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Biomedical subjects

D Kwiatkowski

Publications and source records attributed to D Kwiatkowski.

At least 91 records · Page 5Linked to original sources
PubMed1994

A monoclonal antibody that recognizes phosphatidylinositol inhibits induction of tumor necrosis factor alpha by different strains of Plasmodium falciparum.

The clinical symptoms of human malaria are mediated, at least in part, by the release of tumor necrosis factor alpha (TNF) by monocytes and macrophages. We have found that lysates of Plasmodium falciparum-infected erythrocytes stimulate the secretion of TNF from human mononuclear cells, and we have generated several immunoglobulin M monoclonal antibodies (MAbs) that inhibit the induction of TNF by such lysates. Here we describe the properties of MAb 5AB3-11, which causes dose-dependent inhibition of the TNF-inducing factors derived from P. falciparum-infected erythrocytes, with a 50% reduction in TNF secretion at nanomolar concentrations (1 to 2 micrograms/ml). The inhibitory effect appears to be malaria specific in that the induction of TNF by either lipopolysaccharide or lipoteichoic acid is not affected. MAb 5AB3-11 binds to liposomes containing phosphatidylinositol but not to other phospholipid liposomes, showing that it recognizes a phosphatidylinositol-like epitope. MAb 5AB3-11 inhibits the induction of TNF by whole lysates from several strains of P. falciparum which originated from different parts of the tropics, indicating that all of the major TNF-inducing factors derived from Plasmodium-infected erythrocytes contain a common epitope. A phosphatidylinositol-like epitope expressed by Plasmodium-infected erythrocytes may be a suitable immunological target for the prevention or treatment of severe malaria.

Animals↗
PubMed1994

Inhibitory immunoglobulin M antibodies to tumor necrosis factor-inducing toxins in patients with malaria.

Cytokines such as tumor necrosis factor alpha (TNF) appear to play an important role in the pathogenesis of malaria. We have previously shown that TNF is produced in response to substances released at schizont rupture, which we have called malaria toxins. In mice these toxins stimulate a T cell-independent antibody response, generating short-lived immunoglobulin M (IgM) antibodies that inhibit the TNF-inducing activity of the toxins. We report here that a similar antibody response is seen in humans. Serum from a European adult infected with Plasmodium falciparum inhibited the induction of TNF by malaria toxins derived from P. falciparum-infected erythrocytes. We found that IgM antibodies were responsible for the inhibitory activity. These inhibitory antibodies could not be detected in convalescent-phase serum collected from the same patient 6 weeks later or in sera from healthy European and African controls. The antibodies appeared to be malaria specific in that they inhibited TNF induction by a variety of P. falciparum isolates but failed to inhibit TNF induction by bacterial lipopolysaccharide or lipoteichoic acid. The inhibitory antibodies bound to liposomes containing phosphatidylinositol but not other phospholipids. Serum from a European adult infected with P. vivax also inhibited the activity of toxins derived from P. falciparum-infected erythrocytes, and this too was mediated by IgM antibodies which were malaria specific and bound to phosphatidylinositol liposomes.

Adult↗
PubMed1993

TNF-inducing malaria toxin: a sheep in wolf's clothing?

It has long been believed that paroxysms of malaria fever are due to a toxin released by rupturing schizonts. The nature of this toxin is beginning to be understood. A critical mediator of malaria fever is tumour necrosis factor (TNF), which is released by monocytes/macrophages and is a potent pyrogen. Rupturing schizonts release a toxin (or toxins) that stimulate macrophages to release TNF. The precise structure of the toxin is unknown but it appears to involve a phosphatidylinositol-like moiety. In addition to causing fever, TNF-inducing toxins are believed to be involved in the pathogenesis of cerebral malaria. However, cerebral malaria occurs in only a small proportion of infected individuals; for the population as a whole, the benefits of the TNF response to the malaria toxin probably outweigh its disadvantages.

Fever↗
PubMed1993

Plasmodium falciparum varies in its ability to induce tumor necrosis factor.

