Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026918 (Mycobacterium)
 52,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability to select for a cell-mediated response rather than antibody production following infection with intracellular mycobacteria, would be an advantage in preventing the occurrence of disease. Recent work suggests that the two members of the B7 family of costimulatory molecules, B7-1 and B7-2, may differentially influence the nature of primary immune responses but little is known of their role in this capacity in secondary responses. We have used an in vitro model to investigate whether blocking B7-1 and B7-2 affects changes in the cytokine profiles of Th lymphocytes previously primed to purified protein derivative (PPD) from Mycobacterium bovis. In C57BL/6 and BALB/c mice we found that the proliferative responses of a component of recently activated T lymphocytes, and those returning to the resting state, were inhibited by B7-2 blockade. B7-1 blockade had no distinguishable effect. However, in cultures containing anti-B7-2 antibody, the production of both interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), indicative of cell-mediated and antibody responses, respectively, were reduced. This suggests that intervention in a recall response to mycobacterial antigen by blocking B7-1 or B7-2 molecules, is unlikely to alter the nature of the immune response.
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PMID:Blockade of B7-2, not B7-1, inhibits purified protein derivative-primed T-lymphocyte responses but fails to influence the proportion of Th1 versus Th2 subsets. 960 Mar 17

We used human leprosy as a model to compare patterns of costimulatory molecule expression in respect to the clinical/immunologic spectrum of disease. We found that B7-1, B7-2, and CD28 transcripts dominated in tuberculoid leprosy patients, who have potent T cell responses to Mycobacterium leprae. In contrast, CTLA-4 was more strongly expressed in lesions from lepromatous patients, who manifest specific T cell anergy to the leprosy bacterium. T cell clones from tuberculoid lesions were CD4+CD28+ or CD4+CD28-, and T cell clones from lepromatous lesions were predominantly CD8+CD28-. The M. leprae-specific recall response of CD4+ T cell clones from tuberculoid lesions was blocked by anti-B7-1 mAb, but not by anti-B7-2 mAb or CTLA-Ig. However, anti-CD28 and anti-CTLA-4 mAbs did not block activation of clones from tuberculoid lesions, suggesting that B7-1 may utilize another costimulatory pathway. Peripheral blood T cell responses in the lepromatous form were strongly regulated by CD28 during T cell activation, in contrast to the tuberculoid form. Thus, B7-1 costimulation could play a role in maintaining a strong immune response to the pathogen.
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PMID:B7-1, but not CD28, is crucial for the maintenance of the CD4+ T cell responses in human leprosy. 972 37

Mycobacterium tuberculosis is the etiologic agent of human tuberculosis and is estimated to infect one-third of the world's population. Control of M. tuberculosis requires T cells and macrophages. T-cell function is modulated by the cytokine environment, which in mycobacterial infection is a balance of proinflammatory (interleukin-1 [IL-1], IL-6, IL-8, IL-12, and tumor necrosis factor alpha) and inhibitory (IL-10 and transforming growth factor beta [TGF-beta]) cytokines. IL-10 and TGF-beta are produced by M. tuberculosis-infected macrophages. The effect of IL-10 and TGF-beta on M. tuberculosis-reactive human CD4(+) and gammadelta T cells, the two major human T-cell subsets activated by M. tuberculosis, was investigated. Both IL-10 and TGF-beta inhibited proliferation and gamma interferon production by CD4(+) and gammadelta T cells. IL-10 was a more potent inhibitor than TGF-beta for both T-cell subsets. Combinations of IL-10 and TGF-beta did not result in additive or synergistic inhibition. IL-10 inhibited gammadelta and CD4(+) T cells directly and inhibited monocyte antigen-presenting cell (APC) function for CD4(+) T cells and, to a lesser extent, for gammadelta T cells. TGF-beta inhibited both CD4(+) and gammadelta T cells directly and had little effect on APC function for gammadelta and CD4(+) T cells. IL-10 down-regulated major histocompatibility complex (MHC) class I, MHC class II, CD40, B7-1, and B7-2 expression on M. tuberculosis-infected monocytes to a greater extent than TGF-beta. Neither cytokine affected the uptake of M. tuberculosis by monocytes. Thus, IL-10 and TGF-beta both inhibited CD4(+) and gammadelta T cells but differed in the mechanism used to inhibit T-cell responses to M. tuberculosis.
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PMID:Regulation of human CD4(+) alphabeta T-cell-receptor-positive (TCR(+)) and gammadelta TCR(+) T-cell responses to Mycobacterium tuberculosis by interleukin-10 and transforming growth factor beta. 1056 64

