[Prevention of tuberculosis: current approaches to development of vaccines].

This review is focused on recent advances in development of new vaccines for the prevention of tuberculosis. The main reasons for lack of BCG vaccine efficacy in different populations and geographic regions are presented. Design of new vaccines based on live modified strains of Mycobacterium bovis BCG, attenuated strains of Mycobacterium tuberculosis, recombinant proteins and viral vectors is considered in the specific examples. The usage of the heterologous "prime-boost" vaccination strategy against tuberculosis is discussed.

[Population-based epidemiological study of pulmonary tuberculosis in a number of rural regions of Tatarstan].

The paper presents the results of a population-based, geneticoepidemiological, and immunological study conducted in two regions of Tatarstan. The population-based risks for tuberculosis were established for males and females. Based on the population and family data, the authors calculated the genetic liability to tuberculosis, namely hereditability that is in the range of 0.8 to 1.0 and includes the contribution of nongenetic and environmental factors. Analysis of the results of immunogenetic studies of the northwestern region of Tatarstan has ascertained that patients have an association with the HLA antigen B22, in the Kama Region there is an association with other HLA antigens: B12 and B16. The higher frequency of the HLA antigens B28 and CW1 in healthy individuals as compared with that in patients with pulmonary tuberculosis (PT) suggests the resistance of PT carriers of these antigens for the disease. A study of the distribution of HLA genes by polymerase chain reaction has established the association of the disease with the DR-B1-15 genes in the Kama Region.

[Study of the polymorphic markers--the PARK2 and PACRG genes due to the incidence of pulmonary tuberculosis in two districts of the Republic of Tyva].

Polymerase chain reaction-RFLP was used to distribute two polymorphic markers (SNP) PARK2-e01 (-697) and rs1333955 located at the common promoter site of the PARK2 and PACRG genes in order to reveal assumed associations with the incidence of pulmonary tuberculosis in the Barum-Khemchiksky and Ovyursky Districts of the Republic of Tyva. No significant differences were found in the frequencies of these two polymorphic markers between the groups of patients with tuberculosis and healthy individuals, residing in the above districts, and between the total control samples from both districts. The total group of patients with tuberculosis from the two districts from the Republic of Tyva showed a significant surplus of heterozygotes in both study markers, as compared with the group of healthy individuals, which was also observed for the marker rs1333955 in the Barum-Khemchksky District alone. The observed features of genotypic distribution by the two study markers point to the influence of the considered markers on the incidence of tuberculosis.

[Genetic HLA markers associated with pulmonary tuberculosis in the Barum-Khemchiksky District, Republic of Tyva].

Detection of the genetic markers determining a predisposition to pulmonary tuberculosis is a necessary condition for the warranted formation of risk groups in the populations. On this basis, the authors used immunogenetic studies to examine 60 patients with pulmonary tuberculosis and 96 healthy individuals of Tuvinian nationality, who lived in the Barum-Khemchiksky District, Republic of Tyva. The microlymphocytotoxic test was used to determine class I HLA antigens and polymerase chain reaction was employed to reveal the specificity of class II HLA-DRB1 gene. The study revealed a positive association of HLA-B27 antigen and the specificities of HLA-DRB1 13(6) HLA-DRB1 14(6) with tuberculosis, which permits tuberculosis risk groups to be formed, by taking into account the immunogenetic data obtained in this district of the Republic of Tyva.

[Effect of use of bone marrow cells in therapy for experimental tuberculosis].

The authors studied the efficiency of use of bone marrow cells in the treatment of experimental tuberculosis. Bone marrow cell transplantation to H37Rv tuberculosis-infected H37Rv mice was shown to prolong the life span in the animals as compared to untreated animals. Examination of humoral immunity indicated that administration of allogenic bone marrow cells resulted in the nonspecific polyisotypic stimulation of antituberculosis antibodies, which is essential in producing the protective humoral background. A more significant generation of IgG2a antibodies than that of IgG1 antibodies was also found in therapy with bone marrow cells, which pointed to the fact that there was a Th1 response that is obviously protective in tuberculosis. The high level of IgG2a antibodies correlated with the high specific cellular immune response estimated by the delayed hypersensitivity reaction.

[Individual approaches to complex treatment of disseminated tuberculous processes in adolescents].

