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Biomedical subjects

C Behr

Publications and source records attributed to C Behr.

At least 19 recordsLinked to original sources
PubMed2002

Cytokine production and apoptosis among T cells from patients under treatment for Plasmodium falciparum malaria.

Available evidence suggests that Plasmodium falciparum malaria causes activation and reallocation of T cells, and that these in vivo primed cells re-emerge into the periphery following drug therapy. Here we have examined the cytokine production capacity and susceptibility to programmed cell death of peripheral T cells during and after the period of antimalarial treatment. A high proportion of peripheral CD3+ cells had an activated phenotype at and shortly after time of admission (day 0) and initiation of therapy. This activation peaked around day 2, and at this time-point peripheral T cells from the patients could be induced to produce cytokines at conditions of limited cytokine response in cells from healthy control donors. Activated CD8hi and TCR-gammadelta+ cells were the primary IFN-gamma producers, whereas CD4+ cells constituted an important source of TNF-alpha. The proportion of apoptotic T cells was elevated at admission and peaked 2 days later, while susceptibility to activation-induced cell death in vitro remained increased for at least 1 week after admission. Taken together, the data are consistent with the concept of malaria-induced reallocation of activated T cells to sites of inflammation, followed by their release back into the peripheral blood where they undergo apoptotic death to re-establish immunological homeostasis as inflammation subsides. However, the high proportion of pre-apoptotic cells from the time of admission suggests that apoptosis also contributes to the low frequency and number of T cells in the peripheral circulation during active disease.

Animals↗
PubMed2001

[Severe malaria].

Falciparum malaria remains a major killer in developing countries, particularly for African children. Moreover, France is the leading European country in term of incidence of imported malaria. Parasitized erythrocytes, which can form rosettes or auto-agglutinate, are sequestrated in the deep microvasculature and stick to activated endothelium by the mean of various receptors. Activation of T lymphocytes and macrophages induces secretion of proinflammatory cytokines, including tumour necrosis factor, which contributes to severe disease. However, the pathophysiology of coma remains poorly understood. In nonimmune adults, besides cerebral malaria, pictures of severe sepsis with shock, acute renal failure and respiratory distress syndrome are common. Although chemotherapy of malaria is challenged by the continuing evolution of antimalarial resistance, quinine remains the first-line drug for severe imported disease. In addition, early symptomatic management in the intensive care unit setting is of paramount importance. Prevention of severe imported malaria lays on prophylactic measures during travel, as well as adequate management of uncomplicated disease after return. In developing countries, early and adequate treatment of uncomplicated disease using cheap alternatives to classical compounds should contribute to "roll back" malaria, particularly in sub-Saharan Africa.

Africa↗
PubMed2001

Perturbation and proinflammatory type activation of V delta 1(+) gamma delta T cells in African children with Plasmodium falciparum malaria.

gamma delta T cells have variously been implicated in the protection against, and the pathogenesis of, malaria, but few studies have examined the gamma delta T-cell response to malaria in African children, who suffer the large majority of malaria-associated morbidity and mortality. This is unfortunate, since available data suggest that simple extrapolation of conclusions drawn from studies of nonimmune adults ex vivo and in vitro is not always possible. Here we show that both the frequencies and the absolute numbers of gamma delta T cells are transiently increased following treatment of Plasmodium falciparum malaria in Ghanaian children and they can constitute 30 to 50% of all T cells shortly after initiation of antimalarial chemotherapy. The bulk of the gamma delta T cells involved in this perturbation expressed V delta 1 and had a highly activated phenotype. Analysis of the T-cell receptors (TCR) of the V delta 1(+) cell population at the peak of their increase showed that all expressed V gamma chains were used, and CDR3 length polymorphism indicated that the expanded V delta 1 population was highly polyclonal. A very high proportion of the V delta 1(+) T cells produced gamma interferon, while fewer V delta 1(+) cells than the average proportion of all CD3(+) cells produced tumor necrosis factor alpha. No interleukin 10 production was detected among TCR-gamma delta(+) cells in general or V delta 1(+) cells in particular. Taken together, our data point to an immunoregulatory role of the expanded V delta 1(+) T-cell population in this group of semi-immune P. falciparum malaria patients.

