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At least 307 records · Page 17Linked to original sources
PubMed2006

The LFA-1 adhesion molecule is required for protective immunity during pulmonary Mycobacterium tuberculosis infection.

Host immunity to Mycobacterium tuberculosis is mediated by T cells that recognize and activate infected macrophages to control intracellular bacterial replication. The early appearance of T cells in the lungs of infected mice correlates with greater resistance to infection. However, it is unknown whether the trafficking of T cells to the lung following infection is dependent upon the expression of certain adhesion molecules. To address this question, we infected knockout (KO) mice that have defective expression of CD11a, CD11b, CD18, CD62, CD103, or beta7. We found that the integrins CD11a and CD18 are absolutely required for host resistance following infection with aerosolized M. tuberculosis. Although Ag-specific T cells are generated following infection of CD11a KO mice, T cell priming is delayed, T cell trafficking to the lung is impaired, and fewer ESAT6-specific CD4+ T cells are found in the lungs of CD11a KO mice compared with control mice. Thus, LFA-1 (CD11a/CD18) plays an essential role in immunity to M. tuberculosis infection.

Animals↗
PubMed1997

Adjuvant modulation of immune responses to tuberculosis subunit vaccines.

Mice were immunized with experimental subunit vaccines based on secreted antigens from Mycobacterium tuberculosis in a series of adjuvants, comprising incomplete Freund's adjuvant (IFA), dimethyl dioctadecyl ammoniumbromide (DDA), RIBI adjuvant, Quil-A saponin, and aluminum hydroxide. Immune responses induced by these vaccines were characterized by in vitro culture of primed cells, PCR analysis for cytokine mRNA, detection of specific immunoglobulin G isotypes induced, and monitoring of protective immunity to tuberculosis (TB). The study demonstrated marked differences in the immune responses induced by the different adjuvants and identified both IFA and DDA as efficient adjuvants for a TB subunit vaccine. Aluminum hydroxide, on the other hand, induced a Th2 response which increased the susceptibility of the animals to a subsequent TB challenge. DDA was further coadjuvanted with either the Th1-stimulating polymer poly(I-C) or the cytokines gamma interferon, interleukin 2 (IL-2), and IL-12. The addition of IL-12 was found to amplify a Th1 response in a dose-dependent manner and promoted a protective immune response against a virulent challenge. However, if the initial priming in the presence of IL-12 was followed by two booster injections of vaccine without IL-12, no improvement in long-term efficacy was found. This demonstrates the efficacy of DDA to promote an efficient immune response and suggests that IL-12 may accelerate this development, but not change the final outcome of a full vaccination regime.

Adjuvants, Immunologic↗
PubMed1999

Generation of CD8(+) T-cell responses to Mycobacterium bovis and mycobacterial antigen in experimental bovine tuberculosis.

Protective immunity against tuberculosis is considered to be essentially cell mediated, and an important role for CD8(+) T lymphocytes has been suggested by several studies of murine and human infections. The present work, using an experimental model of infection with Mycobacterium bovis in cattle, showed that live M. bovis elicits the activation of CD8(+) T cells in vitro. However, a sonic extract prepared from M. bovis (MBSE) and protein purified derivative (PPDb) also induced a considerable degree of activation of the CD8(+) T cells. Analysis of proliferative responses of peripheral blood mononuclear cells, purified CD8(+) T cells, and CD8(+) T-cell clones to M. bovis and to soluble antigenic preparations (MBSE, PPDb) showed that the responses of all three types of cells were always superior for live mycobacteria but that strong responses were also obtained with complex soluble preparations. Furthermore, while cytotoxic capabilities were not investigated, the CD8(+) T cells were found to produce and release gamma interferon in response to antigen (live and soluble), which indicated one possible protective mechanism for these cells in bovine tuberculosis. Finally, it was demonstrated by metabolic inhibition with brefeldin A and cytochalasin D at the clonal level that an endogenous pathway of antigen processing is required for presentation to bovine CD8(+) cells and that presentation is also dependent on phagocytosis of the antigen.

