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Biomedical subjects

A Meager

Publications and source records attributed to A Meager.

At least 91 records · Page 5Linked to original sources
PubMed1990

Role of tumor necrosis factor in flavone acetic acid-induced tumor vasculature shutdown.

Flavone acetic acid (FAA), a novel investigational antitumor agent, has been shown to cause early vascular shutdown in several experimental murine tumors, and this phenomenon is believed to be crucial to FAA's antitumor effects. However, the basis of this FAA-induced tumor vascular shutdown is unknown. In this study a radioactive tracer-clearance technique has been used as an objective indication of tumor blood flow to show that i.p. administered FAA induces a progressive and sustained reduction in blood flow in a colon 26 tumor growing s.c. in syngeneic mice. As early as 1 h after administration, there was a significant increase in the t1/2 clearance value for intratumorally injected 133Xe, reaching a peak at 3 h (117.3 +/- 36.4 versus 7.8 +/- 0.85 min for controls). Significant inhibition of blood flow was still apparent 48 h after a single injection of drug. This FAA-induced vascular shutdown was virtually abolished in tumor-bearing mice pretreated with an antiserum against tumor necrosis factor, while no such effect was observed in controls pretreated with nonimmune serum (t1/2 of 10.8 +/- 1.2 versus 65.6 +/- 8.0 min for controls). Furthermore, in vitro FAA was seen to induce tumor necrosis factor secretion from murine peritoneal cells and splenocytes. These studies suggest that FAA-induced tumor vascular shutdown in the colon 26 tumor is mediated by tumor necrosis factor.

Animals↗
PubMed1990

Expression of intercellular adhesion molecule-1 (ICAM-1) on human thyroid cells lines correlated with their binding of lymphoblasts.

We have investigated the expression of intercellular adhesion molecule-1 (ICAM-1) by novel functional human thyroid cell lines (designated SGHTL). ICAM-1 is constitutively expressed and it is rapidly upregulated in response to each of the recombinant cytokines: gamma-interferon, interleukin-1 and tumour necrosis factor. This contrasts with the more slowly increased expression of major histocompatibility complex (MHC) class II antigens in response to gamma-interferon alone. We have also demonstrated binding of activated lymphocytes to SGHTL cells: this interaction is increased following treatment with these cytokines and is inhibited by monoclonal antibodies directed against ICAM-1 or lymphocyte function-associated antigen-1 (LFA-1) but not by antibodies against CD2 or MHC class II antigens. Hence, we conclude that the binding of lymphoblasts to human thyroid cells involves an LFA-1- and ICAM-1-dependent pathway as well as other basal and cytokine-inducible pathway(s). These do not appear to involve MHC class II antigens, CD2 or an LFA-1 ligand other than ICAM-1.

Antibodies, Monoclonal↗
PubMed1990

Spontaneous production of tumour necrosis factor alpha and interleukin-1 beta during interferon-alpha treatment of chronic HBV infection.

Seven chronic carriers of hepatitis B virus (HBV) were studied during treatment with interferon-alpha to determine whether tumour necrosis factor alpha (TNF alpha) or interleukin-1 beta (IL-1 beta) contributed to the elimination of HBV. Four patients responded to interferon-alpha with clearance of HBeAg and permanent inhibition of HBV replication within 3-12 weeks; in each of these patients, the changes were accompanied by substantial rises in spontaneous in-vitro production of TNF alpha and IL-1 beta by peripheral blood mononuclear cells from previously undetectable levels. There was little or no change in spontaneous TNF alpha and IL-1 beta production in the three patients who did not lose HBeAg in response to interferon-alpha. These findings suggest that TNF alpha and IL-1 beta may contribute to the permanent elimination during interferon-alpha treatment of hepatocytes supporting viral infection and that the therapeutic potential of these cytokines is worthy of investigation.

Adult↗
PubMed1990

Cytokines in skin lesions of psoriasis.

