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Biomedical subjects

J H Playfair

Publications and source records attributed to J H Playfair.

At least 19 recordsLinked to original sources
PubMed1992

Malarial toxic antigens synergistically enhance insulin signalling.

Hypoglycaemia is a major complication of severe malaria [(1990) Trans. Roy. Soc. Trop. Med. 84 (suppl. 2) 1-65], especially cerebral malaria, in which it is associated with increased mortality [(1990) Lancet 336, 1039-1043; (1989) Quart. J. Med. (New series) 71, 441-459]; however, the mechanisms responsible have not been fully explained. Preparations containing toxic malaria antigens (TMA) released by blood stage Plasmodium yoelii malaria parasites have been shown to induce hypoglycaemia in mice lasting at least 8 h [(1992) Clin. Exp. Immunol. (in press)]. Here we report that TMAs can act synergistically with insulin in both stimulating lipogenesis and inhibiting lipolysis in rat adipocytes in vitro, and, furthermore, that they act synergistically with insulin in the induction of hypoglycaemia in vivo.

Adipose Tissue↗
PubMed1992

Cytokines as immunological adjuvants.

Various cytokines have been shown to be effective immunological adjuvants in a variety of model systems, enhancing protection induced by viral, bacterial and parasitic vaccines, and increasing parameters of immunity in tumour immunization models and in clinical trials. While in most cases cytokine adjuvanticity is not as powerful as that shown by the best experimental adjuvants, such as saponin and Freund's, it can rival that of the adjuvants presently allowed for human use and there are many possible routes to improvement. The use of cytokines may allow for a choice of which immune parameters are enhanced in order to further enhance protective effects and decrease the negative effects of vaccines.

Adjuvants, Immunologic↗
PubMed1992

Phospholipid-containing toxic malaria antigens induce hypoglycaemia.

Hypoglycaemia is associated with severe malaria and is an important prognostic indicator. Molecules liberated during overnight incubation of erythrocytes infected with Plasmodium yoelii induce marked hypoglycaemia in normal mice, with a delayed time course compared with insulin; some, though weaker, activity could also be obtained by overnight incubation of uninfected erythrocytes. The active component shares many properties with the phospholipid-containing molecules which we have previously shown to be toxic and to induce the release of tumour necrosis factor (TNF) from macrophages. However a MoAb which neutralizes the cytotoxicity of tumour necrosis factor in vitro did not prevent this induction of hypoglycaemia, whereas antiserum against the toxic antigens did, as did immunization of normal (but not the immunoglobulin-deficient SCID) mice with the same material. Furthermore, normal mice injected with the antigens after immunization with phosphatidyl inositol or inositol monophosphate did not develop hypoglycaemia; the latter compound was also inhibitory when mixed with the antigens before injection. These compounds were previously shown to block the induction of TNF by the antigens and to induce the production of inhibitory antibodies. The role of these molecules in the etiology of the hypoglycaemia of malaria is discussed.

Animals↗
PubMed1992

Serological relationship of tumor necrosis factor-inducing exoantigens of Plasmodium falciparum and Plasmodium vivax.

Exoantigens of Plasmodium vivax-parasitized erythrocytes stimulated macrophages to secrete tumor necrosis factor, and antisera raised against the exoantigens inhibited this secretion. The antisera also inhibited the activity of Plasmodium falciparum and Plasmodium yoelii exoantigens, and conversely, antisera against the latter cross-reacted with the exoantigens of P. vivax.

Animals↗
PubMed1992

Detoxified exoantigens and phosphatidylinositol derivatives inhibit tumor necrosis factor induction by malarial exoantigens.