Animals↗
PubMed1986

Immune response gene control of lymphocyte proliferation induced by acetylcholine receptor-specific helper factor derived from lymphocytes of myasthenic mice.

The role of lymphokines secreted by acetylcholine receptor (AChR)-reactive lymphocytes in the regulation of an autoimmune response to AChR has not been studied in the human or murine model of myasthenia gravis. We investigated whether AChR-immune lymphocytes derived from mice with experimental autoimmune myasthenia gravis (EAMG) can produce an AChR-specific, genetically controlled soluble factor with biologic activity. AChR-reactive lymphocytes of mice with EAMG secreted an AChR-specific helper factor in vitro, which induced proliferation of AChR-immune but not Mycobacterium tuberculosis-immune lymphocytes. Recombinant, I-A mutant, and monoclonal anti-I-A antibody analyses suggest that AChR-specific helper factor-induced lymphocyte proliferation is controlled by an immune response gene at the I-A subregion of the murine major histocompatibility complex, and is mediated by the I-A molecule.

Animals↗
PubMedDate not supplied

[Health sector reform in Colombia and its effects on tuberculosis control and immunization programs].

This paper analyzes the effects of health reform in Colombia on public health programs at the local level, particularly the Expanded Program of Immunization (EPI) and the tuberculosis control program. The research was developed in three health districts in two States by analysis of documents, direct observation, and longitudinal follow-up of the transition process. The health districts were unprepared for the change, resulting in insufficient technical skills among staff as well as lack of awareness of important elements in the new system, associated with a reduction in immunization coverage and tuberculosis case detection. Structural problems in the new system included loss of immunization opportunities and lack of examination of tuberculosis contacts. The potentialities of the new system were the local development of a new organizational structure and the improvement of the information system; a limiting factor was exposure of the health system to local political interests. The general conclusion is that the transition period takes far longer than anticipated and requires a much greater information flow to both the local level and the community. There are transitory but also structural maladjustments that require a political response.

Colombia↗
PubMed1999

Susceptibility of mice deficient in CD1D or TAP1 to infection with Mycobacterium tuberculosis.

Cellular immunity against Mycobacterium tuberculosis controls infection in the majority of infected humans. Studies in mice have delineated an important role for CD4(+) T cells and cytokines including interferon gamma and tumor necrosis factor alpha in the response to infection with mycobacteria. Recently, the identification of CD8(+) CD1-restricted T cells that kill M. tuberculosis organisms via granulysin and the rapid death after infection of beta2 microglobulin deficient mice in humans has drawn attention to a critical role for CD8(+) T cells. The nature of mycobacterial-specific CD8(+) T cells has been an enigma because few have been identified in any species. Here, we delineate the contribution of class I MHC-restricted T cells in the defense against tuberculosis as transporter associated with antigen processing (TAP)1-deficient mice died rapidly, bore a greater bacterial burden, and had more severe tissue pathology than control mice. In contrast, CD1D-/- mice were not significantly different in their susceptibility to infection than control mice. This data demonstrates a critical role for TAP-dependent peptide antigen presentation and provides further evidence that class I MHC-restricted CD8(+) T cells, the major T cell subset activated by this antigen processing pathway, play an essential role in immunity to tuberculosis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

HIV-1-related pleural tuberculosis: elevated production of IFN-gamma, but failure of immunity to Mycobacterium tuberculosis.