CD3 Complex↗
PubMed2001

[Laparoscopic emergency surgery in perforated gastroduodenal ulcers].

The value of laparoscopic treatment of perforated gastroduodenal ulcers remains to be determined. To evaluate this modality the results of laparoscopic treatment of 18 patients with perforated gastroduodenal ulcers were compared with 28 patients who were operated by open access. Patients operated on conventionally had a mean ASA score of 2.9 compared to 1.8 in the laparoscopic group (p = 0.0009). Operative time revealed no difference between both groups, no patient had to be converted. Morbidity and mortality was 16.7% (3/18) and 0% in the laparoscopic group compared to 10.7% (3/28) and 35.7% (10/28) in the open group (p = 0.41 and p = 0.19). The mean postoperative hospital stay was 9.4 compared to 15.3 days (p = 0.15). The laparoscopic treatment of perforated gastrointestinal ulcers is an effective method, which can be used in suited patients with a low morbidity and mortality.

Adult↗
PubMed2000

Plasmodium falciparumin the squirrel monkey (Saimiri sciureus): infection of non-splenectomised animals as a model for exploring clinical manifestations of malaria.

Plasmodium falciparum infection in humans leads to a variety of symptoms ranging from an influenza-like syndrome to life-threatening complications. Animal models are useful tools for the detailed analysis of the interaction between both parasite and host factors leading to these various clinical manifestations. In this review, examining the different clinical, parasitological and haematological parameters associated with P. falciparum infection in spleen-intact monkeys, we propose this model as a good alternative for exploring some aspects of the host-parasite relationship in malaria.

Anemia↗
PubMed2000

Mimicking a conformational B cell epitope of the heat shock protein PfHsp70-1 antigen of Plasmodium falciparum using a multiple antigenic peptide.

The Pf72/Hsp70-1 antigen is a major target in the naturally acquired immunity against Plasmodium falciparum malaria. We carried out an extensive analysis of the responses to several epitopes on the least conserved C-terminal domain, according to the mode of sensitization: malaria infection or immunization with different immunogens. We found significant differences in the panel of B-cell epitopes recognized by animal models including primates, and by humans sensitized by natural infection. We focused the analysis on one epitope that is unique to Plasmodium species. It is specifically recognized by a monoclonal antibody that mediates the killing of infected hepatocytes in vitro. We produced a polymeric multiple antigenic peptide (MAP) form of this sequence, which enabled us to identify a new B-cell epitope not detected by ELISA with linear peptides. The polymer was strongly recognized by sera from monkeys or humans sensitized by natural infection, whereas the monomer was not. We modelled the three-dimensional structure of the Pf72/Hsp70-1 sequence, using known Escherischia coli DnaK structures as a template. This predicted that the corresponding region would form a loop in the native antigen. The results presented here suggest that the MAP strategy is also particularly useful as a means of obtaining suitable synthetic models for conformation-dependent epitopes.

Amino Acid Sequence↗
PubMed2000

High frequency of circulating gamma delta T cells with dominance of the v(delta)1 subset in a healthy population.

TCR gamma delta(+) cells constitute <5% of all circulating T cells in healthy, adult Caucasians, and V(delta)1(+) cells constitute a minority of these cells. In contrast to TCR alpha beta(+) cells, their repertoire is selected extrathymically by environmental antigens. Although increased frequencies of V(delta)1(+) cells are found in several diseases, their function remains obscure. Here we show that the frequency of peripheral blood gamma delta T cells in healthy West Africans is about twice that of Caucasians, mainly due to a 5-fold increase in V(delta)1(+) cells, which is consequently the dominant subset. No age dependency of V(delta)1 frequencies was identified and the V(delta)1(+) cells in the African donors did not show preferential V(gamma) chain usage. Analysis of the CDR3 region size did not reveal any particular skewing of the V(delta)1 repertoire, although oligoclonality was more pronounced in adults compared to children. The proportions of CD8(+), CD38(+) and CD45RA(hi)CD45RO(-) cells within the V(delta)1(+) subset were higher in the African than in the European donors, without obvious differences in expression of activation markers. No significant correlations between levels of V(delta)1(+) cells and environmental antigens or immunological parameters were identified. Taken together, the evidence argues against a CDR3-restricted, antigen-driven expansion of V(delta)1(+) cells in the African study population. Our study shows that high frequencies of TCR gamma delta(+) cells with dominance of the V(delta)1(+) subset can occur at the population level in healthy people, raising questions about the physiological role of V(delta)1(+) T cells in the function and regulation of the immune system.

