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Biomedical subjects

E Pearce

Publications and source records attributed to E Pearce.

At least 19 recordsLinked to original sources
PubMed2005

Association of the lymphotoxin-alpha gene Thr26Asn polymorphism with severity of coronary atherosclerosis.

A recent large-scale, genome-wide association study of single nucleotide polymorphisms showed a strong association between susceptibility to myocardial infarction and the Thr26Asn polymorphism in the lymphotoxin-alpha (LTA) gene. In the present study, we investigated whether the LTA Thr26Asn polymorphism was associated with the extent of coronary atherosclerosis in a large cohort (n=1082) of well-documented coronary artery disease patients. Thr26Asn genotypes showed a significant different distribution in male patients, when stratified according to the number of diseased coronary arteries, with an odds ratio of 1.98 (95% CI 1.22-3.22) for multiple-vessel disease in patients of the Asn/Asn genotype, compared with patients of the Thr/Thr or Thr/Asn genotype (P=0.006). Thus, further to the recent finding that LTA gene variation is associated with susceptibility to coronary heart disease, the present study provides evidence of an association between LTA genotype and the extent of coronary atherosclerosis.

Asparagine↗
PubMed2000

Human immune responses to Schistosoma mansoni vaccine candidate antigens.

To determine the naturally occurring immunological responses to the Schistosoma mansoni antigens paramyosin, IrV-5, Sm-23 (MAP-3), and triose phosphate isomerase (MAP-4), a total of 119 subjects from an area of endemicity for schistosomiasis, including "resistant" subjects (n = 17) were evaluated. Specific immunoglobulin G1 (IgG1), IgG2, IgG3, IgG4, and IgA levels for each of the antigens and the cytokine profile in culture supernatants from antigen-stimulated peripheral blood mononuclear cells (PBMC) were determined. Although all the subjects had a high degree of contaminated water exposure, their infection levels were variable (0 to 1,128 eggs/g of stool). There were direct correlations between infection levels and levels of SWAP- and paramyosin-specific IgG1 and IgG4 (P < 0.05). However, an inverse correlation between infection levels and specific IgG2 to IrV-5 (P < 0.01) was observed. The evaluation of the cytokine profile (interleukin 5 [IL-5], IL-10, gamma interferon [IFN-gamma], and tumor necrosis factor alpha) in response to these antigens showed inverse correlations between the degree of infection and IFN-gamma levels in PBMC supernatants stimulated with paramyosin (P < 0.05) and IrV-5 (P < 0.01). Additionally, inverse correlations between the degree of infection and IL-5 levels in MAP-3- and MAP-4-stimulated PBMC supernatants (P < 0.01) were found. Logistic regression analysis was performed to adjust the results of cytokine profile by age. IL-5 production in MAP-3-stimulated PBMC supernatants was associated with lower infection levels (odds ratio = 11.2 [95% confidence interval, 2.7 to 45.8]).

Adult↗
PubMed1998

Plaque minerals and dental caries.

Studies to date show that extracellular fluid obtained from resting plaque is highly supersaturated with respect to enamel mineral and that, after one sugar rinse, it rarely becomes unsaturated, even though the pH decreases markedly. This is partly because Ca2+ is released from plaque pools and minimises the change in saturation level, that is, acts as a "saturation buffer". Theoretical considerations, however, suggest that, with repeated pH cycling, calcium and possibly phosphate and fluoride pools in plaque will become depleted, at which time a state of marked undersaturation of plaque fluid will appear when the pH decreases on glycolysis. Such plaque fluid would have a high demineralisation potential. An artificial solid-phase supplement of the ion reservoirs in plaque would be expected to delay the time when plaque fluid becomes unsaturated during multiple pH cycling events, and would be expected to have marked anti-caries effects.

Buffers↗
PubMed1996

Calpain is the target antigen of a Th1 clone that transfers protective immunity against Schistosoma mansoni.