Cytokine levels were compared in aqueous extracts of stratum corneum from psoriatic lesions and normal heel. Samples from heel contained high levels of interleukin-1 alpha (IL-1 alpha) and beta measured in immunoassays, although only the IL-1 alpha was biologically active. No other cytokines could be detected in heel samples. Interleukin-1 (IL-1) levels were dramatically reduced in lesional samples. A neutrophil chemoattractant was found in all lesional extracts, and was demonstrated to be mainly interleukin-8 (IL-8) using a specific neutralizing antiserum. Tumor necrosis factor alpha (TNF-alpha) and beta (TNF-beta), and interferon alpha (IFN-alpha) and gamma (IFN-gamma) were detected in lesional extracts using immunoassays, however, no equivalent biological activities could be detected. Interleukins 2 (IL-2), 4 (IL-4), and 6 (IL-6), granulocyte and granulocyte/macrophage colony stimulating factor (GM-CSF), could not be detected in any samples. IL-8 is therefore the only biologically active cytokine shown in this study to be elevated in psoriatic lesional extracts, and may therefore play a role in the pathogenesis of the disease.

Chemotaxis, Leukocyte↗
PubMed1990

Tumour necrosis factors (alpha, beta) induced by HIV-1 in peripheral blood mononuclear cells potentiate virus replication.

Cytokines such as tumour necrosis factor (TNF) can induce HIV-1 production in T-cell tumour lines. However, it is not known if the same occurs in freshly isolated mononuclear cells, nor is it known if the virus can itself regulate cellular cytokine production. In this paper we report that HIV-1 induces peripheral blood mononuclear cells (PBMC) and CD4+ T lymphocytes to secrete TNF alpha, TNF beta and interferon-gamma (IFN gamma), three cytokines having multifunctional activities and complex physiological roles. We also show that separate addition of exogenous recombinant (r) TNF alpha or rTNF beta or rIFN gamma increases HIV-1-induced syncytium formation in both PBMC and CD4+ cells by up to 10,000-fold, with TNF alpha being most potent in this regard. Finally, we show that syncytium formation induced by diverse HIV-1 isolates and LAV-2 is inhibited without the addition of exogenous r-cytokines by the respective anti-cytokine antibodies. Our study therefore demonstrates that efficient HIV replication in primary mononuclear cells is associated with the ability of the virus to induce TNF and IFN gamma secretion.

CD4-Positive T-Lymphocytes↗
PubMed1990

Relative increase of inflammatory CD4+ T cells in the cerebrospinal fluid of multiple sclerosis patients and control individuals.

Of three patients with multiple sclerosis (MS) and two non-MS individuals a large number of CD4+ T cell clones was obtained from the cerebrospinal fluid and peripheral blood by direct limiting dilution. The CD4+ T cell clones from cerebrospinal fluid and peripheral blood lymphocytes were compared for their cytotoxic activity and lymphokine production. Cytotoxic capacity of cloned T cells was analysed with the use of anti-CD3 antibodies and target cells bearing Fc receptors for murine IgG. Recently, we demonstrated the existence of two different subsets of human CD4+ T cell clones by phenotypic and functional criteria. One type of CD4+ T cell with anti-CD3 mediated cytotoxic activity, in analogy with murine studies, is the inflammatory or TH1 subtype, the main producer of interleukin (IL-2), interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF)-alpha, -beta, whereas the other type of CD4+ T cell clone lacked anti-CD3 mediated cytotoxicity and produced minimal amounts of IL-2 concomitant with reduced levels of IFN-gamma and TNF-alpha, -beta. The present study demonstrates that among three MS patients, relatively more inflammatory CD4+ T cell clones with cytotoxic activity and IFN-gamma and TNF-alpha, -beta production were derived from the cerebrospinal fluid as compared with peripheral blood lymphocytes. Also among control individuals more inflammatory CD4+ T cell clones could be obtained from the cerebrospinal fluid as from the peripheral blood. The enrichment of inflammatory CD4+ T cells, therefore, appears to be physiological rather than associated with the disease.

CD4-Positive T-Lymphocytes↗
PubMed1990

Alveolar macrophages in AIDS patients: increased spontaneous tumour necrosis factor-alpha production in Pneumocystis carinii pneumonia.

In order to assess the role of alveolar macrophages and their products in the control of Pneumocystis carinii pneumonia (PCP) and other infections in AIDS, bronchoalveolar lavage cells and peripheral blood mononuclear cells from HIV-positive AIDS/ARC patients (with and without PCP) and HIV-negative patients were counted and cultured in vitro; spontaneous and LPS-induced tumour necrosis factor-alpha (TNF-alpha) production was measured. Markedly increased spontaneous TNF-alpha production by alveolar macrophages and, to a lesser extent, peripheral blood monocytes was found in HIV-positive patients with active PCP but not in patients without the infection. Higher TNF production was associated with lower counts of Pneumocystis in the bronchoalveolar lavage fluid. These results suggest that TNF-alpha production by macrophages may play an important role in the control of Pn. carinii infection in AIDS.

