Biomedical subjects

J Taverne

Publications and source records attributed to J Taverne.

At least 73 records · Page 4Linked to original sources

PubMed1990

Malaria exoantigens induce TNF, are toxic and are blocked by T-independent antibody.

The production of cytokines, including tumour necrosis factor (TNF), may be involved in the pathology of malaria, as well as in protection against the parasite. We have shown that parasite exoantigens induce the secretion of TNF in vitro and in vivo and kill mice made hypersensitive to TNF. They elicit T-independent antibody that inhibits their capacity to stimulate TNF production and protects against toxicity in vivo, and those of human and rodent parasites are serologically related. Their active component does not appear to be protein. Here we review their properties and consider the epidemiological significance of our findings and their possible contribution to the development of an "anti-disease" vaccine.

Animals↗

PubMed1990

The malaria vaccine: anti-parasite or anti-disease?

There are three major difficulties hindering the development of a vaccine for malaria. First, for all three stages of the parasite life cycle there is an incomplete understanding of the precise type of immune response to aim for. Second, only a handful of the many hundreds of parasite-derived antigens have been explored, and though several have been shown to be protective in animal models, it is not known if they are the most potent. Third, there is strong evidence that the parasite can evade host immunity, for example by antigenic variation. In this brief article, John Playfair and his colleagues address mainly the first issue and suggest that complete resistance to infection is probably not feasible, and that attention should be directed not so much at vaccines designed to eliminate one or other stage of the parasite, but rather towards the possibility of an 'antitoxic' vaccine that prevents the serious pathological complications of the disease.

Animals↗

PubMed1990

Cytokines, thyroid autoantibody synthesis and thyroid cell survival in culture.

In autoimmune thyroid disease lymphoid cells infiltrating the thyroid gland occur in conspicuous aggregates or as a diffusely distributed population invading the thyroid follicles. Consequently cytokines secreted by activated T cells or macrophages could influence neighbouring thyroid cells as well as other lymphocytes. We have investigated this possibility using recombinant cytokines. Thyroid cell survival was assessed in terms of mitochondrial dehydrogenase activity in monolayers exposed to tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1 (IL-1 alpha and beta) and interleukin-2 (IL-2) in the presence or absence of thyroid-stimulating hormone (TSH). Neither TNF-alpha nor IL-2 affected thyroid cell survival, IFN-gamma was usually inhibitory and IL-1 alpha slightly enhanced cell survival in some experiments. However, the effects were small and variable and were not enhanced by potentially synergistic combinations of cytokines, longer periods of exposure, or different culture conditions. In contrast, IFN-gamma, IL-2 and TNF-alpha inhibited the ability of thyroid lymphocytes from patients with Graves' disease and Hashimoto's thyroiditis to synthesize autoantibodies to thyroid peroxidase (TPO) and thyroglobulin (Tg). Comparison of lymphoid populations isolated by digestion and/or mechanical disaggregation indicated that a population of activated B cells, plasma cells and T cells, intimately associated with thyroid cells since they could only be extracted by digestion, was influenced by cytokines. Our studies suggest that in addition to its well-recognized ability to induce MHC class II antigens on thyroid cells, IFN-gamma may inhibit thyroid cell proliferation and TNF-alpha, IFN-gamma and IL-2 may down-regulate thyroid autoantibody synthesis.

Autoantibodies↗

PubMed1990

Mononuclear cells in glomeruli and cytokines in urine reflect the severity of experimental proliferative immune complex glomerulonephritis.