A CD4+ clone (clone B), characterized as Th1 based on its selective production of IFN-gamma and IL-2, was established from C57Bl/6 mice protectively immunized against Schistosoma mansoni by intradermal vaccination with soluble worm Ags, plus bacillus Calmette Guerin. In agreement with previous results demonstrating an IFN-gamma-dependent cell-mediated protective mechanism in this vaccination model, Ag-elicited peritoneal macrophages from syngeneic recipients of this clone were activated to kill schistosome larvae (schistosomula) in vitro. Moreover, recipients of clone B displayed significant resistance against cercarial challenge. By screening a battery of lambda(gt11) clones from an adult worm cDNA library, one recombinant (25B) was identified that stimulated clone B specifically. Analysis of the 25B cDNA insert revealed a nucleotide sequence identical with that of the large subunit of schistosome calpain, a Ca2+-activated neutral proteinase. By expressing the products of PCR subcloning, we identified a 146-amino acid region of the 25B gene containing immunologic activity equivalent to the whole polypeptide. Overlapping peptides spanning this region were synthesized, and a core epitope was identified with the sequence EWKGAWCDGS. Since clone B responds to supernatants from cultured schistosomula, we postulate that the recognition of calpain released by invading larvae and resulting induction of Th1 cytokines accounts for the protection mediated by the adoptively transferred clone. Our findings thus implicate calpain as a target of protective immunity in schistosomes and provide the first example of a candidate vaccine Ag for this parasite identified on the basis of T cell reactivity.

Adoptive Transfer↗
PubMed1996

Evidence of a T helper type 2 activation in human schistosomiasis.

The lymphocyte proliferative response and cytokine production to S. mansoni antigen in vitro were evaluated in 22 schistosomiasis patients living in an area endemic for this disease. The majority of patients (86%) showed no lymphocyte proliferative response and none of them showed interferon-gamma (IFN-gamma) production, following in vitro stimulation with soluble adult worm antigen preparation (SWAP). In contrast, interleukin (IL)-5 (2038 +/- 1757 pg/ml) and IL-10 (867 +/- 762 pg/ml) were detected in peripheral blood mononuclear cell (PBMC) cultures stimulated with SWAP. Moreover, mRNA for IL-4 was detected in SWAP-stimulated PBMC from 4 of 6 patients evaluated. Restoration of lymphoproliferative response was achieved in 4 of 6 patients by adding anti-IL-10 monoclonal antibody (mAb) to PBMC cultures [mean stimulation index (SI) in the presence of antigen = 2.7 +/- 2.9; SI in the presence of antigen plus anti-IL-10, 21 +/- 16]. Restoration of IFN-gamma production by addition of anti-IL-10 mAb was achieved in 4 of 12 patients evaluated (248, 350, 687 and 710 pg/ml). Moreover, the addition of IL-10 to PBMC cultures of 3 schistosomiasis patients and 2 cured subjects who had high lymphoproliferative responses to SWAP resulted in the suppression of these responses by 90%, and completely suppressed IFN-gamma production in one of the subjects, whose PBMC produced IFN-gamma after stimulation with SWAP. The presence of IL-4 mRNA, high levels of IL-5, and the absence of IFN-gamma in PBMC culture supernatants from infected patients, supports the conclusion that patients living in an endemic area of schistosomiasis express a predominant T helper type 2 response. The high levels of IL-10 and the ability of neutralizing anti-IL-10 mAb to restore T cell responses indicate that this cytokine plays an important role in the modulation of T cell responses in schistosomiasis.

Adolescent↗
PubMed1996

Fluoride distribution in human dental calculus obtained from different sites on the tooth surface.

We examined the site specificity of fluoride (F) distribution in human dental calculus. Teeth with supra- and subgingival calculus were obtained from patients who resided in non-fluoridated areas in Japan and China. Sequential layers of the dental calculus (30 microns thick) were abraded by an abrasive micro-sampling technique and fluoride and phosphorus in the powdered samples were analyzed. Fluoride concentrations were highest in the outer, lowest in the middle and intermediate in the inner layers of dental calculus in general. In the outermost layers fluoride concentrations were highest in calculus found near the tooth cervix both in supra- and subgingival calculus. Fluoride concentrations decreased markedly toward the apical region in subgingival calculus, while it did not change toward the incisal or occlusal region in supragingival calculus. In the inner layers, fluoride concentrations in both supra- and subgingival calculus were not affected by position on the teeth. Fluoride concentrations in subgingival calculus near the apex were lower than in supragingival calculus near the incisal or occlusal region. It was concluded that the fluoride concentrations differ in different regions of dental calculus, probably due to their different mechanisms of formation.