Bronchoalveolar Lavage Fluid↗
PubMed1990

Tumour necrosis factor production in fulminant hepatic failure: relation to aetiology and superimposed microbial infection.

Tumour necrosis factor-alpha (TNF-alpha), a cytokine derived from macrophages, is considered to be an important endogenous mediator of endotoxic shock. Patients with fulminant hepatic failure are particularly susceptible to infection and the development of multi-organ failure and similarities to endotoxic shock suggest a possible pathogenetic role for TNF in fulminant hepatic failure. In vitro TNF production was therefore investigated serially in 21 consecutive patients with fulminant hepatic failure and in 21 healthy controls. Spontaneous and lipopolysaccharide-stimulated TNF production were elevated in viral-induced fulminant hepatic failure, compared with healthy controls (P less than 0.05 and P less than 0.01, respectively). By contrast, patients with paracetamol-induced fulminant hepatic failure had normal spontaneous and lipopolysaccharide-stimulated TNF production, while those who died had significantly reduced spontaneous TNF production compared with survivors (P less than 0.02); this difference was present throughout admission. In this group elevations in TNF production above baseline were associated with Gram-positive bacterial or fungal infection but not Gram-negative bacterial infection. There was no correlation between any of the clinical complications of fulminant microbial stimuli in fulminant hepatic failure, but do not support a direct role for TNF in the evolution of the clinical complications of fulminant hepatic failure.

Acetaminophen↗
PubMed1990

Suppression of lymphokine-activated killer (LAK) cell induction mediated by interleukin-4 and transforming growth factor-beta 1: effect of addition of exogenous tumour necrosis factor-alpha and interferon-gamma, and measurement of their endogenous production.

Recombinant human interleukin-4 (rhIL-4) and transforming growth factor-beta 1 (TGF-beta 1) suppressed the induction of lymphokine-activated killer (LAK) activity induced by recombinant human interleukin-2 (rhIL-2) in peripheral blood lymphocytes. DNA synthesis and the expression of the p55 alpha chain of the IL-2 receptor (Tac antigen) were also inhibited. The inhibitory effect was greatest when these factors were added during the first 48 h of a 4-day culture, with reduced cytolytic activity against both natural killer (NK) resistant and NK-sensitive tumour cell line targets. The suppressive action of both cytokines was accompanied by a reduction in tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) levels in lymphocyte culture supernatants. Recombinant human IFN-gamma (rhIFN-gamma), but not recombinant human TNF-alpha (rhTNF-alpha) was able to overcome the inhibitory effect of recombinant human interleukin-4 (rhIL-4) on LAK induction and DNA synthesis but not Tac antigen expression. However, cytotoxicity induced by rhIFN-gamma alone was also suppressed by rhIL-4 and TGF-beta 1, inferring that rhIFN-gamma-mediated abrogation of rhIL4 suppression was not simply a direct IL-2-independent effect on cytotoxicity. In addition, rhIL-4 did not increase TGF-beta production from rhIL-2-activated peripheral blood mononuclear cells, suggesting that rhIL-4 did not mediate reduction of rhIL-2 responses through the induction of TGF-beta release.

Cell Division↗
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

The effect of HLA and insulin-dependent diabetes mellitus on the secretion levels of tumour necrosis factors alpha and beta and gamma interferon.

Tumour necrosis factors alpha and beta (TNF-alpha and TNF-beta) and gamma interferon (IFN-gamma) were measured by ELISA in the supernatants of phytohaemagglutinin (PHA)-activated peripheral blood mononuclear cells (PBMNC) from 98 individuals (60 controls and 38 patients with insulin-dependent diabetes mellitus [IDDM]). The PBMNC were incubated with varying concentrations of PHA (0, 1, 5, and 10 micrograms/ml) for 72 h. In our population study we observed a correlation between the levels of secretion of TNF-alpha and IFN-gamma but not TNF-beta. The complete data set was analysed by non-parametric tests, and no associations with HLA phenotypes existed. Reduced levels of TNF-beta, but not TNF-alpha or IFN-gamma, secretion were found in IDDM patients stimulated with 1 and 5 micrograms/ml of PHA (P = 0.001 and 0.02 respectively). None of the lymphokine secretion levels at any PHA concentration correlated with particular HLA phenotypes. Analysis of the natural log-transformed data indicated that only for the TNF-beta levels (at 5 micrograms/ml PHA) could subjects be divided into high and low secretors, which also did not correlate with a particular HLA-B or -DR antigen.

