[show abstract][hide abstract] ABSTRACT: This article reviews the significant advances in the past year in the basic and clinical aspects of adult tuberculosis (TB). Further research has deepened our understanding of host susceptibility and resistance mechanisms, including cytotoxicity, apoptosis, and antimicrobial polypeptides such as granulysin. Studies have confirmed the effects of HIV infection on risk of disease and disease manifestations, and have defined the effects of HIV on TB transmission. Recent studies also indicate a possible role for extended treatment of active disease and latent infection in HIV-1 infected individuals. Multidrug-resistant disease has been reported on every continent; rapid molecular approaches to the simultaneous diagnosis of TB and detection of rifampin resistance may facilitate prompt initiation of treatment. TB remains one of the major problems in global health.
Current opinion in pulmonary medicine 06/2001; 7(3):124-32. · 3.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mycobacterium tuberculosis antigen 85 is induced in vitro by isoniazid (INH); its sustained induction in sputum during tuberculosis (TB) therapy predicts relapse. In this trial, rifampin or rifalazil inhibited the induction of sputum antigen 85 by INH in a dose-dependent fashion. This approach may facilitate the evaluation of new TB drugs.
Antimicrobial Agents and Chemotherapy 05/2001; 45(4):1302-4. · 4.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: The bactericidal activity of orally administered antituberculosis (anti-TB) drugs was determined in a whole blood culture model of intracellular infection in which microbial killing reflects the combined effects of drug and immune mechanisms. Rifampin (Rif) was the most active compound studied and reduced the number of viable bacilli by >4 logs. Isoniazid (INH), 2 quinolones, and pyrazinamide (PZA) showed intermediate levels of activity. Ethambutol exerted only a bacteristatic effect; amoxicillin/clavulanate was inactive. The combination of INH-Rif-PZA showed strong activity against 11 drug-sensitive isolates (mean, -3.8 log) but no activity against 12 multidrug-resistant (MDR) strains. The combination of levofloxacin-PZA-ethambutol had intermediate bactericidal activity against MDR isolates (mean, -1.2 log) but failed to equal that of INH-Rif-PZA against sensitive isolates (P<.001). The whole blood BACTEC method (Becton Dickinson) may be useful for the early clinical evaluation of new anti-TB drugs and in the management of individual patients.
The Journal of Infectious Diseases 05/2001; 183(8):1300-3. · 5.85 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cachexia is one of the prominent features of advanced tuberculosis (TB) seen in association with increased expression of the monokine TNF-alpha. Several mycobacterial proteins, including PPD, stimulate TNF-alpha secretion from monocytes. Host factors that may play a role in cytokine expression from monocytes remain largely unknown. One such factor is the opsonizing antibodies. Monocytes have high-affinity receptors (FcgammaI and FcgammaIII) for IgG1 and IgG3 antibodies that mediate antigen uptake. We have reported selective up-regulation of IgG1 (which bind to Fcgamma receptors) in advanced TB and have recently shown the ability of PPD-specific IgG1 antibodies to augment TNF-alpha expression in PPD-stimulated monocytes. These observations have now been extended to other cytokines with semipurified fractions from secreted antigens of Mycobacterium tuberculosis (containing 30 kD and 58 kD) that were devoid of lipids, glycolipids and carbohydrates. In the presence of heat-inactivated TB plasma containing known amounts of antigen-specific IgG1 antibodies, these fractions induced significantly increased TNF-alpha, IL-6 and IL-10 secretion. Absorption of IgG1 with Protein 'A' removed the augmenting activity for TNF-alpha and IL-6 secretion from the TB plasma samples. In the case of IL-10, removal of IgG1 resulted in increased rather than decreased IL-10 secretion. These results suggest a possible pathogenic role for antibodies in TB by enhancing proinflammatory and blocking down-regulatory cytokines such as IL-10 cytokines during the chronic phase of TB.