Immunohistochemical methods were used to investigate the role of macrophages in the progression of proliferative immune complex glomerulonephritis. The mononuclear cell component of glomerular inflammation was analysed in three different stages of chronic serum sickness, each of which was clearly distinguished by criteria of kidney function. Urinary excretion of the macrophage secretory products interleukin-1 and tumour necrosis factor was also evaluated in relation to the functional severity of kidney disease. T lymphocytes and macrophages began to accumulate in glomeruli at the onset of proteinuria, but not before. Urinary excretion of interleukin-1 also began with proteinuria. Proteinuria increased in direct correlation with increases in the number of glomerular macrophages. Development of the most severe stage of glomerulonephritis, characterized by cachexia, declining kidney function, and necrotizing glomerular pathology, was accompanied by the disappearance of T cells from glomeruli and the expression of highly abnormal phenotypes by most macrophages. In addition, there was a switch from urinary excretion of interleukin-1 to excretion of tumour necrosis factor. The progression of proliferative immune complex glomerulonephritis was associated with qualitative as well as quantitative changes in glomerular macrophage populations. Differentiation and/or activation of those glomerular macrophages may have resulted from local T cell-mediated immunoregulation. Measurements of urinary cytokine excretion provided a reliable means of monitoring disease progression. The local action of tumour necrosis factor probably contributed to declining kidney function in the most severe stage of disease.

Animals↗

PubMed1990

Human and murine macrophages produce TNF in response to soluble antigens of Plasmodium falciparum.

Heat-stable antigens of rodent malarial parasites induce the release of tumour necrosis factor (TNF) from mouse macrophages, in vitro and in vivo. We report here that analogous antigens of Plasmodium falciparum trigger the release of TNF from human monocytes in vitro, in conditions that exclude the effects of any contaminating endotoxin. These antigens also induced TNF release from a murine monocytic cell line and from the peritoneal macrophages of several strains of mice, including the LPS-hyporesponsive C3H/HeJ mice. Similarly, boiled soluble antigens from the rodent parasites P. yoelii and P. berghei also stimulated human monocytes. Antisera made by immunizing mice with boiled antigens of P. falciparum or P. yoelii inhibited the stimulation of TNF secretion by P. falciparum antigens. They did not block the induction of TNF by bacterial lipopolysaccharide. Thus mouse macrophages provide a convenient system for investigating the nature, cross-reactions and antigenic variation of human malarial soluble antigens. Since these are known to occur in the circulation of patients with malaria, they may be responsible for excess production of TNF, a mediator that is thought to play a central role in the pathogenesis of the disease.

Animals↗

PubMed1990

Two soluble antigens of Plasmodium falciparum induce tumor necrosis factor release from macrophages.

The production of cytokines such as tumor necrosis factor (TNF) may contribute to the pathology of malaria. We showed previously that crude preparations of heat-stable exoantigens from parasite cultures induce the release of TNF in vitro and in vivo. When separated from the culture medium by affinity chromatography, in which immune immunoglobulin G was used as ligand, the mixture of exoantigens of Plasmodium falciparum retained the capacity to induce the secretion of TNF, both by human monocytes from Gambian children and by mouse macrophages. Two individual antigens, Ag1 and Ag7, further purified by affinity chromatography and identified by crossed immunoelectrophoresis, also stimulated TNF production by both types of cell but differed in other functional properties. Thus, the activity of Ag7, but not that of Ag1, was inhibited by polymyxin B, and antisera made against boiled exoantigens of the rodent parasite Plasmodium yoelii which blocked the ability of these antigens to induce the production of TNF also inhibited the activity of Ag7 without affecting Ag1. Since the prevalence of antibody against Ag7 in sera from children in endemic areas appears to correlate with the development of immunity against the manifestations of the disease, this antigen may be one cause of pathology, perhaps through its ability to induce the production of TNF. Its serological relationship with rodent exoantigens suggests that it might be a candidate for an anti-disease vaccine which has the advantage that its active moiety is not subject to significant antigen polymorphism.

Adult↗

PubMed1990

Malaria exoantigens induce T-independent antibody that blocks their ability to induce TNF.