Calcium Phosphates↗
PubMed1994

The development and testing of a diagnostic scale for incest survivors.

A scale (Diagnostic Scale for Incest Survivors: DSIS) was developed for adult women who experienced incest during childhood. Items were obtained from research on post-traumatic stress, personality disorders, standard psychiatric categories, and clinical observations. The scale was administered to a sample of Australian women and was found to possess satisfactory reliability and validity.

Adolescent↗
PubMed1991

Production of IL-10 by CD4+ T lymphocytes correlates with down-regulation of Th1 cytokine synthesis in helminth infection.

After the onset of parasite egg deposition, mice infected with the helminth Schistosoma mansoni mount strong Th2 cytokine responses in the absence of significant Th1 cytokine synthesis. To examine the basis of this immunoregulatory state, spleen or lymph node cells from schistosome-infected mice were stimulated with parasite-specific Ag and the supernatants tested for their capacity to suppress IFN-gamma synthesis by a Th1 cell line. Strong inhibition was observed that was neutralized by a mAb against IL-10, a cytokine previously shown to down-regulate Th1 cytokine synthesis. By means of ELISA measurements the production of IL-10 in schistosome infection was confirmed and shown to depend on CD4+ T cells. IL-10 synthesis stimulated by either mitogen or Ag was observed only at those stages of infection when Th2 response induction and Th1 cytokine down-regulation also occurred and was not detected in mice vaccinated with attenuated parasites. Moreover, the addition of the neutralizing anti-IL-10 mAb to Ag-stimulated spleen cell cultures from infected mice caused a dramatic augmentation in IFN-gamma synthesis. These findings suggest that IL-10 is responsible for the down-regulation of Th1 responses observed in schistosome infections, a phenomenon that may enable the parasite to escape potentially harmful cell-mediated responses.

Animals↗
PubMed1991

Egg deposition is the major stimulus for the production of Th2 cytokines in murine schistosomiasis mansoni.

To characterize Th cell populations induced by helminth infection, spleen cells from mice infected with Schistosoma mansoni were stimulated with parasite (worm or egg Ag) or mitogen (Con A) and the supernatants assayed for the Th1-specific cytokines IFN-gamma and IL-2 and the Th2-specific cytokines IL-4 and IL-5. Th2 cytokine production was not detected in substantial quantity until the 6 to 8th wk of infection and after reaching peak levels at 8 to 12 wk declined slowly thereafter. The time courses of IL-4 and IL-5 production, whereas differing from each other, closely resembled corresponding published data on IgE and peripheral blood eosinophil levels during murine schistosome infection. In contrast, Th1 cytokine responses occurred only during the first 6 wk of infection and were virtually absent during the peak period of Th2 production. To assess the role of egg deposition in the observed pattern of Th response, cytokine production was assayed in mice carrying unisexual schistosome infections in which parasite eggs are absent. Splenocytes from these animals displayed only marginal Th2 cytokine synthesis but greater Th1 cytokine responses than the corresponding cells from mice with bisexual infections. Moreover, cultures of liver tissue or isolated granulomas from infected mice constitutively produced high levels of IL-4 and IL-5 but failed to synthesize significant amounts of IL-2 and IFN-gamma even when stimulated with egg Ag or mitogen. Taken together the data indicate that egg deposition is the major stimulus of Th2 cytokine response in S. mansoni-infected mice and suggest that T cells belonging to this subset must play a major role in egg granuloma formation.

Animals↗
PubMed1991

Dynamic analysis of splenic Th1 and Th2 lymphocyte functions in mice infected with Schistosoma japonicum.