Adult↗
PubMed2000

Distinct patterns of cytokine regulation in discrete clinical forms of Plasmodium falciparum malaria.

The pathogenesis of two of the most severe complications of Plasmodium falciparum malaria, cerebral malaria (CM) and severe malarial anaemia (SA) both appear to involve dysregulation of the immune system. We have measured plasma levels of TNF and its two receptors in Ghanaian children with strictly defined cerebral malaria (CM), severe malarial anaemia (SA), or uncomplicated malaria (UM) in two independent studies in an area of seasonal, hyperendemic transmission of P. falciparum. Levels of TNF, soluble TNF receptor 1 (sTNF-R1) and 2 (sTNF-R2) were found to be significantly higher in CM than in the other clinical categories of P. falciparum malaria patients. Levels of both receptors depended on clinical category, whereas only sTNF-R1 levels were significantly dependent on parasitemia. Detailed analysis of the interrelationship between these variables resolved this pattern further, and identified marked differences between the patient categories. While levels of TNF, sTNF-R1 and sTNF-R2 correlated with parasitemia in UM, this was not the case in CM and SA. Rather, there was a tendency towards high levels of TNF and its receptors in CM and low levels in SA without significant correlation to parasitemia in either category. This, and the fact that malaria-induced increases in plasma levels of IL-10 are much lower in SA compared to CM, suggest that distinct forms of dysregulation of the immune response to infection contribute to the pathogenesis of CM and SA.

Anemia↗
PubMed1998

Low plasma concentrations of interleukin 10 in severe malarial anaemia compared with cerebral and uncomplicated malaria.

BACKGROUND: Severe anaemia is a major complication of malaria but little is known about its pathogenesis. Experimental models have implicated tumour necrosis factor (TNF) in induction of bone-marrow suppression and eythrophagocytosis. Conversely, interleukin 10 (IL-10), which mediates feed-back regulation of TNF, stimulates bone-marrow function in vitro and counteracts anaemia in mice. We investigated the associations of these cytokines with malarial anaemia. METHODS: We enrolled 175 African children with malaria into two studies in 1995 and 1996. In the first study, children were classified as having severe anaemia (n=10), uncomplicated malaria (n=26), or cerebral anaemia (n=41). In the second study, patients were classified as having cerebral malaria (n=33) or being fully conscious (n=65), and the two groups were subdivided by measured haemoglobin as normal (>110 g/L), moderate anaemia (60-90 g/L), and severe anaemia (<50 g/L). IL-10 and TNF concentrations were measured by ELISA in plasma samples from all patients. FINDINGS: IL-10 concentrations were significantly lower in patients with severe anaemia than in all other groups. In 1995, geometric mean plasma IL-10 in patients with severe anaemia was 270 pg/mL (95% CI 152-482) compared with 725 pg/mL (465-1129) in uncomplicated malaria and 966 pg/mL (612-1526) in cerebral malaria (p<0.03). In 1996, fully conscious patients with severe anaemia also had significantly lower IL-10 concentrations than all other groups, including cerebral-malaria patients with severe anaemia and all patients with moderate anaemia (p<0.001). In both studies, TNF concentrations were significantly higher in cerebral malaria than in fully conscious patients (p<0.01). By contrast, the ratio of TNF to IL-10 was significantly higher in fully conscious patients with severe anaemia than in all other groups (p<0.001). INTERPRETATION: Our findings identify severe malarial anaemia as a distinct disorder in which insufficient IL-10 response to high TNF concentrations may have a central role.