Much of the pathology of malaria may be due to the interactions of cytokines, especially tumour necrosis factor (TNF), with various cell types, including endothelial cells, with consequent widespread systemic effects. It has been shown previously that heat-stable exoantigens in the supernatants of blood-stage parasite cultures induced the release of TNF in vitro from activated macrophages and behaved like toxins in vivo, that mice immunized with the antigens are protected from the toxic effect and that their serum specifically blocks the ability of the antigens to stimulate the production of TNF. It is reported here that the inhibitory antibody is mainly IgM and that it appears to be T-independent, as the titres of antisera from T-deficient and immunologically intact mice were similar. Antisera raised against exoantigens from two species of rodent parasite inhibited TNF production by those of the human parasite Plasmodium falciparum, and vice versa, indicating that the TNF-inducing moieties of the exoantigens cross-react and therefore presumably contain common epitopes. Thus vaccination with these exoantigens might provide a means of protection against the clinical effects of malaria and of generating anti-disease immunity by reducing cytokine production. However, these findings imply that it will be necessary to confer on these antigens the ability to stimulate T cells and generate memory before they can provide a useful basis for an anti-disease vaccine. The results obtained are discussed in relation to some of the epidemiological features of malaria.

Animals↗

PubMed1989

Lipoarabinomannan from Mycobacterium tuberculosis induces the production of tumour necrosis factor from human and murine macrophages.

We show here that purified lipoarabinomannan (LAM) from Mycobacterium tuberculosis can cause the release of tumour necrosis factor (TNF) in vitro from human blood monocytes and activated mouse peritoneal macrophages, and the production of TNF in vivo in mice pretreated with Propionibacterium acnes, with a potency comparable to that of lipopolysaccharide (LPS) from Gram negative bacteria. Like LPS, LAM binds to polymyxin B. We confirmed that its activity was distinct from any contaminating LPS and was associated with the antigenic activity by affinity chromatography, using a monoclonal antibody specific for LAM. Treatment with dilute alkali greatly diminished the TNF-inducing activity, suggesting that omicron-acyl groups may be involved. When LAM was fractionated by electrophoresis on SDS-Page and blotted on nitrocellulose, most TNF-inducing capacity coincided with the bulk of the LAM, as estimated by molecular weight and antigenic activity. This modification of the Western blotting technique may be generally useful for the study of macrophage-triggering molecules. The ability of LAM to cause the release of TNF may be responsible for some of the characteristics of tuberculosis, such as fever, weight loss, raised acute phase reactants and necrosis that can be mediated by this cytokine.

Animals↗

PubMed1989

Soluble malarial antigens are toxic and induce the production of tumour necrosis factor in vivo.

Heat-stable soluble products of rodent malarial parasites induce activated peritoneal macrophages to secrete tumour necrosis factor (TNF) in vitro. Since heat-stable parasite antigens are known to be present in the circulation of patients with malaria and it has been suggested that much of the pathology of malaria is due to TNF, we investigated the ability of such antigens to induce the production of TNF in vivo and to be toxic to mice. Injection of antigens obtained from Plasmodium yoelii or from P. berghei into mice which had previously received the macrophage-activating agent Propionibacterium acnes induced the release of TNF into the serum in amounts equivalent to the maximum release induced by bacterial lipopolysaccharide (LPS). Specific antiserum blocked the ability to the boiled soluble antigens, but not of LPS, to induce release of TNF. Similarly, vaccination specifically inhibited the release of TNF into the serum in response to subsequent stimulation with the antigens, but not with LPS. Mice made hypersensitive to the lethal action of TNF by pretreatment with D-galactosamine were killed in a dose-related fashion by administration of antigen preparations; addition of specific antiserum or prior vaccination with the antigens protected such mice, but not those given LPS, from death. We conclude that, in malaria, soluble antigens derived from the parasites may act like a toxin by stimulating the production of TNF, an important mediator of endotoxic shock, and that immunization with such antigens may diminish TNF secretion and consequently many of the clinical manifestations of the disease.

Animals↗

PubMed1989

Induction of TNF in vitro as a model for the identification of toxic malaria antigens.