[show abstract][hide abstract] ABSTRACT: Adjunctive immunotherapy with heat-killed Mycobacterium vaccae was studied in a randomized, placebo-controlled trial of 120 non-human immunodeficiency virus-infected adults with newly diagnosed pulmonary tuberculosis. Patients were randomized to a single dose of M. vaccae or placebo 1 week after beginning chemotherapy and were followed up for 1 year. M. vaccae was safe and well tolerated. The rate of sputum culture conversion after 1 month of tuberculosis treatment was 35% in the M. vaccae group and only 14% in the placebo group (P=.01) but was comparable at 2 months and thereafter. Patients receiving M. vaccae had greater improvement on chest radiography at 6 months (91% vs. 77% for placebo recipients; P=.04) and 12 months (94% vs. 80%; P=.04) after initiation of tuberculosis treatment. These data provide evidence of an early increase in sputum culture conversion and greater radiographic improvement among patients who received M. vaccae. Further studies are warranted.
The Journal of Infectious Diseases 05/2000; 181(4):1304-12. · 5.85 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cachexia is a prominent feature of advanced tuberculosis, in association with increased expression of the monokine tumour necrosis factor (TNF)-alpha. Monocytes, have high affinity receptors (mannose, complement and Fc gamma1 and gamma111) which mediate antigen uptake and subsequent cytokine activation. Several mycobacterial proteins, including PPD, can stimulate TNF-alpha secretion from monocytes. However, the role of various receptors in stimulating or regulating TNF-alpha secretion is still unclear. We have previously shown selective augmentation of opsonic antibodies (IgG1 and IgG3) in tuberculosis patients with advanced pulmonary disease. We now analyse the role of opsonizing antibodies in modulating TNF-alpha expression in antigen stimulated monocytes. PPD was used as the prototypic mycobacterial antigen to stimulate monocytes from PPD skin test negative donors (n = 7) in the presence of plasma from tuberculosis patients (n = 8), containing known amounts of IgG1 and IgG3 anti-PPD antibodies. TNF-alpha secretion was enhanced in the presence of TB plasma (4/8) but not in the presence of control plasma. Using Spearman Rank analysis (two-tailed Fisher exact test), a significant correlation (rho = 0.762; P = 0. 04) was observed between IgG1 antibodies and enhancement of TNF-alpha secretion. No significant association was observed with IgG2 (rho = 0.310; P = 0.41), IgG3 (rho = 0.089; P = 0.81) or IgG4 (rho = - 0.357; P = 0.347) subclass antibodies. Absorption of IgG1 with protein 'A' removed the enhancement of TNF-alpha secretion activity from the plasma samples. Our results therefore indicate that IgG1 antibodies may enhance the chronic release of TNF-alpha in TB patients with progressive disease and, for the first time, show a direct link between disease pathogenesis and raised antibody levels.
[show abstract][hide abstract] ABSTRACT: Patients vary considerably in their response to treatment of pulmonary tuberculosis. Although several studies have indicated that adverse outcomes are more likely in those patients with delayed sputum sterilization, few tools are available to identify those patients prospectively. In this study, multivariate models were developed to predict the response to therapy in a prospectively recruited cohort of 42 HIV-uninfected subjects with drug-sensitive tuberculosis. The cohort included 2 subjects whose initial response was followed by drug-sensitive relapse. The total duration of culture positivity was best predicted by a model that included sputum M. tuberculosis antigen 85 concentration on Day 14 of therapy, days-to-positive in BACTEC on Day 30, and the baseline radiographic extent of disease (R = 0.63). A model in which quantitative AFB microscopy replaced BACTEC also performed adequately (R = 0.58). Both models predicted delayed clearance of bacilli in both relapses (> 85th percentile of all subjects) using information collected during the first month of therapy. Stratification of patients according to anticipated response to therapy may allow TB treatment to be individualized, potentially offering superior outcomes and greater efficiency in resource utilization, and aiding in the conduct of clinical trials.
American Journal of Respiratory and Critical Care Medicine 04/2000; 161(4 Pt 1):1076-80. · 11.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Immunological and clinical profiles were evaluated in 2 groups: human immunodeficiency virus (HIV)-uninfected and HIV-infected patients, with newly diagnosed pulmonary tuberculosis (TB), and tuberculin-skin-test-reactive healthy control subjects. HIV-uninfected patients with TB were also followed up longitudinally during and after chemotherapy. At the time of diagnosis, purified protein derivative (PPD)-stimulated production of interferon (IFN)-gamma by peripheral blood mononuclear cells from TB patients was depressed, compared with that of healthy control subjects, whereas levels of transforming growth factor (TGF)-beta and interleukin (IL)-10 were increased. In longitudinal studies, PPD stimulated production of IL-10 and TGF-beta returned to baseline by 3 months, whereas IFN-gamma production remained depressed for at least 12 months. These data indicate that the immunosuppression of TB is not only immediate and apparently dependent (at least in part) on immunosuppressive cytokines early during the course of Mycobacterium TB infection but is also long lasting, presumably relating to a primary abnormality in T-cell function.