Complex treatment including an individual selection of chemotherapy regimens with their timely correction and various laser therapy modalities was used in 147 adolescents with a first detected disseminated pulmonary tuberculous process (DPTP). All the patients were initially given treatment regimen 1. According to the results of chemotherapy correction (adverse reactions to antituberculous agents and drug resistance of Mycobacterium tuberculosis), the patients were divided into 3 groups. Inclusion of reserve-series drugs into the initial combination for most critically ill patients could prevent an exacerbation of tuberculosis in most cases (89.7%) during therapy. The employment of various laser therapy modalities in combination with an individual approach to using drugs in the intensive phase of treatment enhanced its efficiency in patients with DPTP, by accelerating the periods of positive changes by 1.5-2 months. This made it possible to achieve a smooth course of tuberculosis in 92.5% of patients with high rates of bacterial isolation cessation (99.2%) and decay cavity closure (97.6%).

[Distribution of HLA antigens in patients with tuberculosis and healthy individuals in the Tatar population]. / Raspredelenie antigenov kompleksa HLA u bol'nykh tuberkulezom i zdorovykh lits v Tatarskoi populiatsii.

The paper presents the results of a study of the distribution of Class I HLA antigens in an ethnic Tatar group (in patients with pulmonary tuberculosis and healthy individuals) in 4 districts of Tatarstan. It has been ascertained that an association with HLA-B22 antigen exists in patients with active pulmonary tuberculosis.

[Tuberculous IgE antibodies. Part II. Study of its concentrations in different forms of tuberculosis]. / Protivotuberkuleznye IgE-antitela. Chast' II. Issledovanie kontsentratsii pri razlichnykh formakh tuberkuleza.

Tuberculosis-afflicted lung are infiltrated by two functionally types of lymphocytes, which presumably counteract with each other by producing proinflammatory (type 1) and anti-inflammatory (type 2) cytokines. It is held that irregular sequestration of antigen into different compartments of the lung may lead to preferential activation of T-helper 1 or T-helper 2 lymphocytes. Unlike IgE antibodies, specific tuberculosis IgE antibodies are seen only in tuberculosis infection. The mean values of IgE antibodies in tuberculosis (7.661 +/- 0.849 IU/ml) are significantly greater than those in other pulmonary diseases (1.768 +/- 0.116 IU/ml). Low concentrations of tuberculosis IgE antibodies in persons with a marked hyperergic response to tuberculin (1.808 +/- 0.097 IU/ml) are of importance. Significant concentrations of mycobacterial IgE antibodies are mainly detected in fibrocavernous (14.56 +/- 1.11 IU/ml), infiltrative (10.10 +/- 1.08 IU/ml), peripheral lymph nodal (10.53 +/- 1.09 IU/ml) tuberculosis rather than intrathoracic lymph nodal tuberculosis (4.555 +/- 0.340 IU/ml). There is a particularly considerable increase in specific IgE antibodies in a phase of decay (15.98 +/- 1.64 IU/ml) and infiltration (12.66 +/- 1.08 IU/ml). These groups also show a concurrent rise in tuberculosis IgG antibodies, which nevertheless disagree with the increase of IgE (the correlation coefficient is 0.599).

[Anti-tuberculous IgE antibodies. I. Immunodominant antigens]. / Protivotuberkuleznye IgE-antitela. I chast'. Immunodominantnye antigeny.

It is widely accepted that protection against tuberculosis is provided by the formation of type 1 immune response, which is characterized by the production of IFN-gamma and IL-2. However, type 2 antimycobacterial immune response is also present: specific IgE antibodies that are IL-4 dependent, are usually found in tuberculosis patients. There is elevated production of type 2 cytokines in some cases. Thus, both types of an immune response can simultaneously develop, probably counteracting with each other. It is unknown which of mycobacterial antigens are capable of inducing a preferential type 2 response. To detect these antigens, the authors studied tuberculosis IgE antibodies in the sera of 500 tuberculosis patients by using the ELISA assay with ultrasonic disintegrated M. Tuberculosis H37Rv (sonicate). Antigens recognized by IgE antibodies were found to be localized in the cell wall of mycobacteria. The IgE-response was specific since the sera did not react with the antigens of atypical mycobacteria and other bacterial species.

[Experience with kipferon use in the treatment of patients with pulmonary tuberculosis]. / Opyt primeneniia kipferona pri lechenii bol'nykh tuberkulezom legkikh.