Recent studies indicate that egg granuloma formation in murine Schistosoma mansoni infection is associated with Th2-mediated immune responses. The present study was designed to analyze dynamically the Th1 and Th2 responses in S. japonicum-infected animals and compare them with the results seen with S. mansoni. C3H mice were infected with 10 to 20 cercariae of S. japonicum and sacrificed 3 to 22 weeks later. Spleen cells were stimulated with parasite antigens (egg and adult worm) or the mitogen concanavalin A. Interleukin-2 (IL-2), IL-4, IL-5, and gamma interferon (IFN-gamma) levels were measured in the culture supernatants by enzyme-linked immunosorbent assay (ELISA) or bioassays. Additionally, cytokine-producing cells were enumerated by ELISPOT. The results show that Th2 cytokine production, characterized by IL-4 and IL-5, represents the major response in the first month after egg laying begins, while the Th1 functions of IFN-gamma and IL-2 production are greatly depressed. However, by 22 weeks Th2 responses have diminished and IFN-gamma production in response to concanavalin A is apparent. IL-2 responses are minimal at all times. In vitro depletion of T-cell subsets indicates that CD4+ cells are the major subset responsible for production of IL-5 at 7 weeks of infection. These findings suggest that, as in the case of S. mansoni infection, S. japonicum-induced immunopathology is temporally associated with the host Th2 response, although other experiments indicate that IFN-gamma is also involved.

Animals↗
PubMed1991

Immunization against parasites: bridging the gap between attenuated and non-living vaccines.

While great progress has been made in the last decade in defining parasite antigens which are targets of host protective responses, only limited success has been achieved in the use of these molecules as effective vaccines. A consistent problem is the failure of the candidate immunogens to induce levels of protection comparable to those obtained with attenuated vaccines against the same organisms. One explanation is that the purified or recombinant molecules employed have not been presented in a form or route which induces the correct T cell or cytokine response necessary for protection. As summarized in this overview, optimal immunization with attenuated vaccines is associated with characteristic patterns of T cell subset and cytokine induction and in at least several examples has been shown to be altered by exogenous cytokine. We hypothesize that cytokine manipulation may offer a useful strategy for improving the action of existing nonliving vaccines. The gap in efficacy between attenuated and dead vaccines could also be bridged by the use of live recombinant vaccine vectors. We have previously reported that paramyosin admixed with BCG can induce partial protection against Schistosoma mansoni in mice. Our preliminary results in the construction and testing of a recombinant BCG vector incorporating schistosome paramyosin are described.

Animals↗
PubMed1990

Tumour necrosis factor (TNF) as a mediator of macrophage helminthotoxic activity.

Lymphokine-activated macrophages are cytotoxic for larvae of the helminth parasite Schistosoma mansoni. That soluble secreted factors may mediate this cytotoxicity was suggested by the observation that culture supernatant fluids from stimulated macrophages also exhibited larvacidal activity. These fluids contain the monokine tumour necrosis factor (TNF). Several observations indicated that TNF is directly toxic to schistosome larvae. Cytotoxic sera taken from BCG- or S. mansoni-immunized mice after endotoxin challenge killed schistosomula in vitro, and upon gel filtration the larvacidal factor(s) in the sera co-eluted with the tumoricidal activity defined as TNF. Recombinant-derived TNF exhibited direct toxicity to schistosomula at high concentrations, or at lower concentrations in the presence of IFN gamma. The larvacidal activity of macrophage supernatant fluids was abrogated by addition of either anti-TNF antisera or Zn+2, which has been shown to inhibit TNF-induced damage of tumour cells. Anti-TNF and Zn+2 likewise suppressed schistosomulum killing by lymphokine-activated peritoneal macrophages or the IC-21 macrophage line, indicating that TNF also plays a role in the effector mechanism of larval killing by whole cells.

Animals↗
PubMed1989

Schistosome vaccines: current progress and future prospects.

Vaccination against human schistosomes in laboratory hosts is now a reality. A number of different parasite molecules have been shown to confer partial protective immunity against challenge infection with Schistosoma mansoni or Schistosoma japonicum in rodent or primate hosts. These antigens are unusually diverse in their structure and stage specificity. Interestingly, although all of the vaccine molecules characterized are situated in the tegument, their exposure on the parasite surface, in most instances, is transient and/or non-essential. The properties of four of these immunogens, glutathione-S-transferase (P26,28), paramyosin (Sm97), GP38, and GP18 are discussed. Despite the identification and recombinant synthesis of several promising protective antigens, vaccination of humans against schistosomiasis remains in the realm of fantasy. At the technical level, a major problem is the failure of any of the current vaccine immunogens and immunization protocols to induce levels of resistance sufficient for significant reduction of human infection or disease. Once this important hurdle is passed, human immunization trials should be attempted as the potential beneficial impact of a vaccine against schistosomiasis remains enormous.

Animals↗
PubMed1989

Role of cytokines and CD4+ T-cell subsets in the regulation of parasite immunity and disease.