Adult↗
PubMed1990

Production of interferon-gamma and tumour necrosis factor-alpha by human T-cell clones expressing different forms of the gamma delta receptor.

Panels of human T-cell clones bearing the gamma delta T-cell receptor (TcR) were obtained from peripheral blood and decidual tissue and maintained in the presence of interleukin-2 (IL-2). TcR V gamma and V delta gene expression was determined in 40 TcR delta 1+ clones using the gamma delta T-cell subset markers Ti gamma A and delta TCS1, in conjunction with Southern blot analysis using TcR J gamma and J delta probes. gamma delta T-cell clones, together with control alpha beta T-cell clones derived from the same lymphocyte populations, were stimulated with phytohaemagglutinin (PHA) and their ability to produce interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) tested using specific ELISA. Many clones representative of the major peripheral V gamma 9/V delta 2J1 subset produced high amounts of both cytokines and mean levels were not significantly different from those produced by alpha beta T-cell clones. Panels of clones expressing V gamma 9 and V delta 2J1 produced significantly higher levels of TNF-alpha than clones not expressing V delta 2J1 and those expressing V delta 1J1. There was no relationship between levels of IFN-gamma and TNF-alpha produced by individual gamma delta T-cell clones and also no relationship between their non-major histocompatibility complex (MHC)-restricted cytotoxic activity and levels of either cytokine. There was a significant tendency for gamma delta T-cell clones to produce more TNF-alpha than IFN-gamma in comparison to alpha beta T-cell clones. The significance of these findings is discussed in the light of the reported differences in distribution in vivo of V delta 1J1+ and V delta 2J1+ cells.

Blotting, Southern↗
PubMed1990

Phenotypic and functional analysis of human CD3- decidual leucocyte clones.

CD3- leucocyte clones were generated from human first-trimester decidualized uterine endometrium in a culture system containing interleukin-2 (IL-2) and phytohaemagglutinin (PHA). All CD3- clones tested by Southern blot analysis had T-cell receptor (TcR) gamma and delta genes in germ-line configuration. Thirty-six CD3- cell clones obtained from eight decidual samples were mostly CD2+CD56+ but, unlike fresh decidual leucocytes, many were also CD16+. Morphological differences were noted between CD16+CD56+ and CD16-CD56+ clones, with the latter cells possessing granules of more variable size. All CD16+ clones expressed strong cytotoxic activity against natural killer (NK) sensitive and NK-resistant cell targets, while CD16- clones had low or negligible activity. Some CD3- clones produced high levels of interferon-gamma, tumour necrosis factor-negligible activity. Some CD3- clones produced high levels of interferon-gamma, tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) upon stimulation, but there was no relationship between specific cytokine production and cell clone phenotype or cytotoxic function. Levels of TGF-beta were generally higher than those produced by decidual CD3+ T-cell clones. Since decidual CD3- CD16- leucocytes have a low proliferative capacity in response to IL-2, and as clones with this phenotype invariably possess low NK cell activity, it is suggested that the NK cell activity of fresh decidual leucocyte populations is mediated largely by the small numbers of CD3- CD16+ cells present.

Antigens, CD↗
PubMed1989

Tumor necrosis factor mediates autocrine growth inhibition in a chronic leukemia.

Autocrine production of growth factors may contribute to the rapid and fatal proliferation of acute hematologic malignancies. We have investigated whether the more controlled growth of less aggressive malignancies such as chronic myeloid leukemia (CML) may be associated with autocrine production of growth inhibitory factors. TNF inhibits the growth of both normal and leukemic hemopoietic progenitor cells. We find that exogenous TNF reduces the viability and DNA synthesis of purified myeloid cells from patients with CML and inhibits myeloid colony formation by patient progenitor cells. However, unlike progenitor cells from normal donors, patient myeloid progenitor cells also constitutively express mRNA for TNF and secrete functional TNF protein in culture. This endogenous TNF impedes the growth of CML cells because anti-TNF mAb shown to neutralize bioactive human TNF increases CML cell DNA synthesis whereas non-neutralizing anti-TNF mAb has no effect. Production of TNF by CML cells is not associated with production of lymphotoxin (TNF-beta), IL-1 or IL-6. TNF-mediated autocrine growth inhibition may contribute to the maintenance of the stable, chronic phase of this disease and similar mechanisms may operate in other malignancies to limit tumor proliferation. Competition between autocrine growth promoting and inhibiting factors may underlie the observed differences in biologic behavior between acute and chronic malignancies.