The Journal of Infectious Diseases 01/2000; 180(6):2069-73. · 5.85 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although Mycobacterium tuberculosis is eradicated rapidly during therapy in some patients with pulmonary tuberculosis, it can persist for many months in others. This study examined the relationship between mycobacterial drug tolerance (delayed killing in vitro), persistence, and relapse. It was performed with 39 fully drug-susceptible isolates from a prospective trial of standard short-course antituberculous therapy with sputum smear-positive, human immunodeficiency virus-uninfected subjects with pulmonary tuberculosis in Brazil and Uganda. The rate of killing in vitro was determined by monitoring the growth index (GI) in BACTEC 12B medium after addition of drug to established cultures and was measured as the number of days required for 99% sterilization. Drugs differed significantly in bactericidal activity, in the following order from greatest to least, rifampin > isoniazid-ethambutol > ethambutol (P < 0.001). Isolates from subjects who had relapses (n = 2) or in whom persistence was prolonged (n = 1) were significantly more tolerant of isoniazid-ethambutol and rifampin than isolates from other subjects (P < 0.01). More generally, the duration of persistence during therapy was predicted by strain tolerance to isoniazid and rifampin (P = 0.012 and 0.026, respectively). Tolerance to isoniazid-ethambutol and tolerance to rifampin were highly correlated (P < 0.001). Tolerant isolates did not differ from others with respect to the MIC of isoniazid; the rate of killing of a tolerant isolate by isoniazid-ethambutol was not increased at higher drug concentrations. These observations suggest that tolerance may not be due to drug-specific mechanisms. Tolerance was of the phenotypic type, although increased tolerance appeared to emerge after prolonged drug exposure in vivo. This study suggests that drug tolerance may be an important determinant of the outcome of therapy for tuberculosis.
Antimicrobial Agents and Chemotherapy 11/1999; 43(11):2600-6. · 4.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: Anergy testing has been used as an adjunct to tuberculin testing for assessing M. tuberculosis (MTB) infection and indications for isoniazid preventive therapy in HIV-infected persons. We examined factors associated with the stability of skin test responses to purified protein derivative (PPD) and candida antigens in a cohort of HIV-infected adults followed prospectively in a tuberculosis preventive therapy trial in Uganda. PPD-positive and anergic subjects in the placebo arms of the preventive therapy study underwent repeat skin testing and immunologic testing including measurement of MTB culture filtrate (CF)-stimulated interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) levels in whole-blood culture supernatants. Anergy was present in 27% of 4,058 HIV-infected subjects screened for the tuberculosis preventive therapy trial compared with 10% of 682 HIV-non-infected persons. On follow-up testing of enrolled subjects, 42% of 139 initially anergic subjects were no longer anergic; two thirds of these had PPD reactions >= 5 mm. Stability of anergy was associated with intercurrent opportunistic infections and AIDS-associated dermatitis at baseline. Thirty-five percent of 313 subjects with an initial positive PPD had a negative PPD test at follow-up, 26% of whom had a positive candida skin test at the same time as the negative PPD test. Baseline MTBCF-stimulated IFN-gamma levels were significantly higher among PPD-positive subjects who remained PPD-positive than in those who were falsely negative. We conclude first that anergy is unstable and second that anergy testing is unreliable in identifying HIV-infected adults who are not infected with MTB and should not be used routinely for this purpose in assessing indications for isoniazid preventive therapy.