Activated dendritic cells are critically important in the priming of T-cell responses. In this report we show that the infection of a conditionally immortalized dendritic cell line (tsDC) with Mycobacterium tuberculosis resulted in the up-regulation of B7-1 and B7-2 co-stimulatory molecules and the induction of several inflammatory cytokines, including tumour necrosis factor-alpha and interleukin-6, -1beta and -12. In addition, we show that these activated dendritic cells were capable of eliciting antigen-specific T-cell responses and potent anti-mycobacterial protective immunity in a murine model of experimental tuberculosis infection.
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PMID:Mycobacterium tuberculosis-activated dendritic cells induce protective immunity in mice. 1071 79

Phenotypic changes of T lymphocytes and B7 costimulatory molecules in mice first vaccinated with mycobacterial 30 kDa secretory protein and then challenged with Mycobacterium tuberculosis H37Rv (Group 2) were monitored using flow cytometry and compared with non-vaccinated, but challenged mice (Group 1). In Group 1, the proportion of CD3+ and CD4+ T cells increased until 28 days postinfection (p.i.) and then declined to levels even less than healthy controls (non-vaccinated and non-challenged healthy mice), especially at later stages of infection (i.e. 72 days p.i.). However, the levels of CD8+ T cells did not decline and remained either significantly higher or similar to healthy control levels. In Group 2, however, the levels of CD3+ and CD4+ T cells did not decline as seen in Group 1, but remained significantly higher than in Group 1. Furthermore, the profile of CD8+ T cells remained similar to what was observed in Group 2. In order to elucidate Th1-Th2 bias, the ratio of IgG2a/IgG1 bearing cells was enumerated by flow cytometry. A predominantly Th1 response was observed in Group 1 until 28 days p.i. (IgG2a/IgG1 ratio was >1). However, in Group 2 a predominantly Th1 bias was observed throughout the period studied in terms of IgG2a/IgG1 ratios. The examination of expression of B7-1 and B7-2 costimulatory molecules on a monocyte gated population was carried out. In Group 2, the B7-1 and B7-2 expression was found to be significantly higher compared to Group 1, especially at later stages of infection (i.e. 60 and 72 days p.i.). Thus, these results suggest the capability of mycobacterial 30 kDa secretory protein in restoring the T-cell responses, especially at later stages of infection, possibly by augmentation of both B7-1 and B7-2. Further, these costimulatory molecules are probably required for effective T-cell responses against virulent mycobacterial challenge in a murine model of tuberculosis.
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PMID:Evaluation of the T cells and costimulatory molecules in the protective efficacy of 30 kDa secretory protein against experimental tuberculosis. 1138 Jun 72

Ability of different adjuvants to promote cell mediated immune responses towards 30 kDa secretory protein of Mycobacterium tuberculosis H37Ra was monitored by assessing the lymphocyte proliferation and IgG1/IgG2a subclass profile in mouse model. Six formulations, viz. poly lactide-co-glycolide (PLG) microspheres, dimethyldioctadecyl ammoniumbromide (DDA), liposomes, liposomes containing monophosphoryl lipid A and coated with alum (L-LIPA-AL) or without alum (L-LIPA) were evaluated in comparison to standard Freund's incomplete adjuvant (FIA). Two adjuvant formulations of 30kDa-L-LIPA-AL and 30kDa-PLG showed maximum reactivity on VIIIth week post immunization (p.im) in terms of lymphoproliferation w.r.t. other adjuvant formulations. Both the vaccine formulations also exhibited a Th1 shift in terms of higher IgG2a response over IgGI. Flowcytometric analysis in the mesenteric lymph nodes (MLNs) of immunized animals revealed the capacity of 30kDa-PLG and 30kDa-L-LIPA-AL to activate T cell subsets like CD4 and CD8 T cells. The upregulation of B7 costimulatory molecules (B7-1 & B7-2) after immunization further proved the ability of the two vaccine formulations to activate antigen presenting cells. The immunostimulatory nature of the two formulations was also reflected in their capacity to reduce the bacilli load from the lungs of the experimentally infected mice. This study demonstrates PLG and L-LIPA-AL as potent adjuvants and their bioacceptibility and nontoxic nature make them suitable candidates for future subunit vaccine development against tuberculosis.
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PMID:Evaluation of immune responses directed against 30kDa secretory protein of Mycobacterium tuberculosis H37Ra complexed in different adjuvants. 1201 16