Antibodies, Monoclonal↗
PubMed1989

Tumour necrosis factor in bronchopulmonary secretions of patients with adult respiratory distress syndrome.

Tumour necrosis factor (TNF) concentrations were measured in the bronchopulmonary secretions of 5 patients with the adult respiratory distress syndrome. Each patient underwent fibreoptic bronchoscopy and bronchopulmonary aspiration, and control samples were obtained in an identical manner from 24 patients who underwent bronchoscopy for other reasons (8 had tuberculosis, 6 had sarcoidosis, and 10 had haemoptysis but no abnormal findings). Aspirated fluid was assayed for the presence of TNF by use of an enzyme-linked immunosorbent assay. In the 5 patients with adult respiratory distress syndrome, TNF concentrations exceeded 500 U/ml (12.5 ng/ml), whereas in the control samples no TNF was detected.

Bronchoalveolar Lavage Fluid↗
PubMed1989

Dengue virus-specific human T cell clones. Serotype crossreactive proliferation, interferon gamma production, and cytotoxic activity.

The severe complications of dengue virus infections, hemorrhagic manifestation and shock, are much more commonly observed during secondary infections caused by a different serotype of dengue virus than that which caused the primary infections. It has been speculated, therefore, that dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) are caused by serotype crossreactive immunopathological mechanisms. We analyzed clones of dengue serotype crossreactive T lymphocytes derived from the PBMC of a donor who had been infected with dengue 3 virus. These PBMC responded best to dengue 3 antigen, but also responded to dengue 1, 2, and 4 antigens, in bulk culture proliferation assays. 12 dengue antigen-specific clones were established using a limiting dilution technique. All of the clones had CD3+ CD4+ CD8 phenotypes. Eight clones responded to dengue 1, 2, 3, and 4 antigens and are crossreactive, while four other clones responded predominantly to dengue 3 antigen. These results indicate that the serotype crossreactive dengue-specific T lymphocyte proliferation observed in bulk cultures reflects the crossreactive responses detected at the clonal level. Serotype crossreactive clones produced high titers of IFN-gamma after stimulation with dengue 3 antigens, and also produced IFN-gamma to lower levels after stimulation with dengue 1, 2, and 4 antigens. The crossreactive clones lysed autologous lymphoblastoid cell line (LCL) pulsed with dengue antigens, and the crossreactivity of CTL lysis by T cell clones was consistent with the crossreactivity observed in proliferation assays. Epidemiological studies have shown that secondary infections with dengue 2 virus cause DHF/DSS at a higher rate than the other serotypes. We hypothesized that the lysis of dengue virus-infected cells by CTL may lead to DHF/DSS; therefore, the clones were examined for cytotoxic activity against dengue 2 virus-infected LCL. All but one of the serotype crossreactive clones lysed dengue 2 virus-infected autologous LCL, and they did not lyse uninfected autologous LCL. The lysis of dengue antigen-pulsed or virus-infected LCL by the crossreactive CTL clones that we have examined is restricted by HLA DP or DQ antigens. These results indicate that primary dengue virus infections induce predominantly crossreactive memory CD4+ T lymphocytes. These crossreactive T lymphocytes proliferate and produce IFN-gamma after stimulation with a virus strain of another serotype, and demonstrate crossreactive cyotoxic activity against autologous cells infected with heterologous dengue viruses.(ABSTRACT TRUNCATED AT 400 WORDS)

Antigens, Differentiation, T-Lymphocyte↗
PubMed1989

Influenza virus-specific T cells lead to early interferon gamma in lungs of infected hosts: development of a sensitive radioimmunoassay.

A sensitive immunoradiometric assay for murine interferon gamma (MuIFN-gamma) has been developed and used reproducibly to measure low levels of MuIFN-gamma in lung lavage samples from influenza-infected mice. In control infected mice, IFN-gamma peaked on day 6, but transfer of virus-specific cytotoxic T cells or T helper cells, which reduced virus replication in vivo in infected hosts, resulted in an earlier peak on day 4.

Animals↗