CD4+ T cells have been separated into two subsets, designated TH1 and TH2, based upon the repertoire of lymphokines that they produce following stimulation. We have analyzed the role of these T-cell subsets in two chronic parasitic infections, leishmaniasis and schistosomiasis. In both diseases, we found a strong association with TH1 stimulation and protection, and TH2 stimulation and immunopathology. In addition, certain parasite antigens appeared to be strongly linked with either TH1 or TH2 cell development. This led to the establishment of protective T-cell lines and clones in a L. major model, from which we identified a new candidate antigen for vaccination against Leishmania parasites. Moreover, we show that protection against L. major infection can be significantly augmented by coadministration of IFN-gamma with antigen, a lymphokine known to inhibit TH2 cell proliferation. In S. mansoni-infected mice, animals with a patent infection exhibit an overwhelming TH2 response, while animals protectively immunized with irradiated cercariae preferentially produce IFN-gamma, a lymphokine associated with TH1 cell stimulation. In addition, we show that ablation of schistosome-induced eosinophilia by in vivo anti-IL-5 monoclonal treatment fails to reduce the protection induced by irradiated cercariae. Similarly, anti-IL-5 treatment resulted in egg-induced granulomas nearly devoid of eosinophils, but only caused a marginal reduction in granuloma size. These results demonstrate that an understanding of the factors controlling TH1 and TH2 development will significantly facilitate the identification and development of vaccines for parasitic infections.

Animals↗
PubMed1988

Immunoregulation of cutaneous leishmaniasis. T cell lines that transfer protective immunity or exacerbation belong to different T helper subsets and respond to distinct parasite antigens.

BALB/c mice can be protected against a normally fatal Leishmania major infection by immunization with a partially purified, soluble subfraction of the parasite (fraction 9). In this study, we demonstrate that a T cell line established against fraction 9, designated line 9, transfers protection equivalent to that obtained by active immunization. In contrast, T cell lines (lines 1 and 9.2) responsive to a nonprotective soluble fraction (fraction 1) not only failed to protect BALB/c mice against L. major, but exacerbated the infection. Most importantly, in addition to differing in their antigen specificity, protective and exacerbative T cells lines could be distinguished on the basis of the lymphokines produced, a characteristic previously used to separate murine Th cells into two subsets, designated Th1 and Th2. We found that the protective cell line, line 9, displayed the Th1 property of secreting IL-2 and IFN-gamma, while the exacerbating lines secreted IL-4 and IL-5, a characteristic of Th2 cells. Our results demonstrate that Th1 and Th2 cells may have dramatically different effects on the outcome of an infection, and suggest that susceptibility and resistance in experimental leishmaniasis may depend upon a balance between the Th subsets induced.

Animals↗
PubMed1987

Vaccination against cutaneous leishmaniasis in a murine model. II. Immunologic properties of protective and nonprotective subfractions of soluble promastigote extract.

We have previously demonstrated that BALB/c mice can be protected against a fatal infection with Leishmania major by i.p. immunization with a soluble leishmanial antigen (SLA) preparation in conjunction with the adjuvant, Corynebacterium parvum (CP). In this study, SLA was separated into nine distinct fractions by anion exchange liquid chromatography, and the fractions were analyzed for their ability to stimulate T cells obtained from immunized mice, to be recognized by vaccine-induced antibodies, and to induce protective immunity. While all but one of the fractions were recognized by antibodies from SLA + CP immunized mice, only two fractions (fractions 1 and 9) stimulated lymphocytes to produce macrophage-activating factor and elicited significant delayed-type hypersensitivity in vivo. When mice were immunized with the fractions, only fraction 9 stimulated significant immunity (76% protection in seven experiments). Proteins (accounting for 1.3% of the total in SLA) appear to be responsible for the protection elicited with fraction 9, since protease treatment of this fraction destroyed its immunogenicity. Thus, a partially purified protective protein antigen fraction has been obtained and protection with this fraction correlated with cell-mediated immune responses. However, these results also demonstrate that the ability of leishmanial antigens to be recognized by T cells and produce macrophage-activating factor does not in itself predict whether such molecules will induce immunity, suggesting that protective leishmanial antigens may have additional unique properties.

Animals↗