American Journal of Respiratory and Critical Care Medicine 12/1998; 158(6):1790-6. · 11.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Responses to mycobacterial and nonmycobacterial antigens were examined in bronchoalveolar cells (BAC) and peripheral blood mononuclear cells (PBMC) from patients with active pulmonary tuberculosis (n=16) and healthy subjects (n=23). DNA synthesis in BAC (but not PBMC) from tuberculosis patients was significantly increased in response to the mycobacterial antigens purified protein derivative (PPD), antigen 85, and mannose-capped lipoarabinomannan but not to nonmycobacterial antigens. The response to PPD was also increased in enriched alveolar lymphocytes from tuberculosis patients (P<.05). The frequency of interferon-gamma but not interleukin-4- or -10-producing cells by ELISAspot was increased in PPD-stimulated BAC from patients with tuberculosis (P<.05). Accessory function of alveolar macrophages for T lymphocyte responses was similar and suppressive activity was variably decreased in tuberculosis patients. Thus, there is compartmentalization of mycobacterial antigen-specific lymphocytes to the lungs during active tuberculosis that on challenge produce a Th1-type cytokine host response.
The Journal of Infectious Diseases 12/1998; 178(5):1434-45. · 5.85 Impact Factor
[show abstract][hide abstract] ABSTRACT: Sputum quantitative culture, acid-fast smear, days-to-positive by BACTEC, and Mycobacterium tuberculosis antigen 85 complex were monitored during therapy in 42 patients with pulmonary tuberculosis (TB). By BACTEC, 4 patients were persistently positive on days 90-180, and treatment ultimately failed in 2 of these. Antigen 85 expression increased in subjects in whom disease persisted (persisters) from days 0 to 14 when the difference between persisters and nonpersisters was statistically significant (P = .002). Only antigen 85 complex values at day 14 suggested TB persistence at or after day 90. All subjects with day 14 antigen 85 complex values < 60 pg/mL responded rapidly to treatment and were cured. Of those with values > 60 pg/mL, in 33% TB persisted at or after day 90 and treatment failed in 17%. Biologic factors expressed early in therapy, not related to compliance or resistance, may exert a substantial influence on outcome. The antigen 85 complex is critical in cell wall biosynthesis and is induced by isoniazid in vitro. Its induction may represent an adaptive transition to a persistent state during therapy.
The Journal of Infectious Diseases 10/1998; 178(4):1115-21. · 5.85 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Tubercle and Lung Disease 02/1997; 78(3-4):145-58.
[show abstract][hide abstract] ABSTRACT: Tuberculosis Treatment Center, Kampala, Uganda.
HIV-1 affects outcome in pulmonary tuberculosis (TB). Immune mechanisms triggered by Mycobacterium tuberculosis may lead to increased HIV expression and accelerated disease progression. This study was conducted to correlate serum levels of markers of immune activation with mortality and drug toxicity in HIV + TB.
Substudy of a randomized clinical trial of streptomycin-thiacetazone-isoniazid (STH) vs. rifampin-isoniazid-pyrazinamide (RHZ) in HIV + TB.
Neopterin > or = 14 ng/ml, TNF-alpha receptors > or = 6.5 ng/ml, and negative skin test were independently associated with increased mortality (P < 0.01). Among STH-treated subjects, dermatologic toxicity and mortality were respectively 13- and 6.3-fold more likely to occur in subjects with elevated neopterin (P < 0.05), although these two adverse events occurred independently. Activation markers increased from baseline after 2 months of therapy with the less rapidly bactericidal STH regimen, whereas they declined in those treated with RHZ, suggesting a relationship with continued mycobacterial replication.
Immune activation in HIV + TB is associated with shortened survival and increased risk of drug toxicity. HIV + TB patients with elevated serum neopterin should be treated with a rapidly-bactericidal drug regimen which does not include thiacetazone.
[show abstract][hide abstract] ABSTRACT: Macrophage activation and tumor necrosis factor-alpha (TNF-alpha) production are critical in tuberculosis immunity but may result in increased human immunodeficiency virus (HIV) expression and accelerated HIV disease progression in HIV-infected persons. Pentoxifylline inhibits expression of TNF-alpha and HIV. A double-blind, placebo-controlled study of adjunctive therapy with pentoxifylline (1800 mg/day) as a timed-release formulation was done in Ugandan HIV-infected patients with pulmonary tuberculosis. Subjects had early HIV disease (mean CD4 cell count, 380/microL) and did not receive other antiretroviral drugs. Pentoxifylline resulted in decreased plasma HIV RNA and serum beta 2-microglobulin and, in a subset of moderately anemic patients, improved blood hemoglobin levels. Trends were noted toward reduced TNF-alpha production in vitro and improved performance scores, but these did not reach statistical significance. No effect was noted on body mass, CD4 cell count, or survival. Additional studies of more potent TNF-alpha inhibitors in HIV-positive subjects with tuberculosis are warranted.
