Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Astrocytes, when appropriately stimulated, produce a variety of cytokines including TNF-alpha. Production of TNF-alpha by astrocytes stimulated with Newcastle disease virus (NDV) is achieved by transcriptional activation and mRNA stabilization. A PKC-dependent pathway is responsible for a 10-fold increase in TNF-alpha mRNA stability by reducing poly(A) tail removal. The present study examined signal pathways induced by NDV in primary rat astrocytes that are responsible for TNF-alpha gene transcription as well as the possible source of kinase activity required for mRNA stabilization. Transcription of TNF-alpha gene in astrocytes stimulated by NDV or LPS and IFN-gamma was inhibited completely by the tyrosine kinase inhibitor herbimycin, and partially by a PKC inhibitor H7, as determined by nuclear run-on assay. HA-1004, a cyclic nucleotide-dependent kinase inhibitor, showed no effect. These results indicated that tyrosine kinase signaling pathways seemed to precede the activation of PKC in induction of TNF-alpha gene. Increase in tyrosine kinase activity in NDV-infected astrocytes was demonstrated by a two- to threefold increase in tyrosine phosphorylation of Pl-PLC gamma 1. Because astrocytes contain minimal Pl-PLC beta, and NDV-induced TNF-alpha mRNA was affected by pertussis toxin only modestly, Pl-PLC gamma 1 is likely the enzyme responsible for DAG generation and the PKC-dependent mRNA stabilization in response to NDV.
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PMID:Tyrosine kinase activation by Newcastle disease virus is required for TNF-alpha gene induction in astrocytes. 808 95

The adherence of Bordetella pertussis to respiratory cilia and its survival in neutrophils and macrophages is crucial to the pathogenesis of whooping cough. To investigate the role of endogenous interferon (IFN)-gamma in acute infection, levels of IFN-gamma in bronchoalveolar lavage (BAL) fluid of mice infected intranasally with B. pertussis were determined. Since pertussis toxin is released during infection by B. pertussis either locally or systemically, serum levels of IFN-gamma in mice injected intravenously with pertussis toxin were also determined. A persistent and significant increase of IFN-gamma levels with concomitant peripheral blood lymphocytosis was observed after 5 and 10 days. The results of this study showed an early but transitory production of endogenous IFN-gamma in BAL fluid of mice infected with B. pertussis.
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PMID:Interferon-gamma levels in serum and bronchoalveolar lavage fluid of mice infected with Bordetella pertussis. 844 Sep 45

This study examines whether genetic susceptibility vs genetic resistance to experimental autoimmune uveoretinitis (EAU) are connected to a predisposition to mount a Th1-dominated (IFN-gamma high, IL-4 low) vs a Th2-dominated (IL-4 high, lFN-gamma low) response. Lewis rats developed disease with high incidence after immunization with the uveitogenic peptide R16, whereas F344 rats were resistant. Primed lymph node cells from both strains proliferated in culture in response to R16. However, while the Lewis cultures transferred EAU to syngeneic recipients, those of F344 did not. The Lewis cultures produced substantially more IFN-gamma mRNA and protein in response to R16, than did those of F344. Both strains made low levels of IL-10 mRNA and IL-4 mRNA. Unlike the primary cultures, long-term (R16-specific) T cell lines derived from each of the strains transferred EAU equally well to their respective recipients, and produced similar, high levels of IFN-gamma mRNA and protein. Treatment of F344 with Bordetella pertussis toxin concurrently with immunization abrogated its resistance, enhanced Ag-specific IFN-gamma production in culture, and yielded a primed cell population capable of transferring EAU. Conversely, immunization of Lewis rats with R16 in IFA induced little or no disease; the primed cells produced minimal amounts of IFN-gamma and did not transfer EAU. However, addition of IL-12 into the culture resulted in a highly pathogenic, IFN-gamma-producing cell population. We conclude that genetic susceptibility to ocular autoimmunity in this model is connected to an elevated Th1 response. Genetic resistance, however, does not seem to involve an elevated Th2 response, but rather an inhibited development of Th1-like effector cells.
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PMID:Genetic susceptibility to experimental autoimmune uveoretinitis in the rat is associated with an elevated Th1 response. 880 72

The recombinant cytokines interferon (IFN)-gamma and interleukin (IL)-12 stimulate several macrophage-mediated functions that are important in host defense. An experimental pertussis model showed that intraperitoneal (i.p.) administration of 10,000 U of recombinant murine (rm) IFN-gamma to mice at the time of Bordetella pertussis infection caused a marked and significant reduction in the number of colony-forming units of bacteria in the lungs. Administration i.p. of 1 microgram of rmIL-12 or 1 microgram of rmIL-12 at the time of and for 5 consecutive days after B. pertussis challenge also induced a significant reduction in the number. However, i.p. administration of 1 microgram of rmIL-12 with 10,000 U of IFN-gamma at the time of B. pertussis challenge did not provide protection. These findings indicate that exogenous administration of rmIL-12 and rmIFN-gamma enhances resistance of mice to B. pertussis infection.
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PMID:Effects of recombinant murine (rm) interleukin-12 and rm interferon-gamma in mice infected with Bordetella pertussis. 884 17