Tumour necrosis factor (TNF) has been implicated as a mediator of toxicity in a number of infectious diseases, including malaria. We have shown that human and rodent blood-stage parasites liberate heat-stable soluble antigens that induce the release of TNF by activated macrophages in vitro and in vivo, and are toxic to mice made hypersensitive to TNF by D-galactosamine. These antigens induce T-independent antibodies which specifically block their ability, but not that of bacterial lipopolysaccharide, to cause the secretion of TNF. Cytokine release in vitro may be a useful strategy for identifying potentially toxic molecules of infectious organisms and for investigating the nature of antibodies that can protect the host against their damaging effects.

Animals↗

PubMed1988

Malarial parasites induce TNF production by macrophages.

Mouse peritoneal macrophages incubated with erythrocytes infected with non-lethal or lethal variants of Plasmodium yoelii or with P. berghei, in the presence of polymyxin B to exclude the effects of any contaminating endotoxin, secreted a cytotoxic factor into the supernatant that was shown to be tumour necrosis factor (TNF). No differences were observed in the ability of the three types of parasite to induce TNF production, which was maximal in the range of 0.2-5 infected erythrocytes per macrophages. TNF production was equivalent to that induced by lipopolysaccharide (LPS) and was enhanced by pretreatment of the macrophages with interferon-gamma (IFN-gamma) or with indomethacin. Culture media containing parasite products also induced macrophages to secrete TNF. The activity withstood boiling and was inhibited by malaria-specific antisera. Since heat-stable antigens are present in the circulation of patients with malaria, they may induced the secretion of TNF, a mediator of endotoxic shock, which could contribute to the pathology of the disease.

Animals↗

PubMed1987

Antiparasitic effects of tumour necrosis factor in vivo and in vitro.

Early experiments in mice suggested that tumour necrosis factor (TNF) might be cytotoxic to asexual blood-stage malaria parasites. This was based on the striking activity of tumour necrosis serum (TNS) on the parasite both in vitro and in vivo, and the inability to separate by physical means the parasite-killing and tumour-killing components. However, recombinant TNF does not have this cytotoxic effect in vitro, while its antiparasitic activity in vivo, though significant, is not as strong as that of an equivalent amount of TNS. Thus it appears that TNS contains another cytotoxic molecule and that TNF itself may act indirectly in vivo, perhaps by activating an effector cell. An example of this has been found in murine schistosomiasis, where macrophage-derived TNF is able to activate eosinophils to attack the infecting worms. One mechanism of schistosomule damage is by eosinophil cationic proteins, and these have also been found to be cytotoxic to blood-stage malaria. There may therefore be a pathway of TNF activity common to both parasites. In a similar way, the crisis-forming factor (CFF) found in the serum of certain immune Sudanese adults is clearly distinct from TNF, since CFF-containing sera do not kill TNF-susceptible tumour cells and rTNF does not kill Plasmodium falciparum in vitro. This confirms that there are other cytotoxic molecules, still to be identified, with a role in immunity to malaria and perhaps other parasites. TNF is also active against intracellular Trypanosoma cruzi and against some viruses but in both cases this appears to be an interferon-like mediatory effect and not direct cytotoxicity. It is not yet clear whether these antiparasitic activities are part of the biological role of TNF.

Animals↗

PubMed1987

Cytotoxicity of tumor necrosis factor for thyroid epithelial cells and its regulation by interferon-gamma.

The FRTL-5 line of differentiated rat thyroid epithelial cells was shown to be sensitive to the cytotoxic action of recombinant tumor necrosis factor. The sensitivity of the cells varied with the conditions of culture. It was markedly increased by preincubation with recombinant interferon-gamma, and the magnitude of this enhancement was affected by the presence of thyroid-stimulating hormone. The increased susceptibility of the cells to the cytotoxicity of tumor necrosis factor was clear as early as 2-4 h after the addition of interferon-gamma and greatly preceded the induced expression of major histocompatibility complex class II antigen. Since cells secreting interferon-gamma and tumor necrosis factors may co-exist in inflammatory infiltrates, our observations suggest that these factors may be early mediators of cell destruction in autoimmune thyroid disease.

Animals↗

PubMed1987

Expression and rescuing of a cloned human tumour necrosis factor gene using an EBV-based shuttle cosmid vector.

