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Results for “TUBERCULOSIS IMMUNITY”

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At least 19 recordsLinked to original sources
PubMed2002

Investigation of the relationships between immune-mediated inhibition of mycobacterial growth and other potential surrogate markers of protective Mycobacterium tuberculosis immunity.

Tuberculosis (TB) vaccine development is hindered by the lack of clear surrogate markers of protective human immunity to Mycobacterium tuberculosis. This study evaluated the hypothesis that immune-mediated inhibition of mycobacterial growth would more directly correlate with protective TB immunity than other immunologic responses. Bacille Calmette-Guérin (BCG) vaccination, known to induce partial protection against TB, was used as a model system to investigate mechanistic relationships among different parameters of antigen-specific immunity. Effects of primary and booster intradermal BCG vaccinations were assessed in 3 distinct assays of mycobacterial inhibition. Correlations between vaccine-induced growth inhibition and other immune responses were analyzed. BCG significantly enhanced all antigen-specific responses. Peak responses occurred at 2 months after boosting. Statistical analyses suggested that each assay measured unique aspects of mycobacterial immunity. Despite previous evidence that type 1 immune responses are essential for TB immunity, interferon-gamma production did not correlate with mycobacterial inhibition. These results have important implications for TB vaccine development.

BCG Vaccine↗
PubMed1986

Function and antigen recognition pattern of L3T4+ T-cell clones from Mycobacterium tuberculosis-immune mice.

T-cell clones were established from Mycobacterium tuberculosis-immunized mice. These clones had the phenotype Thy-1+ L3T4+ Lyt-2- and were restricted by the H-2I-A locus. After antigen stimulation, the T-cell clones secreted interleukin-2 and gamma interferon. Factors produced by these T-cell clones activated normal bone marrow macrophages for antimycobacterial activity in vitro. Furthermore, the T-cell clones could adoptively confer delayed-type hypersensitivity on normal recipient mice. These findings indicate that the T-cell clones clones expressed relevant functions of antimycobacterial immunity. The antigen reactivity of the T-cell clones to different mycobacterial species ranged from broad cross-reactivity to stringent specificity, and none of the clones distinguished between M. tuberculosis and M. bovis. Thus, M. tuberculosis-immune helper/inducer T cells of identical phenotype, genetic restriction, and function varied in their antigen specificity. T-cell clones of the type described will facilitate functional characterization of mycobacterial antigens on the T-cell level.

Animals↗
PubMed2000

Bovine tuberculosis: immune responses in the peripheral blood and at the site of active disease.

This report describes a comparison of immune responses in the peripheral blood and at the site of active disease in cattle 20 weeks after experimental infection with Mycobacterium bovis. Lymphocyte proliferation, and the production of interferon-gamma (IFN-gamma) and interleukin (IL)-2 were measured in response to tuberculin and a number of mycobacterial antigens, including ESAT-6, MPB64, MPB70, MPB83, hsp 16.1, hsp 65, hsp 70 and the 38 000 MW lipoprotein antigen. The level of transforming growth factor-beta (TGF-beta) was measured following stimulation of cells with tuberculin. Our results suggest little difference in the responses of peripheral blood and lymph node cells to most of the antigens used. However, tuberculin purified protein derivative (PPD) and ESAT-6 elicited stronger responses in the peripheral blood compared with lymph node cells. Investigation of the responding T-cell subpopulations in the peripheral blood showed that both CD4+ and, to a lesser extent, gammadelta T-cell receptor-positive (TCR+) T cells contributed to these responses. This is the first report to compare peripheral and local immune responses in bovine tuberculosis. Unlike cases of human tuberculosis where immune activity at the site of disease and anergy in the peripheral blood have been reported, our results suggest that for bovine tuberculosis immune responses occurring in the peripheral blood reflect those at the site of disease.

Animals↗
PubMed1980

Properties of peritoneal exudate lymphocytes that mediate tuberculin delayed-type hypersensitivity and anti-tuberculosis immunity. I. The effect of cytotoxic agents.