Kipferon that is a combination of recombinant human (2-interferon and a complex of immunoglobulins G, M and A, was used in suppositories as an auxiliary agent in the routine chemotherapy in 36 new cases of pulmonary tuberculosis. A control group included 19 patients identical in sex, age, and the pattern of pulmonary tuberculosis. The clinical, X-ray, and laboratory indices (primarily cellular immunity) were studies before and 1 and 3 months after treatment. The beneficial effect of kipferon was manifested by a more rapid arrest of symptoms of total intoxication eliminated after 2 weeks in 39% of patients in the experimental group and only in 21% in the controls. Normalization of blood parameters occurred following a month in 58.3 and 47% of patients, respectively. Mycobacteria tuberculosis disappeared in the sputum smears following a month of treatment in 62% of those isolating bacteria in the experimental group and only in 37.5% in the controls (P > 0.1; t = 1.6). Positive lung X-ray changes as resolved infiltration, the reduction and closure of caverns were more pronounced in the patients of the experimental group. The most characteristic change in the parameters of cellular immunity during kipferon was a short (as long as 1-1.5 months) decrease in RBT to FGA, which was noted in 47% and 6.7% of patients in the experimental and control groups, respectively (P < 0.01) and which was followed by an increase in the count of CD8+ cytotoxic lymphocytes. This is indicative of the enhancement of these mechanisms of immunity and a reduced need of enhancing or maintaining the activity of proliferative reactions of immunocompetent cells under the conditions of a favourable influence on the course of tuberculous infection.

[Mycobacterial antigens and tuberculosis antibodies in the blood and pleural exudate of patients with tuberculous pleurisy]. / Antigeny mikobakterii i protivotuberkuleznye antitela v krovi i plevral'nom ékssudate u bol'nykh tuberkuleznym plevritom.

To enhance the efficiency of treating tuberculous pleurisy, a complex of therapeutical measures was supplemented by the immunomodulator licopid in 51 patients. The control group included 52 patients with pleurisy who received the same treatment regimen without licopid. Comparing the outcomes of treatment has revealed that licopid reduced the time of treatment, promotes the substantial diminution of antigenemia and the production of tuberculosis antigens, improves cell immunity and natural resistance.

[Immunology of tuberculosis: current status]. / Immunologiia tuberkuleza: sovremennoe sostoianie problemy.

The paper outlines the high-priority trends in basic and applied investigations of antituberculous immunity. It presents the results obtained from studies of the genetic mechanisms responsible for the control of susceptibility in experimental tuberculosis, from analyses of novel chemical and recombinant tuberculosis vaccines, from examinations of the role of immunological memory in the disease. While describing the results of tuberculosis immunodiagnosis, particular emphasis is laid on its major aspects: on the differential diagnosis of tuberculosis and other lung diseases and on the screening of high-risk group populations for disease progression in order to made further in-depth studies. Current aspects of evaluating the immune status and nonspecific responsiveness in patients with tuberculosis are considered.

[Improving the efficacy of tuberculosis immunodiagnosis using anti-human IgG monoclonal antibodies]. / Povyshenie éffektivnosti immunodiagnostiki tuberkuleza putem primeneniia monoklonal'nykh antitel protiv IgG cheloveka.

Monoclonal antibodies (MAb) F5 to human IgG were used for creating immunoperoxidase conjugate. MAb dissociation constant was 10(-9)M-1 and the number of binding sites 1. Enzyme immunoassay (EIA) and immunoblotting showed that MAb F5 specifically recognize conformation epitope on intact human IgG molecule but not on other human immunoglobulins or denatured IgG. The resultant peroxidase conjugate with MAb F5 was used for EIA titration of antibacterial antibodies in sera from 30 patients with pulmonary tuberculosis, 28 patients with nonspecific pulmonary diseases (bronchitis and/or asthma, pneumonia), and 12 donors. For comparison similar studies were carried out with reference commercial immunoperoxidase conjugate to human IgG(H + L) manufactured at N. F. Gamaleya Institute of Epidemiology and Microbiology. Mycobacterium tuberculosis monoantigen (mol. weight 15-18 kD), affinity isolated by antibacterial MAb S4C1G4 (alpha S4C1G4), and PPD (Batch RT 45, Stattens Seruminstitut, Denmark) were used. Sensitivity and specificity of serum antibacterial antibodies were compared. The specificity of conjugate based on MAb F5 with monoantigen alpha S4C1G4 was 78.21%, sensitivity 94.50%, while those of conjugate to human IgG(H + L) were 53.30 and 76.89%, respectively (p < 0.001). For PPD the specificity and sensitivity were 56.75 and 72.33%, respectively (conjugate with MAb F5) versus 47.67 and 62.38% for conjugate against IgG(H + L), p < 0.001. Similar values were obtained in assessment of the concentrations of antibodies to alpha S4C1G4 for MAb F5 conjugate: specificity and sensitivity 47.16 and 71.56%, respectively, versus 23.67 and 95.16% for PPD (p < 0.05). No statistically significant differences between the experimental groups were detected with IgG(H + L) conjugate. We believe that specific MAb-based conjugate to human IgG will improve the efficacy of EIA as a method for the diagnosis of pulmonary tuberculosis.