Cytokine profiles were examined 1 month after primary vaccination of infants with a whole-cell pertussis vaccine (wP) (Connaught) or either of two acellular pertussis vaccines, aP-Chiron Biocine (aP-CB) or aP-SmithKline Beecham (aP-SB), each combined with diphtheria-tetanus toxoids (DT), in Bordetella pertussis antigen-stimulated or unstimulated peripheral blood mononuclear cells (PBMC). Pertussis toxin (PT), filamentous hemagglutinin (FHA), and pertactin (PRN) were used as antigens, and the children were defined as responsive when their PBMC proliferated in response to these antigens. The controls were either children who received only DT or children who received pertussis vaccine but whose PBMC did not proliferate upon stimulation with B. pertussis antigens (unresponsive children). Antigen-stimulated PBMC of responsive wP recipients were characterized by an elevated production of T-helper-cell type 1 cytokines gamma interferon (IFN-gamma) and interleukin 2 (IL-2), low to minimal production of IL-5, and no production of IL-4. The PBMC of aP vaccine-responsive recipients showed, in addition to the elevated IFN-gamma production, a consistent, antigen-dependent production of type 2 cytokines (IL-4 and IL-5), with PRN being the most and PT being the least effective antigen. Type 2 cytokine induction was more pronounced in aP-SB than in aP-CB recipients, as shown by the presence of IL-4 mRNA transcripts and higher IL-5 production in the former (161.6 +/- 36 and 47.9 +/- 44 pg/ml [mean +/- standard error for five subjects each], respectively, after PRN stimulation). Appreciable, antigen-unstimulated (constitutive) IFN-gamma production was also detected in PBMC cultures of all vaccinees. However, this spontaneous IFN-gamma production was, in most vaccinees, significantly lower than the antigen-driven cytokine production. In contrast, no constitutive type 2 cytokine production was ever observed in any vaccine group. PBMC from the two control groups (either DT or pertussis vaccine recipients) did not show any type 2 cytokine production, while IFN-gamma production was comparable in both antigen-stimulated and unstimulated conditions. Absence of type 2 cytokines and low levels of constitutive IFN-gamma production were also seen in prevaccination children. Thus, pertussis vaccines induce in infants a basically type 1 cytokine profile, which is, however, accompanied by some production of type 2 cytokines. The latter are more expressed by aP-SB than by aP-CB recipients, and with PRN than with other antigens, and they are minimally expressed in wP recipients and with PT as antigen. Our data also highlight a constitutive IFN-gamma production in infancy, which might reflect natural immunization and/or the burden of concomitant vaccinations and which may have an impact on T-helper-cell cytokine pattern polarization consequent to pertussis vaccination.
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PMID:Vaccine- and antigen-dependent type 1 and type 2 cytokine induction after primary vaccination of infants with whole-cell or acellular pertussis vaccines. 916 47

This study addresses the question whether susceptibility versus resistance to experimental autoimmune uveoretinitis (EAU) is connected to a Th1-type (interferon-gamma high, interleukin-4 low), versus a Th2-type (IFN-gamma low, IL-4 high) response. Primed lymph node cells of susceptible Lewis rats produced IFN-gamma in response to antigen in culture and transferred EAU to syngeneic recipients, whereas lymph node cells of resistant F344 rats made no IFN-gamma and did not transfer disease. Reversal of the disease pattern, by treatment of F344 rats with B. pertussis toxin and immunisation of Lewis rats with antigen in incomplete Freund's adjuvant, resulted in a parallel reversal of these response patterns. Neither strain produced significant IL-4 responses. A study of the response patterns in mice confirmed that high Th1 responders were susceptible, whereas low Th1 responders and Th2 responders were resistant. We conclude that susceptibility to EAU is connected with a Th1-dominant response, but resistance can involve either a 'null', F344-like response (Th1-low/Th2-low) or a Th2-dominant response.
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PMID:T cell mechanisms in experimental autoimmune uveoretinitis: susceptibility is a function of the cytokine response profile. 934 14

Mice inoculated with whole cell pertussis vaccine (WCV) acquired protection against intracerebral challenge with Bordetella pertussis without any appreciable antibody production against pertussis toxin or filamentous hemagglutinin. Spleen cells from mice immunized with WCV produced a significant amount of IFN-gamma upon stimulation in vitro with WCV. Furthermore, mice inoculated with recombinant IFN-gamma along with a suboptimal dose of WCV survived longer than those that received WCV alone. These results suggest that, in WCV-immune mice, IFN-gamma plays an important role in protection against intracerebral challenge with B. pertussis.
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PMID:IFN-gamma-mediated protection against intracerebral challenge with Bordetella pertussis in mice. 935 68