The Journal of Infectious Diseases 11/1996; 174(4):727-33. · 5.85 Impact Factor
[show abstract][hide abstract] ABSTRACT: Native 30-kD antigen, also known as alpha antigen, is a fibronectin-binding protein that is secreted by live Mycobacterium tuberculosis. This antigen may play an important biological role in the host-parasite interaction since it elicits delayed type hypersensitivity response and protective immunity in vivo and T lymphocyte blastogenesis and IFN-gamma production in vitro. In the present study, we show that, TNF-alpha protein is produced in monocyte culture supernatants in response to 30-kD antigen and the level is as high as that to purified protein derivative of M. tuberculosis. This stimulatory effect was not due to contamination with either bacterial lipopolysaccharide or mycobacterial lipoarabinomannan. The preincubation of monocytes with plasma fibronectin significantly enhanced the release of TNF-alpha into the culture supernatants in response to 30-kD antigen. This effect was blocked by polygonal antibody to plasma fibronectin. In contrast, the monocytic cell line U937 failed to release TNF-alpha protein in the culture supernatants in response to 30-kD antigen with or without preincubation with plasma fibronectin. To determine whether this observation was due to differential binding of the 30-kD to fibronectin on these cells, a cell based ELISA was used. Pretreatment of monocytes with fibronectin enhanced their binding of the 30-kD antigen. U937 cells bound the 30-kD antigen weakly with or without fibronectin pretreatment. These results indicate that 30-kD antigen which is a known secretary antigen of M. tuberculosis is a stimulus for human monocytes to express TNF-alpha and that stimulatory effect may be mediated through plasma fibronectin.
Journal of Clinical Investigation 10/1996; 98(5):1261-8. · 12.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: Setting: Tuberculosis Treatment Center, Kampala, Uganda.Objective: HIV-1 affects outcome in pulmonary tuberculosis (TB). Immune mechanisms triggered by Mycobacterium tuberculosis may lead to increased HIV expression and accelerated disease progression. This study was conducted to correlate serum levels of markers of immune activation with mortality and drug toxicity in HIV+TB.Design: Substudy of a randomized clinical trial of streptomycin-thiacetazone-isoniazid (STH) vs. rifampinisoniazid-pyrazinamide (RHZ) in HIV+TB.Results: Neopterin ≥ 14 ng/ml, TNF-α receptors ≥ 6.5 ng/ml, and negative skin test were independently associated with increased mortality (P < 0.01). Among STH-treated subjects, dermatologic toxicity and mortality were respectively 13- and 6.3-fold more likely to occur in subjects with elevated neopterin (P < 0.05), although these two adverse events occurred independently. Activation markers increased from baseline after 2 months of therapy with the less rapidly bactericidal STH regimen, whereas they declined in those treated with RHZ, suggesting a relationship with continued mycobacterial replication.Conclusions: Immune activation in HIV+TB is associated with shortened survival and increased risk of drug toxicity. HIV+TB patients with elevated serum neopterin should be treated with a rapidly-bactericidal drug regimen which does not include thiacetazone.RésuméCadre: Centre de traitement de la tuberculose à Kampala, Uganda.Objectif: Le virus VIH-1 intervient dans l'évolution de la tuberculose pulmonaire. Les mécanismes immunologiques stimulés par Mycobacterium tuberculosis peuvent entraíner une expression accrue du VIH et une progression accélérée de la maladie due à ce virus. Cette étude a été conduite pour corréler les niveaux sériques des marqueurs d'activation immunitaire avec la mortalité et la toxicité médicamenteuse chez les sujets tuberculeux séropositifs pour le VIH.Schéma: Il s'agit d'une étude complémentaire dans le cadre d'un essai clinique randomisé du traitement de sujets tuberculeux VIH-positifs soit par streptomycine-thiacétazone-isoniazide (STH), soit par rifampicineisoniazide-pyrazinamide (RHZ).Résultats: On note que des taux de néoptérine égaux ou supérieurs à 14 ng/ml, des taux de récepteurs de TNF-α égaux ou supérieurs à 6,5 ng/ml et des tests cutanés négatifs sont associés de manière indèpendante à une mortalité