Tumor necrosis factor (TNF) has a variety of protective and pathological actions in human malaria. We report that different laboratory lines of Plasmodium falciparum which were derived from a single wild isolate (IT 4/25/5) varied widely in their ability to stimulate TNF production by human mononuclear cells. In the cloned line R29 we observed that subcultures selected for high rosetting frequency gave significantly higher levels of TNF stimulation than subcultures with low rosetting frequency, indicating that TNF induction can vary within populations that have originated from a single genotype. These results raise the possibility that the clinical severity of malaria is partly determined by the TNF-inducing activity of the infecting strain of parasite.

Animals↗
PubMed1993

Anti-TNF therapy inhibits fever in cerebral malaria.

The clinical effects of a murine monoclonal antibody (CB0006) directed against tumour necrosis factor were investigated in an open study of 41 Gambian children receiving otherwise conventional therapy for cerebral malaria. Ten children received a single i.v. dose of CB0006 at 0.1 mg/kg, 10 received 1 mg/kg, 10 received 5 mg/kg, and 11 were randomly selected as controls. CB0006 rapidly formed complexes with tumour necrosis factor, which were cleared from the circulation over several days. This was associated with a dose-dependent increase in total plasma tumour necrosis factor levels and a dose-dependent reduction of fever, implying that CB0006 inhibits tumour necrosis factor by retaining it in the circulation and reducing its availability to tissue receptors. Parasite clearance rates were not impaired. The fatality rate (29% overall) was similar in CB0006-treated patients and controls, but evaluation of possible effects on mortality requires a much larger blinded study. These data show that tumour necrosis factor is involved in the pathogenesis of malaria fever, and are the first direct evidence that inhibition of a specific endogenous pyrogen can attenuate fever in man.

Animals↗
PubMed1993

Phospholipids coupled to a carrier induce IgG antibody that blocks tumour necrosis factor induction by toxic malaria antigens.

Phospholipid-containing antigens of malaria parasites stimulate macrophages to secrete tumour necrosis factor (TNF), induce hypoglycaemia and are toxic to mice. This TNF induction is inhibited by antisera made against the antigens, the inhibitory activity of which can be removed specifically by adsorption to phosphatidylinositol (PI) liposomes. Although the same was true of antisera made against PI, the inhibitory activity of antisera made against some other phospholipids appeared to be directed against a common determinant, probably the phosphate ester head group. We have shown previously that the activity of all the antisera was associated mainly with IgM and was not boosted by repeated injections of the antigens. To try and induce a secondary response against the parasite antigens using non-toxic molecules, mice were immunized with various phosphorylated compounds coupled to keyhole limpet haemocyanin (KLH). Three injections of PI-KLH or of phosphatidylserine (PS) coupled to KLH induced significantly higher titres of inhibitory antibody than one; furthermore, the inhibitory activity was mainly in the IgG fraction. The antisera did not inhibit TNF induction by lipopolysaccharide (LPS) or lipoteichoic acid. However, antisera against PS-KLH, though not PI-KLH, inhibited the induction of TNF by the phospholipid, platelet-activating factor (PAF). These antisera, and antisera from mice immunized with phospho-threonine or galactosamine-1-phosphate conjugated to KLH, contained inhibitory antibodies of differing specificities. Mice immunized with PI-KLH, PS-KLH or phospho-threonine-KLH did not develop hypoglycaemia when challenged with the parasite toxic antigens. These results indicate that the antigenicity of non-toxic analogues can be dramatically enhanced by coupling to a protein carrier.

Animals↗
PubMed1992

Extensive genetic diversity in the HLA class II region of Africans, with a focally predominant allele, DRB1*1304.