We have previously shown that malaria parasites liberate exoantigens which, through a phospholipid component, stimulate mouse macrophages to secrete tumor necrosis factor (TNF), which are toxic to D-galactosamine-sensitized mice, and which therefore might be involved in pathology. Plasmodium yoelii exoantigens detoxified by dephosphorylation or digestion with lipases do not induce TNF production. However, these partial structures inhibited its production in response to the exoantigens, although not to bacterial lipopolysaccharide (LPS). When pure phospholipids were tested in a macrophage assay, none stimulated the production of TNF, but phosphatidylinositol (PI) inhibited TNF induction by P. yoelii exoantigens. Moreover, inositol monophosphate (IMP) was the only one of a number of monophosphate saccharides tested which was inhibitory; inositol was not. Macrophages pretreated with PI, IMP, or detoxified exoantigens and then incubated with parasite exoantigens also yielded much less TNF. PI, IMP, and lipase-digested exoantigens of P. yoelii similarly inhibited the TNF-inducing activity of exoantigens of the human parasites Plasmodium falciparum and Plasmodium vivax. Neither PI nor IMP diminished TNF production in response to LPS, in contrast to a platelet-activating factor antagonist [1-O-hexadecyl-2-acetyl- sn-glycero-3-phospho(N,N,N-trimethyl hexanolamine)] which inhibited both exoantigen- and LPS-induced production of TNF. We conclude that at least two different parts of the molecule are involved in the induction of TNF secretion by parasite exoantigens: one requires the presence of a phosphate bound to inositol, and, since dephosphorylated exoantigens were also inhibitory, one does not. It would seem that both affect interactions between parasite-derived exoantigens and the macrophage receptors.

Animals↗
PubMed1992

Tumour necrosis factor induction by malaria exoantigens depends upon phospholipid.

In patients with malaria, the clinical manifestations of the disease are associated with the presence of high concentrations of tumour necrosis factor (TNF) in the serum. Blood-stage parasites of human and rodent malarial parasites release serologically related exoantigens which induce the production of TNF in vitro and in vivo and which can kill mice made hypersensitive to TNF by pretreatment with D-galactosamine. They also elicit the production of T-independent antibody, which blocks these effects. The capacity of the exoantigens to stimulate macrophages to secrete TNF does not require the presence of protein or carbohydrate, but is associated with a lipid whose activity can be abolished by treatment with phospholipase C. Treatments of the exoantigens which destroyed their activity in vitro also abrogated their immunogenicity and their toxicity for mice. No TNF-inducing activity could be detected in preparations of parasitized erythrocytes that was not associated with phospholipid, and the TNF-inducing properties of the malarial phospholipids are quite distinct from those of bacterial lipopolysaccharide. We conclude that release of potentially toxic phospholipids by parasites may be responsible for some of the pathology of malaria.

Animals↗
PubMed1992

Antibodies against phosphatidylinositol and inositol monophosphate specifically inhibit tumour necrosis factor induction by malaria exoantigens.

The active component of the exoantigens of malarial parasites which stimulates macrophages to secrete tumour necrosis factor (TNF) has been shown to depend upon a phospholipid, the activity of which was blocked by phosphatidylinositol (PI) and inositol monophosphate (IMP) in competitive inhibition studies. Antisera made against the exoantigens of Plasmodium yoelii, which inhibited their induction of TNF, were found by an ELISA assay to contain antibody against several other phospholipids. However, the inhibitory antibody was removed specifically by adsorption with liposomes containing PI, but not other phospholipids. Furthermore, PI was the only phospholipid in non-liposomal form which induced the production of inhibitory antisera. Mice immunized with IMP, but not inositol, also produced inhibitory antisera. When incorporated into liposomes several other phospholipids did give rise to inhibitory antibodies but, in contrast to the antisera against parasite exoantigens, PI and IMP, the inhibitory activity was removed by adsorption with heterologous phospholipid liposomes, suggesting that it was directed against a common determinant, presumably the phosphate ester head group. Inhibitory antibodies in the antisera tested were predominantly IgM and titres were not increased after repeated injections. Antisera raised against PI, IMP or the cross-reacting phospholipid liposomes also inhibited TNF secretion by macrophages stimulated by exoantigens of the human parasites P. falciparum and P. vivax, but not by bacterial lipopolysaccharide. These findings confirm our conclusion that exoantigens from these different species contain phosphate bound to inositol in their TNF-inducing moiety.