Analysis of Variance↗
PubMed1997

Expression of major histocompatibility complex antigens on mouse brain microvascular endothelial cells in relation to susceptibility to cerebral malaria.

The physiopathology of experimental cerebral malaria (CM), an acute neurological complication of Plasmodium berghei ANKA (PbA) infection, involves interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), two cytokines that are known to modulate major histocompatibility complex (MHC) molecule expression. The aim of this study was to evaluate whether the genetic susceptibility to CM is related to the constitutive or IFN-gamma-induced expression of MHC molecules on brain microvessels. To this end, brain microvascular endothelial cells (B-MVEC) were isolated from CM-susceptible (CM-S, CBA/J) and resistant (CM-R, BALB/c) mice. By flow cytometry, we found that less than 5% of CM-S B-MVEC constitutively expressed MHC class I molecules, in contrast to up to 90% of CM-R B-MVEC. Upon stimulation with IFN-gamma, the percentage of positive cells for MHC class I molecules in CM-S B-MVEC became comparable to CM-R B-MVEC, but a higher fluorescence intensity existed on CM-S B-MVEC compared with CM-R B-MVEC. MHC class II molecules were not constitutively expressed on B-MVEC from either strain. IFN-gamma-induced expression of MHC class II (I-A, I-E) molecules was significantly higher in CM-S than CM-R B-MVEC both in percentage of positive cells and fluorescence intensity. These data demonstrate that absent or low MHC class I and higher inducibility of MHC class II expression on B-MVEC are associated with the genetic susceptibility to CM.

Animals↗
PubMed1996

Plasmodium falciparum stimuli for human gammadelta T cells are related to phosphorylated antigens of mycobacteria.

The presence in Plasmodium falciparum of a mitogenic factor for the major human blood gammadelta T-cell subset has been known for years. These gammadelta T cells bearing T-cell receptor Vgamma9 and Vdelta2 variable regions also respond to Mycobacterium tuberculosis, through recognition of several phosphorylated nonpeptidic antigens. In this study, we undertook a better characterization of the malarial stimulus and show that the polygonal activation of Vgamma9/Vdelta2 gammadelta T cells by P. falciparum schizonts is also and exclusively attributable to two phosphorylated malarial compounds. The finding of such stimuli in eukaryotic cells evidence an antigenic link between intracellular parasites as different as Plasmodium and Mycobacterium species. Hence, phosphorylated antigens could be involved in a common pattern of transdisease T-cell responses against various human pathogens.

Animals↗
PubMed1996

[Immunopathology of malaria: emergence of a new T-lymphocyte reactivity].

Recent knowledge on certain populations of non-conventional T-lymphocytes has suggested that gamma delta T cells might play an important role in the orientation of the immune response. In human and mouse malaria, massive activation of the gamma delta T cell population is observed. This activation can lead to the production of high levels of pro-inflammatory cytokines relevant for malaria pathology induction. Studies investigating the role of gamma delta T cells have been conducted in different mice model where alpha beta T cells have been eliminated. In these studies, gamma delta T cells have been shown to be protective against the pre-erythrocytic stage of malaria infection but their role remains unclear concerning the blood infection. The recent discovery of the set of ligands leading to simulation of Human gamma delta T cell subsets expressing the V gamma 9V delta 2 chains of the T cell receptor may give new insights about their mode of activation and their potential role in the induction of malaria pathology.

Animals↗
PubMed1995

Flow cytometry detection of surface antigens on fresh, unfixed red blood cells infected by Plasmodium falciparum.