Molecular HLA class II typing of greater than 1700 individuals from The Gambia in West Africa and Malawi in South-Central Africa revealed a striking diversity of HLA DRB-DQB haplotypes as defined by restriction fragment length polymorphism (RFLP); this diversity is twice as extensive as that found in northern Europeans. Despite this diversity, sequence and PCR/oligonucleotide analysis showed that the recently described variant DRB1*1304 is the commonest DRB1 allele in The Gambia. The sequence, geographical distribution, and RFLP association of this allele, together with homozygosity test results, suggest that DRB1*1304 may have arisen from DRB1*1102 and have reached its remarkably high frequency as a result of recent directional selection. The prevalence of this unusual allele has implications for trials of subunit vaccines in this area. The extensive and distinctive HLA class II region polymorphism in sub-Saharan Africans is consistent with evidence from other genetic loci implying an African origin of modern Homo sapiens.

Alleles↗
PubMed1992

Systemic cytokine response after major surgery.

The systemic cytokine response to major surgical trauma was studied in 20 patients undergoing elective aortic surgery and five patients after inguinal hernia repair. Tumour necrosis factor alpha and interferon gamma were not detected in these patients. An early and short-lived interleukin 1 beta (IL-1 beta) response to major surgery was detected only by intensive sampling in the perioperative period. The IL-1 beta peak preceded a more marked interleukin 6 (IL-6) response that peaked 4-48 h after surgery. IL-6 levels had fallen sharply by 48-72 h in all patients who had an uneventful postoperative course. The IL-6 peaks were significantly lower after hernia surgery than after major aortic operations (P < 0.001); IL-1 beta was not detected in any samples. Three patients undergoing aortic surgery developed unexpected major postoperative complications. IL-6 levels in this group were significantly higher than those of the other patients undergoing aortic surgery within 6-8 h of skin incision, and remained elevated for longer. These rises in plasma IL-6 levels preceded the clinical onset of major complications by 12-48 h. The systemic IL-1 beta and IL-6 response to surgical trauma increased with the severity of the surgical insult. An early, exaggerated IL-6 response was associated with the subsequent clinical development of major complications.

Aged↗
PubMed1992

Malaria: becoming more specific about non-specific immunity.

For the hundreds of millions of people presently infected with malaria, survival may depend on relatively non-specific immune effector mechanisms. Progress has been made in understanding the anti-parasitic properties of tumor necrosis factor-alpha, interferon-gamma and nitric oxide, in defining the parasite toxins that induce tumor necrosis factor-alpha production, and in exploring the role of cytokines and adhesion molecules in the pathogenesis of cerebral malaria.

Animals↗
PubMed1992

Tumor necrosis factor in septicemic melioidosis.

Plasma concentrations of the cytokine tumor necrosis factor (TNF) were measured serially in 91 patients suspected of having septicemic melioidosis. This was confirmed in 55. TNF was detectable in admission plasma (TNF0) in 3 of 15 survivors of septicemic melioidosis and 21 of 26 fatal cases (P less than .001). The median (range) TNF0 concentration in melioidosis patients who died was 96 (1-4774) pg/ml, and the median time to death was 25 (5-672) h. TNF0 was inversely correlated with the lowest mean arterial pressure in the succeeding 12 h (Spearman's rank correlation coefficient = .67, 2P less than .001). Three patterns of TNF plasma concentrations were evident: relatively constant values between 100 and 500 pg/ml (n = 7), high admission concentrations (greater than 1000 pg/ml) associated with early death (n = 4), and an apparent pulse release after treatment, with peak values greater than 1000 pg/ml, which then declined with a mean (SD) apparent half-time of 131 (50) min (n = 8). Further studies are necessary to determine whether TNF contributes to lethality in melioidosis.

Adolescent↗
PubMed1992

Tumour necrosis factor-dependent parasite-killing effects during paroxysms in non-immune Plasmodium vivax malaria patients.