A cosmid vector carrying the Epstein-Barr virus origin of replication, the EBNA-1 gene, the hygromycin phosphotransferase (hph) gene and pBR322 sequences has been constructed. This cosmid can replicate autonomously in the nucleus of human tissue culture cells, even when it carries a 35-kb long insert. The cosmid can be rescued from the transfected cells by cloning it directly into ampicillin-sensitive Escherichia coli. A gene for human tumour necrosis factor (TNF) cloned into this cosmid vector was introduced in tissue culture cells, where it was transcribed into mature mRNA.

Cell Line↗

PubMed1987

Killing of Plasmodium falciparum by eosinophil secretory products.

The multiplication of two strains of Plasmodium falciparum in culture, as measured by [3H]hypoxanthine incorporation, was inhibited in a dose-dependent manner by granule proteins secreted by purified eosinophils obtained from patients with the hypereosinophilic syndrome. Morphological examination revealed the presence of abnormal parasites inside erythrocytes, indicating that they were killed in situ, and the later stages of the developmental cycle were found to be most susceptible to these toxic effects. A monoclonal antibody against eosinophil cationic protein partially blocked the inhibitory effect, suggesting that it was caused by more than one of the eosinophil granule proteins. Thus some of the antimalarial effects of molecules such as the tumor necrosis factor, which activates eosinophils, may be mediated through the enhanced production of eosinophil secretion products.

Antibodies, Monoclonal↗

PubMed1987

Activation of liver macrophages in murine malaria is enhanced by vaccination.

During blood-stage infection of mice with a lethal variant of Plasmodium yoelii, cells in both spleen and liver became activated to reach a peak at day 5. In mice protected by vaccination, activation was accelerated after infection. The most striking difference observed was in the 10-fold greater yield of infiltrating cells, including macrophages, obtained from the liver just before the mice recovered. Their capacity to give an oxidative burst and their cytotoxic activity against tumour cells was also more than 10 times normal. This suggests that the recruitment of inflammatory cells to the liver plays an important role in the protection of vaccinated mice against malaria.

Animals↗

PubMed1987

The role of gamma-interferon, vitamin D3 metabolites and tumour necrosis factor in the pathogenesis of tuberculosis.

Endotoxin (LPS)-triggered release of tumour necrosis factor (TNF) from human monocytes is high for the first 3 days in culture, and then falls to a trough between Days 4 and 6. This trough is less deep if the cells are cultured in the presence of indomethacin. If monocytes are cultured in the presence of either recombinant gamma-interferon or 1,25-(OH)2 vitamin D3, their capacity for LPS-triggered TNF release is increased. Live virulent Mycobacterium tuberculosis can substitute for the LPS, and is markedly more effective as a trigger than several strains of BCG prepared in an identical manner. Since secretion of IFN-gamma and conversion of circulating 25-(OH) vitamin D3 to the active dihydroxy metabolite by interferon-activated macrophages probably occur in tuberculosis, we suggest that triggering of TNF release from the resulting activated macrophage populations might explain much of the weight loss and tissue damage that characterize this disease. IFN-gamma does not activate effective anti-mycobacterial mechanisms in human monocytes, so its role in tuberculosis may be immunopathological rather than protective.

Antigens, Bacterial↗

PubMed1987

Recombinant tumour necrosis factor inhibits malaria parasites in vivo but not in vitro.

As tumour necrosis serum kills malarial parasites in vitro and inhibits the multiplication of some species of Plasmodium in mice, we examined the effect of recombinant mouse tumour necrosis factor (rTNF) on P. yoelii both in vitro and in vivo. Parasites incubated overnight with rTNF showed no loss of viability, but repeated injection of rTNF into infected mice reduced parasitaemia and significantly prolonged survival of mice infected with a lethal variant of the parasite. We conclude that TNF acts on blood-stage malaria in vivo via a host cell and that another molecule in tumour necrosis serum is involved in killing the parasite in vitro.

Animals↗