accrue (P < 0,01). Parmi les sujets traités par STH, la toxicité dermatologique et la mortalité sont respectivement 13 et 6,3 fois plus fréquentes chez les sujets avec des taux de néoptérine élevé (P < 0,05), quoique ces deux effets défavorables se développent indépendamment l'un de l'autre. Les marqueurs d'activation augmentent depuis leur valeur de base après 2 mois de traitement avec le régime STH (moins rapidement bactéricide) alors qu'ils diminuent chez ceux traités par RHZ, ce qui suggère une relation avec la persistance d'une réplication mycobactérienne.Conclusions: L'activation immunitaire chez les sujets tuberculeux séropositifs pour le VIH va de pair avec un raccourcissement de la survie et une augmentation du risque de toxicité médicamenteuse. Les patients tuberculeux VIH-positifs dont le taux sérique de néoptérine est élevé devraient être traités par un régime rapidement bactéricide n'incluant pas la thioacétazone.ResumenMarco de referencia: Centro de Tratamiento de la Tuberculosis, Kampala, Uganda.Objetivo: El VIH-1 afecta la evolución de la tuberculosis pulmonar (TB). Los mecanismos inmunes desencadenados por Mycobacterium tuberculosis pueden provocar un aumento de la expresión del VIH y acelerar la progresión de la enfermedad. Este estudio analiza la correlación entre los niveles séricos de parámetros de activación inmune y la mortalidad y toxicidad medicamentosa en la asociación VIH+TB.Método: Estudio derivado de un protocolo clínico aleatorio que compara la asociación estreptomicina, tioacetazona y isoniacida (STH) con la asociación isoniacida, rifampicina y pirazinamida (RHZ) en VIH+TB.Resultados: Neopterina ≥ 14 ng/ml, receptores TNF-α ≥ 6,5 ng/ml y una prueba cutánea negativa estaban asociados independientemente con un aumento de la mortalidad (P < 0,01). Entre los individuos tratados con STH, la toxicidad dermatológica y la mortalidad fueron respectivamente 13 y 6,3 veces más frecuentes en los individuos con una neopterina elevada (P < 0,05), pero estos dos efectos adversos se presentaban independientemente. Los parámetros de activación aumentaron desde un nivel basal después de 2 meses de tratamiento con el esquema más lentamente bactericida (STH), mientras que disminuyeron en los individuos tratados con RHZ, lo que sugiere una relación con la mantención de la replicación micobacteriana.Conclusiones: La activación inmune en VIH+TB está asociada con una menor sobrevida y un aumento del riesgo de toxicidad medicamentosa. Los pacientes VIH+TB con niveles séricos de neopterina elevados deben ser tratados con un esquema rápidamente bactericida que no incluye la tioacetazona.
[show abstract][hide abstract] ABSTRACT: The fibronectin-binding 30-kDa alpha Ag is a major secretory protein of growing mycobacteria that stimulates in vitro lymphocyte blastogenesis in most healthy purified protein derivative-positive individuals, but only a minority of patients with active tuberculosis. T cell epitopes of the alpha Ag were assessed using blastogenic responses of PBMC from 12 healthy purified protein derivative-positive subjects to a set of synthetic peptides based on the 325-amino acid sequence of the alpha Ag of Mycobacterium bovis BCG. Because epitope-specific precursor cells are infrequent and randomly distributed, we used Poisson analysis to determine positive responses to 10 micrograms/ml of each peptide in 12 replicate culture wells. Seven immunodominant regions of the alpha Ag were identified. Each subjects responded to at least one of the two most dominant epitopes, which correspond to amino acids 131-155 and 233-257 (from N terminus). Peptides of these two epitopes induced production of IFN-gamma by sorted CD4+ T cells. The immunodominant peptides may have use a components of a vaccine and as tools to study the evolution of the immune response to M. tuberculosis. The two most dominant epitopes both occur in regions of the alpha Ag that differ from those of the atypical pathogens M. avium and M. kansasii. In addition, the M. bovis epitope of amino acids 133-155 differs from that of M. tuberculosis by a single amino acid. It may be possible to exploit the sequence differences for development of diagnostic tests with increased specificity.
The Journal of Immunology 06/1995; 154(9):4665-74. · 5.52 Impact Factor