Plasmodium vivax malaria infections in non-immune individuals manifest as periodic clinical episodes of fever with chills and rigors known as paroxysms. We have demonstrated that in non-immune patients the period of paroxysm is associated with the transient presence of plasma factors which kill gametocytes, the intra-erythrocytic sexual stages of the malaria parasite which transmit the infection from humans to mosquito, rendering them non-infectious to mosquitoes. Gametocyte killing in paroxysm plasma is mediated by tumour necrosis factor (TNF) acting in conjunction with other essential serum factor(s). Plasma TNF levels were elevated during a paroxysm. In semi-immune individuals from a P. vivax-endemic area clinical symptoms of malaria are mild and the parasite killing factors are not induced during paroxysm. Serum TNF levels were correspondingly lower in endemic patients during a paroxysm. Human peripheral blood mononuclear cells (PBMC) can be stimulated in vitro by extracts of P. vivax blood stage parasites to produce TNF and associated parasite killing factor(s), thus simulating in vitro the events that occur during a paroxysm, this being the release of parasite exo-antigens by rupturing schizonts and the subsequent induction of PBMC to produce TNF and other parasite-killing factors. We were able to show that convalescent serum from P. vivax semi-immune individuals block the induction of TNF and parasite-killing factors by malaria antigens in vitro, presumably through antibodies that neutralize parasite exo-antigens. Thus, individuals living in malaria-endemic areas appear to acquire clinical immunity to malaria by avoiding their induction during infection; we have shown that one such mechanism is the neutralization of parasite exo-antigens that induce the production of parasite killing factors.

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

Rosette formation in Plasmodium falciparum isolates and anti-rosette activity of sera from Gambians with cerebral or uncomplicated malaria.

The ability of Plasmodium falciparum-infected red blood cells (RBC) to form spontaneous erythrocyte rosettes was studied in 130 fresh isolates from Gambian children with cerebral or uncomplicated malaria from August to November 1990. All isolates (24 of 24) from patients with cerebral malaria formed rosettes, but only 61 of 106 isolates from children with uncomplicated malaria formed rosettes. The mean rate of rosette formation in isolates from children with cerebral malaria (28.3%) was significantly greater than that in isolates from children with uncomplicated malaria (8.5%). Giant rosettes were more frequently formed in isolates from patients with cerebral malaria than in those from patients with uncomplicated malaria. Sera of children with cerebral disease generally lacked anti-rosette activity, while many sera from children with uncomplicated malaria showed strong anti-rosette activity when tested against the patients' ow parasites. Some sera that were devoid of autologous rosette-disrupting activity were able to disrupt rosettes formed in other isolates, indicating the presence of different rosette formation mechanisms. Forty percent (6 of 15) of the sera from patients with cerebral malaria caused microagglutination of the patients' own uninfected and infected RBC, while only 10% (3 of 31) of sera from children with uncomplicated disease caused microagglutination. The ability of infected RBC to bind to melanoma cells grown in vitro did not differ between patients with cerebral or uncomplicated malaria. The results of this study, taken in conjunction with our previous findings, establish a strong association between rosette formation in P. falciparum-infected RBC and cerebral malaria.

Adolescent↗
PubMed1992

Interethnic genetic differentiation in Africa: HLA class I antigens in The Gambia.

A total of 752 individuals from The Gambia, west Africa who are representative of the major ethnic groups in the capital, Banjul, were serologically typed for HLA-A, -B, and -C antigens. Although all were typically "African" in their antigenic profiles, some marked frequency differences were found between the ethnic groups. Genetic distance comparisons with several other African populations showed that, although these west African populations clustered closely together, the positions of the various ethnic groups in The Gambia were consistent with historical and linguistic evidence of their affinities with one another and with other African populations. Despite the potential confounding effects both of selection by infectious diseases and of genetic drift caused by local differences in population structure, HLA frequencies appear to be of value in measuring inter- and intraregional population affinities in sub-Saharan Africa.

Africa↗
PubMed1991

Common west African HLA antigens are associated with protection from severe malaria.

A large case-control study of malaria in West African children shows that a human leucocyte class I antigen (HLA-Bw53) and an HLA class II haplotype (DRB1*1302-DQB1*0501), common in West Africans but rare in other racial groups, are independently associated with protection from severe malaria. In this population they account for as great a reduction in disease incidence as the sickle-cell haemoglobin variant. These data support the hypothesis that the extraordinary polymorphism of major histocompatibility complex genes has evolved primarily through natural selection by infectious pathogens.

Animals↗