Acute peritoneal exudates were raised in rats that had been immunized by BCG, in order to draw into the peritoneal cavity sensitized immunoblasts. The peritoneal exudate cells (PEC) were harvested 24 h after exudate induction. The ability of these cells to confer tuberculin delayed-type hypersensitivity (DTH) and anti-tuberculosis immunity upon syngeneic recipients was examined after treatment with various cytotoxic agents. The transfer of DTH and immunity was entirely unaffected by in vitro exposure of PEC to high specific activity [3H]-thymidine, 5-bromodeoxyuridine or a low dose of mitomycin C. agents that adversely affect DNA-synthetic cells. Treatment of immunized rats with vinblastine reduced the number of PEC, but the cells were able to transfer DTH and immunity. In vitro exposure of PEC to vinblastine ablated the transfer of DTH but spared immunity. A moderate dose of mitomycin C suppressed immunity but not DTH; but a high dose abolished both expressions of cell-mediated immunity. The transfer of immunity was highly susceptible to ionizing radiation whereas DTH was resistant. These results suggest that the lymphocytes mediating DTH and anti-tuberculosis immunity are not actively replicating cells.

Animals↗
PubMed2003

[Up-to-date understanding of tuberculosis immunity].

This symposium was organized to provide the up-to-date knowledge on tuberculosis immunity, especially on the understanding of cytokines or Th1 cells involved in pathophysiology/protective immunity and vaccine development. Dr. Kazuo Kobayashi (Osaka City Univ.) reported their findings on the immune response to bioactive lipid component from M. tuberculosis, trehalose-dimycolate (TDM) and sulfolipid (SL) in mice. Their unique and novel finding was that TDM is capable of inducing T-dependent immune response in euthymic mice. The specific immune response in TDM-immune mice was consisting of CD4+ cell response and expression of chemokines, inflammatory cytokines and then TH1-related cytokines. In contrast, SL did not show such an activity. TDM may be one of the protective antigens and may modulate the specific immune response of the host. Dr. Isamu Sugawara's group (JATA) has examined the involvement of various cytokines in the host response to aerosolic infection with virulent strain of M. tuberculosis by using cytokine-knockout mice. The single deletion of IFN-gamma or TNF alpha resulted in a severe lesion of multiple necrosis without granuloma, and cytokine mRNA level other than knocked out cytokine was normal, suggesting that IFN-gamma and TNF alpha are principally important cytokines. In knockout mice for IL-12 or IL-18, necrotic lesion was not induced after infection and the pathological change was not so significant as in IFN-gamma/TNF alpha knockout mice. By using IFN-gamma knockout mice, it became possible to generate a granulomatous lesion with central necrosis and cavity resembling the lesion in humans. These mouse model appeared to be useful in the analysis of pathophysiology of human tuberculosis. Dr. Kazuyoshi Kawakami (Ryukyu Univ.) reported the importance of TH1 cytokines in anti-tuberculous immunity. By using IL-12, IL-18 knockout mice or double knockout mice, it was shown that IL-12 exhibits more important role than IL-18 in the protection. A possible contribution of IL-23 was also suggested. In most of the clinical cases of tuberculosis, the production of IL-12, IL-18 and IFN-gamma is increased, however, the group of relatively lower cytokine production did not respond well to the treatment. In addition, the plasma level of one of the chemokines, IP-10, was shown to be an indicator for the severity of the disease. Thus, some cytokines appear to be employable for the novel treatment in the near future. Dr. Saburo Yamamoto (NIH) summarized the recent advance in the understanding of biological function of CpG motifs. Immunostimulatory DNA is effective in the modulation of TH1/TH2 polarity and the enhancement of protective immunity to M. tuberulosis in animals. CpG motif (immunostimulatory DNA) appears to exert its activity by signaling cascade via TLR9 resulting in NF-kappa B activation and cytokine gene expression. Analysis of basic mechanism of action by CpG motif should pave the way to the clinical application in the future. Dr. Masaji Okada (Kinki Chuo Hospital) reported the current situation in the development of novel vaccines against tuberculosis. They have extensively constructed and examined the efficacy of various types of vaccines including subunit, DNA and recombinant BCG vaccines. Various vector systems have been tested for DNA vaccine. As immunizing antigens, a-Ag, ESAT-6, HSP65, 38kD-lipoprotein and so on have been employed. A large body of experimental data are accumulating for final evaluation, and among them, it is noteworthy to mention that HSP65DNA + IL-12DNA was 100 times more effective than conventional BCG in animal model. Among subunit vaccines, Mtb72f vaccine appears to be one of the promising candidates. In addition to the trial with various candidates, they have established a new mouse model, SCID/human PBL. This model animal has been employed for the development of vaccine effective for the induction of ESAT-6-specific human T cells.