Using a murine respiratory challenge model we have previously demonstrated a role for Th1 cells in natural immunity against Bordetella pertussis, but could not rule out a role for antibody. Here we have demonstrated that B. pertussis respiratory infection of mice with targeted disruptions of the genes for the IFN-gamma receptor resulted in an atypical disseminated disease which was lethal in a proportion of animals, and was characterized by pyogranulomatous inflammation and postnecrotic scarring in the livers, mesenteric lymph nodes and kidneys. Viable virulent bacteria were detected in the blood and livers of diseased animals. An examination of the course of infection in the lung of IFN-gamma receptor-deficient, IL-4-deficient and wild-type mice demonstrated that lack of functional IFN-gamma or IL-4, cytokines that are considered to play major roles in regulating the development of Th1 and Th2 cells, respectively, did not affect the kinetics of bacterial elimination from the lung. In contrast, B cell-deficient mice developed a persistent infection and failed to clear the bacteria after aerosol inoculation. These findings demonstrate an absolute requirement for B cells or their products in the resolution of a primary infection with B. pertussis, but also define a critical role for IFN-gamma in containing bacteria to the mucosal site of infection.
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PMID:Atypical disease after Bordetella pertussis respiratory infection of mice with targeted disruptions of interferon-gamma receptor or immunoglobulin mu chain genes. 938 83

The results of phase 3 efficacy trials have shown that acellular and whole-cell pertussis vaccines can confer protection against whooping cough. However, despite the advances in vaccine development, clinical trials have not provided significant new information on the mechanism of protective immunity against Bordetella pertussis. Classical approaches based on measurement of antibody responses to individual antigens failed to define an immunological correlate of protection. A reliable animal model, predictive of acellular and whole-cell pertussis vaccine potency in children, would facilitate an elucidation of the mechanism of immune protection against B. pertussis and would assist in the regulatory control and future development of pertussis vaccines. In this study, we have shown that the rate of B. pertussis clearance following respiratory challenge of immunized mice correlated with vaccine efficacy in children. Using this model together with mice with targeted disruptions of the gamma interferon (IFN-gamma) receptor, interleukin-4 or immunoglobulin heavy-chain genes, we have demonstrated an absolute requirement for B cells or their products in bacterial clearance and a role for IFN-gamma in immunity generated by previous infection or immunization with the whole-cell pertussis vaccine. The results of passive immunization experiments suggested that protection early after immunization with acellular pertussis vaccines is mediated by antibody against multiple protective antigens. In contrast, more complete protection conferred by previous infection or immunization with whole-cell pertussis vaccines reflected the induction of Th1 cells. Our findings suggest that the mechanism of immunity against B. pertussis involves humoral and cellular immune responses which are not directed against a single protective antigen and thus provide an explanation for previous failures to define an immunological correlate of protection.
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PMID:A murine model in which protection correlates with pertussis vaccine efficacy in children reveals complementary roles for humoral and cell-mediated immunity in protection against Bordetella pertussis. 945 14

The effect on antigen (Ag)-specific Th2 response as well as IgE production of continuous oral administration of micro-doses of Ag was investigated. Transgenic (Tg) mice carrying the alphabeta-T cell receptor (TCR) genes specific for ovalbumin (OVA) peptide fragment 323-339 were continuously fed with micro-doses of OVA (100 microg/day) for 14 days. Mice were first immunized by OVA in alum and pertussis toxin 7 days before the oral feeding and given a second immunization 1 day after the oral treatment. This feeding regimen tolerized Th2 but not Th1 responses as shown by decrease of Ag-driven cell proliferation and cytokine secretion of IL-4 but not of IL-2 or IFN-gamma as well as by the absence of Ag-specific antibody production of IgE and IgG1, but not of IgG2a or total IgG. Numbers of clonotype-specific TCR-high CD4-positive T cells in peripheral lymphoid tissues markedly decreased in the orally treated group but not in the control group. However, total numbers of CD4-positive T cells in thymus, spleen and lymph nodes were not affected by the oral treatment, indicating that tolerance induction in Th2 cells was mainly due to the down-regulation of TCR and not clonal deletion. The population of antigen-presenting cells expressing B7-2 (CD86) Ag on the surface was decreased in the spleen of the mice which underwent the feeding regimen. The present results suggest that Ag-specific low responsiveness in Th2 cells, which resulted in suppression of the Ag-specific IgE production, can be achieved by continuous feeding with microdoses of Ag.
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PMID:Selective suppression of antigen-specific Th2 cells by continuous micro-dose oral tolerance. 948 93


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