DNA vaccination is known to elicit robust cellular and humoral responses to encoded antigen. The co-administration of costimulatory molecules CD80 (B7-1), CD86 (B7-2) and CD154 (CD40L) has been shown to enhance immune responses in several murine models. The role of specific costimulatory molecules in non-rodent species remains incompletely characterized. In these studies, we demonstrate that the co-administration of CD80 and CD86, but not CD154, to an existing candidate subunit DNA vaccine (ESAT-6) against bovine tuberculosis, enhances protection after aerosol challenge with virulent Mycobacterium bovis. Additionally, we have shown that vaccination with M. bovis BCG is protective against tuberculosis following aerosol challenge in cattle. Two independent trials were conducted in cattle to determine the adjuvant effect of encoded antigen + CD80/CD86 and directly compare the adjuvant activities of CD80/CD86 to those of CD154. Co-administration of either CD80/CD86 or CD154 enhanced ESAT-6-specific IFN-gamma responses as compared to animals vaccinated with ESAT-6 DNA alone. However, following aerosol challenge, only animals vaccinated with CD80/CD86 possessed decreased pathology of the lungs and associated lymph nodes, as measured by gross examination, radiographic lesion morphometry and bacterial recovery. Collectively, these results demonstrate that the co-administration of costimulatory molecules with a protective antigen target enhances bovine immune responses to DNA vaccination, and that CD80/CD86 is superior to CD154 in augmenting DNA vaccine-induced protection in experimental bovine tuberculosis.
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PMID:CD80 and CD86, but not CD154, augment DNA vaccine-induced protection in experimental bovine tuberculosis. 1554 1

The critical role of cellular immunity during tuberculosis (TB) has been extensively studied, but the impact of Abs upon this infection remains poorly defined. Previously, we demonstrated that B cells are required for optimal protection in Mycobacterium tuberculosis-infected mice. FcgammaR modulate immunity by engaging Igs produced by B cells. We report that C57BL/6 mice deficient in inhibitory FcgammaRIIB (RIIB-/-) manifested enhanced mycobacterial containment and diminished immunopathology compared with wild-type controls. These findings corresponded with enhanced pulmonary Th1 responses, evidenced by increased IFN-gamma-producing CD4+ T cells, and elevated expression of MHC class II and costimulatory molecules B7-1 and B7-2 in the lungs. Upon M. tuberculosis infection and immune complex engagement, RIIB-/- macrophages produced more of the p40 component of the Th1-promoting cytokine IL-12. These data strongly suggest that FcgammaRIIB engagement can dampen the TB Th1 response by attenuating IL-12p40 production or activation of APCs. Conversely, C57BL/6 mice lacking the gamma-chain shared by activating FcgammaR had enhanced susceptibility and exacerbated immunopathology upon M. tuberculosis challenge, associated with increased production of the immunosuppressive cytokine IL-10. Thus, engagement of distinct FcgammaR can divergently affect cytokine production and susceptibility during M. tuberculosis infection.
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PMID:Fc gamma receptors regulate immune activation and susceptibility during Mycobacterium tuberculosis infection. 1829 58

Secretory proteins of Mycobacterium tuberculosis are the major immunomodulators of the host immune response. Open reading frame (ORF) Rv2626c, encoding a conserved hypothetical protein eliciting a strong humoral immune response in patients with tuberculosis (TB), was shown to be up-regulated upon infection in mice under hypoxic conditions. We now show that recombinant Rv2626c protein (rRv2626c) can bind to the surface of murine macrophages and elicit the type-1 immune response, as manifested by nitric oxide (NO) secretion and expression of inducible nitric oxide synthase (iNOS). Significant induction of pro-inflammatory cytokines [interleukin (IL)-12 and tumour necrosis factor (TNF)-alpha] was evident upon stimulation of murine macrophages, as well as peripheral blood mononuclear cells (PBMCs) isolated from patients with active TB disease, with rRv2626c. Stimulation with rRv2626c also enhanced the expression of costimulatory molecules such as B7-1, B7-2 and CD40 on murine macrophages. We further show that the production of NO and pro-inflammatory cytokines in response to rRv2626c is mediated by the transcription factor nuclear factor (NF)-kappaB, and this was further confirmed using pyrrolidine dithiocarbamate (PDTC), a specific pharmacological inhibitor of NF-kappaB. Rv2626c therefore appears to modulate macrophage effector functions by eliciting both innate and adaptive immune responses, suggesting its possible use as a vaccine candidate.
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PMID:Mycobacterium tuberculosis conserved hypothetical protein rRv2626c modulates macrophage effector functions. 2020 90