Animals↗
PubMed1997

Examining a paradox in the pathogenesis of human pulmonary tuberculosis: immune activation and suppression/anergy.

Protective immunity against Mycobacterium tuberculosis (MTB) in animal models is based on cell-mediated immunity (CMI), involving bi-directional interactions between T cells and cells of the monocyte/macrophage (MO/MA) lineage. Key factors include MO-derived interleukin (IL)-12 and tumor necrosis factor (TNF)-alpha as well as T cell derived IL-2 and interferon (IFN)-gamma. These cytokines appear particularly crucial in the induction of MA-mediated elimination of mycobacteria. Several lines of evidence indicate that similar mechanisms are operating in humans. During active pulmonary tuberculosis (PTB), signs of both immune depression and immune activation are concomitantly present. Decreased tuberculin skin test reactivity in vivo and deficient IFN-gamma production by MTB-stimulated mononuclear cells in vitro are observed. On the other hand, the serum levels of several cytokines, including TNF, and other inflammatory mediators are increased and circulating MO and T cell show phenotypic and functional evidence of in vivo activation. In this review, we will discuss the evidence for three models, which could explain this apparent paradox: 1. Stimulation of the T cell-suppressive function from MO/MA; 2. Intrinsic T cell refractoriness, possibly associated with tendency to apoptosis (programmed cell death), and 3. Compartmentalization and redistribution of immune responses to the site of disease. The opportunistic behavior of MTB during human immunodeficiency virus (HIV) infection can be explained by suppression of type-1 responses at the level of antigen-presenting cells, CD4 T cells and effector macrophages. The ominous prognostic significance of intercurrent PTB during HIV infection seems primarily due to prolonged activation of HIV replication in macrophages. Supportive immune therapy during PTB could aim at correcting the type-1 deficiency either by IFN-gamma inducers (e.g. IL-12, IL-18) or by neutralizing the suppressive cytokines transforming growth factor beta (TGF-beta) and IL-10. Alternatively, inflammatory over-activity could be reduced by neutralizing TNF. Finally, anti-apoptotic therapies (e.g. IL-15) might be considered.

Cytokines↗
PubMed1980

Properties of peritoneal exudate lymphocytes that mediate tuberculin delayed-type hypersensitivity and anti-tuberculosis immunity.

Rats were immunized with living BCG and acute peritoneal exudates were induced on the ninth day of infection. The peritoneal exudate cells (PEC), that confer adoptive anti-tuberculosis immunity and tuberculin delayed-type hypersensitivity (DTH), were subject to velocity sedimentation analysis. It was found that the ability to confer immunity of DTH was limited to a population of cells that sedimented at a rate of 3-4 mm/h. This sedimentation rate corresponds to that of small lymphocytes. No significant immunological activity was detected in large lymphocytes that incorporate [3H]-thymidine in vitro, regardless of whether the exudates were obtained 14 to 24 h after induction of peritoneal inflammation. The failure of large lymphocytes to confer immunity and DTH was not due to adherent cells with suppressor activity, because removal of adherent cells failed to amplify the transfer of immunological activity by non-adherent cells. The persistence of the ability to express immunity and DTH in adoptively immunized rats was studied. There was no decay of adoptive immunity during a 4 week period following cell transfer, but there was a rapid reduction in the expression of DTH.

Animals↗