Animals↗
PubMed1991

Effects of interferon gamma and saponin on lymphocyte traffic are inversely related to adjuvanticity and enhancement of MHC class II expression.

Interferon gamma (IFN-gamma) is an effective immunological adjuvant when mixed with vaccines prior to injection, but the way in which it exerts this effect has been unclear. Because some adjuvants have been shown to affect lymphocyte traffic, and interferons have been shown to have effects on lymphocyte homing molecules, we examine in this study the effects of IFN-gamma and the potent adjuvant saponin on lymphocyte traffic, and show that both of these adjuvants increase lymphocyte homing to an injection site in mice. We have then compared effects on lymphocyte traffic and on MHC class II expression with adjuvant effects in different mouse strains. Effects on lymphocyte traffic were the inverse of adjuvant effects in different strains, however both materials enhanced MHC class II expression, and this enhancement corresponded with adjuvanticity in different strains of mice. A possible explanation for the negative effect of lymphocyte homing may be that the vast majority of T cells homing to the injection sites in response to both IFN-gamma and saponin were of the CD8+ (suppressor/cytotoxic) phenotype.

Animals↗
PubMed1991

Don't kill the parasite: control the disease.

It is clear from both laboratory and clinical studies that the blood-stage malaria parasite does not itself directly cause most of the serious complications of the disease, with the possible exception of anaemia. For example, T cell- deprived mice with lethal infections survive longer and mice can be protected against early death by vaccines that appear not to affect parasitaemia. In certain cases antibodies to TNF have the same effect. Clinically it has been known for over 50 years that children in endemic areas develop immunity to the serious toxic aspects of malaria several years before their parasitaemias start to fall. Recent work on the induction of cytokines such as tumour necrosis factor (TNF) by exoantigens of the blood-stage parasite and on the role of cytokines in this and other toxic diseases suggests that an appropriate vaccine might induce antibody that blocks the effect of the exoantigens, thus conferring on young children the anti-disease immunity that normally takes years to appear. Such vaccines might be less hampered by the antigenic variation that makes anti-parasite immunity slow to develop. Characterisation of the molecules involved is a high priority.

Animals↗
PubMed1990

Inhibition of intraerythrocytic development of Plasmodium falciparum by proteinase inhibitors.

A group of inactivators of cysteinyl proteinases which function by covalent bond formation have been examined for their ability to inhibit the development of Plasmodium falciparum within red blood cells. The most effective of these caused inactivation of the parasite near 10(-8) M concentration. The range of inhibitory action varied with peptide structure in a manner characteristic of affinity labels for proteinases suggesting that the target of inhibition was an unidentified proteinase, probably of the cysteinyl type, but different from cathepsins B and L.

Animals↗
PubMed1990

Polyclonal in vitro proliferative responses from nonimmune donors to Plasmodium falciparum malaria antigens require UCHL1+ (memory) T cells.

The in vitro polyclonal proliferative responses of peripheral blood mononuclear cells to whole blood stage parasites or fractionated antigens from the human malaria parasite Plasmodium falciparum were studied. Cells from healthy laboratory donors who had never been exposed to malaria antigens in vivo consistently proliferated to P. falciparum antigens, as did cord blood mononuclear cells. This response was only observed in sheep rosette-positive cells in the presence of adherent cells and was inhibited by NH4Cl, indicating a requirement for antigen processing. The proliferative response was strongest at day 6 and was dependent on the presence of cells expressing high levels of CD45 180-kD isomer (UCHL1 monoclonal antibody), a marker for activated or memory cells, but not for CD45R (SN130 monoclonal antibody) a marker for naive or unprimed T cells. This suggests a similarity to the recall response to tuberculin antigen. These results suggest that the proliferative response to malaria antigens observed previously and described as a nonspecific mitogenic response may be a cross-reactive response to epitopes shared between P. falciparum and other common immunogens. This would explain the establishment of T cell clones to malaria antigens from such donors, but might suggest that the epitopes to which such clones are specific may be of questionable protective or diagnostic use.

Adult↗
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↗