Cameroon, 38 (51%) of 74 individuals harbored chloroquine-resistant isolates. The EC50 ranged from 8 to 553 nmol and the mean +/- SD EC50 was 154 +/- 148 nmol. In contrast, in the northern area, all but one of the 120 subjects studied had EC50 values below the cutoff limit of 80 nmol (mean = 20 nmol). In vivo 7-day assays performed with chloroquine at a dose of 25 mg/kg in 389 individuals from the southwestern part of the country clearly confirmed RII-RIII levels of resistance in 18-52% of the cases, depending on the location studied. In the northern area, in vivo 7-day assays at a chloroquine dose of 10 mg/kg showed 36 of 39 subjects studied to have drug-sensitive parasites. Based on these results, it appears that after a rapid emergence of resistance that occurred in southern Cameroon, the prevalence of chloroquine- and quinine-resistant parasites remained fairly stable from 1986 to 1988. The stable difference between the northern and southern areas is believed to be related to both the lower rate of transmission and lower chloroquine drug pressure in the north.

Animals↗
PubMed1992

Multi-drug resistant falciparum malaria in Cameroon in 1987-1988. II. Mefloquine resistance confirmed in vivo and in vitro and its correlation with quinine resistance.

To further document the phenomenon of Plasmodium falciparum resistance to mefloquine formerly described in Cameroon, complementary in vivo and in vitro studies were conducted. Two hundred six P. falciparum isolates were studied in vitro using an isotopic microassay with mefloquine solutions prepared daily. Using the cutoff limit of 30 nmol, 26 (20%) of 133 isolates from the northern part of the country were defined as being resistant to mefloquine. In contrast, only one of 73 isolates collected in the southern part of the country was resistant. In vivo 7-day assays were performed in the northern area in 57 asymptomatic P. falciparum carriers (age range 1-10 years) who were given a single 25 mg/kg dose of mefloquine (Lariam). Among 46 cases in which followup was possible, P. falciparum asexual parasites were cleared within five days in 38 cases, by days 6 and 7 in two cases, and remained detectable up to day 7 in six cases. Thus, these latter patients have a RII-RIII level of resistance by in vivo criteria. No resistance was found in 40 additional patients studied similarly in the southern region. These observations were made before any mefloquine drug pressure was exerted in the country, but results of cross-resistance and drug consumption studies support the hypothesis that in the northern region, where a close correlation (r = 0.67) was found between the response to quinine and mefloquine, the more frequent use of quinine may have induced a primary quinine resistance and a secondary mefloquine resistance (without chloroquine resistance).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Vector density gradients and the epidemiology of urban malaria in Dakar, Senegal.

The dispersion of anopheline mosquitoes from their breeding places and its impact on malaria epidemiology has been investigated in Dakar, Senegal, where malaria is hypoendemic and almost exclusively transmitted by Anopheles arabiensis. Pyrethrum spray collections were carried out along a 910-meter area starting from a district bordering on a permanent marsh and continuing into the center of the city. According to the distance from the marsh, vector density (the number of An. arabiensis per 100 rooms) at 0-160, 160-285, 285-410, 410-535, 535-660, 660-785, and 785-910 meters was 84, 40, 5, 2, 2, 0.4, and 0, respectively, during the dry season, and 414, 229, 110, 84, 99, 69, and 21, respectively, during the rainy season. The proportion of 8-11-year-old children with negative immunofluorescent antibody test results for Plasmodium falciparum was 17%, 28%, 44%, 54%, 50%, 63%, and 73%, respectively, in these different sections. Malaria prevalence in the community was maximum in the area bordering on the marsh where it ranged from 1% to 15% (average 6%) according to age and season of the year. These findings show the epidemiologic importance of vector density gradients in Dakar. The implications for malaria control in urban areas are discussed.

Adolescent↗
PubMed1992

Pharmacokinetics of quinine, quinidine and Cinchonine when given as combination.

Pharmacokinetics of quinine, quinidine and cinchonine when given as a combination were evaluated in Thai patients with falciparum malaria during acute infection and convalescence. The combination of quinine, quinidine and cinchonine was randomly given to thirteen patients at 400 mg or 600 mg (consisting of one-third of each component; 7 patients were enrolled in 400 mg regimen and 6 in 600 mg regimen) intravenously every 8 hours for 7 days. The drug combination was given again at day 35 to define the pharmacokinetics of each drug during convalescence. All patients with the 600 mg regimen had good response with 100% cure rate while patients with the 400 mg regimen had a good initial response but one patient recrudesed on day 46. This particular patient had plasma concentrations of all three drugs lower than the mean values of patients with sensitive responses. The plasma levels of quinine and quinidine obtained from the present study were higher than that expected from one-third of the conventional dose (600 mg) when given alone, suggesting drug combination interaction. The terminal half-lives of each of the three components were prolonged during acute malaria when compared to those obtained during convalescence.

Adult↗