BACKGROUND: Pleural tuberculosis can resolve spontaneously, suggesting that the inflammatory process may represent a protective immune response. However, pleural tuberculosis is strongly associated with HIV infection. It has been suggested that cell-mediated immune responses may be reduced, and direct bacterial invasion may have a role in pathogenesis, in HIV-positive cases. To test this hypothesis, we compared production of the pro-inflammatory cytokines, interferon (IFN)-gamma and tumour necrosis factor(TNF)-alpha, production of the immunosuppressive cytokine, interleukin (IL)-10, and mycobacterial culture positivity, in HIV-negative and HIV-positive patients with pleural tuberculosis. METHODS: Cytokine levels were measured in serum and pleural fluid, and in supernatants of blood and pleural fluid stimulated in vitro using mycobacterial antigens. Intracellular IFN-gamma and TNF-alpha production was measured after stimulation with phorbol myristate acetate and ionomycin in vitro. RESULTS: IFN-gamma was strikingly elevated in serum and pleural fluid in HIV-positive, compared to HIV-negative subjects (P < or = 0.02). TNF-alpha was elevated, but this was not statistically significant. IL-10 levels were higher in serum (P < 0.001), but similar in pleural fluid. IFN-gamma responses to soluble mycobacterial antigen in vitro were reduced in peripheral blood (P = 0.006), but not pleural fluid, of HIV-positive subjects. Intracellular cytokine staining suggested that CD8+ T cells were a major source of IFN-gamma in HIV-positive subjects. The proportion of subjects with a positive culture for Mycobacterium tuberculosis from pleural fluid was higher in the HIV-positive group. CONCLUSIONS: HIV-positive patients with pleural tuberculosis show elevated production of IFN-gamma, for which CD8+ T cells may be a major source. Mycobacterium tuberculosis can proliferate despite high levels of pro-inflammatory cytokines.

Adult↗
PubMed2000

Immunization with f-Met peptides induces immune reactivity against Mycobacterium tuberculosis.

OBJECTIVE: To determine whether synthetic peptides containing an amino terminal formyl-methionine residue and corresponding to the sequence of several proteins produced by Mycobacterium tuberculosis, would elicit an immune response in mice. DESIGN: Peptides corresponding to the amino termini of 8 M. tuberculosis proteins and initiating with formyl methionine residues were synthesized. The ability of these peptides to bind to the mouse non-classical MHC class I molecule H-2M3a was determined by flow microfluorimetry. These peptides were used to pulse dendritic cells that were then injected into normal mice. These mice were subsequently challenged with aerosolized M. tuberculosis and, 30 days later, the number of viable bacteria in the lungs was determined. RESULTS: Four of the 8 synthetic peptides bound to H-2M3a and stabilized its expression on the cell surface. Injection of mice with dendritic cells pulsed with H-2M3a binding peptides elicited non-MHC restricted cytotoxic T lymphocytes that killed peptide pulsed target cells and macrophages infected with M. tuberculosis. Immunization of mice with syngeneic dendritic cells pulsed in vitro with 2 of these peptides led to retardation of the growth of M. tuberculosis following aerosol challenge. CONCLUSION: Peptides that bind to non-polymorphic class I molecules can elicit immune reactivity directed towards M. tuberculosis.

Animals↗
PubMed2000

Correlates of protective immunity to Mycobacterium tuberculosis in humans.

Correlates of protective immunity to Mycobacterium tuberculosis in humans are desirable for identifying protective antigens, demonstrating the immunogenicity of a vaccine candidate and its potential efficacy, and permitting optimization of the dose, vehicle, adjuvant, and schedule of immunization. Potential correlates can be proposed on the basis of animal models and ex vivo/in vitro studies in humans. Most critical is their validation; ultimate validation will require correlation with protection in a phase III efficacy trial of an effective vaccine. Other approaches, however, can allow selection of the most promising correlates for inclusion in phase I and II and, ultimately, phase III vaccine trials. Current data from experimental models and studies of patients with pulmonary tuberculosis and their household contacts indicate that Mycobacterium tuberculosis-stimulated whole-blood production of interferon-gamma, although imperfect, is the best available correlate. Nonetheless, further refinement of this assay and additional studies of more complex assays that model M. tuberculosis killing and cytotoxic T lymphocyte activity are warranted. During planning of a vaccine trial, the best available correlates of immunity can be selected for inclusion.

Animals↗
PubMed1981

The immune spectrum in patients with pulmonary tuberculosis.