The immunofluorescence detection of parasite-specific antigens on the surface of red blood cells infected by Plasmodium falciparum parasites is usually performed by visual detection under a fluorescence microscope. We describe here a technique permitting the analysis of surface immunofluorescence labelling by flow cytometry. Infected red blood cells are selected on the basis of their parasitic DNA and RNA content by Hoechst and Thiazole Orange vital dyes. Cytometric analysis of these labels, as well as general erythrocyte characteristics assessed by analysis of forward and side scatter allows the selection of viable intact infected erythrocytes from other blood cells. The integrity of these selected erythrocytes was confirmed by the absence of labelling with antibodies directed against internal components such as spectrin. This technique permits the detection of specific surface immunofluorescence staining on red blood cells infected with mature stages of P. falciparum by antibodies in sera from hyperimmune Saimiri monkeys. Using Thiazole Orange dye for detection of parasitised cells, this analysis was performed on a FACSscan apparatus equipped with a single laser.

Adult↗
PubMed1994

Manipulating blood T cells and B cells from squirrel monkeys: some technical considerations.

The squirrel monkey Saimiri sciureus is an experimental host for a range of human pathogens, and for the assessment of vaccine candidate antigens and vaccine strategies. This experimental host is thus particularly suitable for the follow-up of humoral responses. To understand some of the mechanisms that underlie the defense against experimental pathogens, there is a need of basic knowledge on cellular immune effectors also. The authors report here their experience in characterizing squirrel monkey blood T and B lymphocytes, and in studying in vitro induced activation and proliferation of T and B cells. Particular emphasis is given to the in vitro differentiation of squirrel monkey B cells into immunoglobulin secreting cells, with respect to Plasmodium falciparum antigens.

Animals↗
PubMed1994

One-stage versus 2-stage bilateral total knee arthroplasty.

This retrospective study reviews 155 bilateral total knee arthroplasties, of which 99 were simultaneous and 56 staged. The results revealed that blood loss and postoperative blood requirements were higher in the simultaneous group, with 60% requiring homologous blood. The simultaneous approach was advantageous for a reduction in hospital stay, physical therapy, and resultant hospital costs. The complication rate was similar for both groups when examining pulmonary embolism, wound problems, infection, deep venous thrombosis, and death. The authors' incidence of fat embolism syndrome was similar for both groups but higher than that reported in the literature. Attempts with present preoperative evaluation cannot predict the incidence of fat embolism syndrome. A more invasive preoperative workup may identify those at risk. Preoperative marrow stimulants and the use of reinfused blood may eliminate the use of homologous blood in the simultaneous group.

Aged↗
PubMed1993

Immune response in mouse and malaria-exposed humans to peptides derived from Pf11-1, a highly repetitive megadalton protein of Plasmodium falciparum.

We have investigated the immune response against the Plasmodium falciparum gametocyte-specific antigen Pf11-1. This megadalton parasite molecule has been implicated in the process of erythrocyte rupture during gametogenesis. The molecule is composed in great part of degenerated nonapeptide motifs which are tandemly repeated several hundred times. A computer algorithm searching for T sites predicted that the entire repeat region of the Pf11-1 represents potential T cell antigenic major histocompatibility complex class II-binding sites. To test this hypothesis, synthetic peptides corresponding to two nonamer subtype repeats, differing only at two amino acid positions, were used to immunize congenic mouse strains. Both peptides were shown to contain both B and T cell epitopes. The immune response is restricted to the H-2d and H-2k haplotypes. The T cell response against the peptides appeared to be highly specific, clearly discriminating between the two similar nonamer repeat sequences, whereas the humoral response produced cross-reacting antibodies. We also investigated the humoral and T cell reactivities of P. falciparum-primed individuals in West Africa against the synthetic Pf11-1 peptides. Among 51 individuals 35 had antibodies to at least one of the two peptides and a majority of them (28) had antibodies reacting with both peptides. The cellular response was analyzed by [3H]thymidine incorporation or interferon-gamma release. There was considerable variation in the response to the two peptides. Among the human samples 36% responded to one repeat subtype, while only 13% responded to the second subtype. Interestingly, in individual donors the T cell response to both peptides are associated, suggesting that, as shown for mice, the response is restricted by a genetic element. The data obtained on the two subtypes of the nonamer repeat region suggest that the entire Pf11-1 molecule might induce an unusually heterogenous B and T cell response during natural infection in man.

Adolescent↗