The immune response to mycobacterial antigens of 65 patients with pulmonary tuberculosis was studied using delayed skin test reactions and enzyme-linked immunosorbent antibody assays. Evidence for a spectrum of immune response was found. Six of 35 patients studied during the first month of therapy had tuberculin skin test anergy. Anergy was not related to state of nutrition or extent of disease, but it may have been associated with radiographically acute disease. The 6 anergic patients had somewhat higher antibody titers to mycobacterial protein, but not polysaccharide antigens, than did nonanergic patients.

Acute Disease↗
PubMed1990

Immunobiological studies with mycobacterial ribonucleic acid-protein complex: Part II--Mechanism of protective immunity against experimental tuberculosis.

Passive transfer of protective antituberculous immunity against LD50 dose of M. tuberculosis H37Rv was found to be mainly mediated by immune T-cells harvested from spleens of donor mice immunized with Myc. RNA-P-FIA complexes as monitored by indices of percent survival, root specific lung weight, lung density and by bacterial enumeration from different organs. Treatment of immune T-cells with anti-Thy 1.2. monoclonal antibodies plus complement prior to passive transfer, completely abrogated its protective effect thereby confirming their protective nature. Passive transfer of immune sera as well as immune T + B cells did not induce any enhancement in protective immunity.

Animals↗
PubMed2006

A deletion defining a common Asian lineage of Mycobacterium tuberculosis associates with immune subversion.

Six major lineages of Mycobacterium tuberculosis appear preferentially transmitted amongst distinct ethnic groups. We identified a deletion affecting Rv1519 in CH, a strain isolated from a large outbreak in Leicester U.K., that coincidentally defines the East African-Indian lineage matching a major ethnic group in this city. In broth media, CH grew less rapidly and was less acidic and H2O2-tolerant than reference sequenced strains (CDC1551 and H37Rv). Nevertheless, CH was not impaired in its ability to grow in human monocyte-derived macrophages. When compared with CDC1551 and H37Rv, CH induced less protective IL-12p40 and more antiinflammatory IL-10 and IL-6 gene transcription and secretion from monocyte-derived macrophages. It thus appears that CH compensates microbiological attenuation by skewing the innate response toward phagocyte deactivation. Complementation of Rv1519, but none of nine additional genes absent from CH compared with the type strain, H37Rv, reversed the capacity of CH to elicit antiinflammatory IL-10 production by macrophages. The Rv1519 polymorphism in M. tuberculosis confers an immune subverting phenotype that contributes to the persistence and outbreak potential of this lineage.

Asia↗
PubMed1992

Case-control study of the efficacy of BCG immunization against pulmonary tuberculosis in young adults in Santiago, Chile.

We performed a case-control study of the efficacy of BCG immunization against pulmonary tuberculosis in 15- to 35-year-old Chilean patients born during a period when BCG coverage was incomplete. Our aims were to determine BCG efficacy against pulmonary tuberculosis in young adults, to determine if repeated BCG immunization increased its protective effect, and to determine factors that could explain the failure of BCG immunization in patients with tuberculosis. We studied 68 patients who had pulmonary tuberculosis based on positive AFB in at least 1 of 2 sputum smears, a positive confirmatory culture and compatible chest roentgenogram abnormalities. The control group were 188 individuals without pulmonary tuberculosis seeking medical care for other ailments. The percentage of non-immunized individuals was 13.2 among patients with tuberculosis and 12.2 among controls. The vaccine efficacy calculated from these data was 10%. There was no difference in the percentage of individuals with 1, 2 and 3 BCG scars between tuberculosis patients and controls. The number and percent of individuals exposed to tuberculosis among BCG-immunized and non-immunized tuberculosis patients and controls were similar. No significant differences between BCG-immunized and non-immunized individuals were detected in tuberculosis patients or in the control group. However, tuberculosis patients as a group had significantly lower weight, education level, employment rate and family income than controls. These observations suggest that the development of pulmonary tuberculosis in BCG-immunized young adults is favored by the presence of genetic and/or acquired predisposing factors capable of overriding protective immunity induced by BCG vaccination.

Adolescent↗