[Specific features of cellular immunity of pulmonary tuberculosis in patients with diabetes mellitus]. / Osobennosti kletochnogo immuniteta pri tuberkuleze legkikh u bol'nykh sakharnym diabetom.

The parameters of cellular immunity were studied in 64 patients with pulmonary tuberculous developed in the presence of type 1 diabetes mellitus and compared with those in 36 patients with pulmonary tuberculosis alone. Patients with concomitant abnormalities showed higher depression of cellular immunity appeared as fewer T lymphocytes and their decreased capacity for blast-cell transformation than those with tuberculosis alone. Immunological parameters became normal only due to complex chemo- and immunotherapies (with T-activin). In addition, treatment outcomes improve and more rapid and frequent abacillation occurs. The development of tuberculosis in patients with diabetes mellitus is an additional indication for immunostimulant therapy with T-activin.

[The activity of immunocompetent cells and macrophages in pulmonary sarcoidosis (in comparison to tuberculosis)]. / Aktivnost' immunokompetentnykh kletok i makrofagov pri sarkoidoze legkikh (v sravnenii s tuberkulezom).

Composition of immunocompetent cells and production of cytokins (IL-1, IL-2, IL-6 and PNO) by stimulated and nonstimulated cells of blood and bronchoalveolar lavage (BAL) were evaluated in 35 and 25 sarcoidosis and tuberculosis patients, respectively. Comparable differences were recorded in concentration of T-cells and T-helpers versus BAL in sarcoidosis and tuberculosis as well as in intensity of cytokin production by mononuclears obtained from various sources.

[The immunomodulating action of cyclosporin A in vitro and in vivo on the lymphocytes of patients with alveolitis]. / Immunomoduliruiushchee deistvie tsiklosporina A in vitro i in vivo na limfotsity bol'nykh al'veolitami.

The paper presents the first results of using cyclosporin A (CsA) to treat lymphocytes during their extracorporeal immunomodulation (EIL) in patient with fibrotic alveolitis of various etiology. Two-hour lymphocytic incubation in the medium containing 0.1-10 micrograms per ml of CsA was sufficient for CsA to show its in vitro immunosuppressive effect, which resulted in a substantial inhibition of a proliferative lymphocytic response to mitogens and antigens. Administration of CsA-treated lymphocytes induced no profound structural changes in lymphocytic subpopulations (CD3, CD4, CD8), but it was followed by a reduction in the baseline high proliferative lymphocytic response to PHA. The clinical effect, alveolitis alleviation was noted in all patients. It is suggested that clinical effects may be produced by a local concentration of the treated lymphocytes and their transferred CsA as well.

[Cytokines in tuberculosis]. / Tsitokiny pri tuberkuleze.

The paper presents the data available in the literature and the authors' own findings concerning the production of cytokines, such as interleukins 1, 2, 4, 6, and 8, interferons and tumor necrosis factor, in patients with different stages of tuberculosis. A relationship between the production rate of some cytokines and the stage of the disease, the extent of the process, chemotherapeutical efficiency and other clinically important factors is discussed. The prospects of further investigations in this area are dealt with.

[Tuberculin-BCG therapy in combined treatment of patients with pulmonary tuberculosis]. / Tuberkulin-BTsZh-terapiia v kompleksnom lechenii bol'nykh tuberkulezom legkikh.

The efficacy of combined use of tuberculin and BCG vaccine (tuberculin-BCG-therapy) given to 70 patients with new-onset and recurrent pulmonary tuberculosis was compared to that of BCG treatment only received by 24 patients. Bacterial discharge and caverns were registered in 80 and 78 patients, respectively. 25 patients underwent stimulating, 37, 8 paradoxical tuberculin-BCG-therapy. BCG vaccine (1-4 injections) was given 2 weeks after the course of individual tuberculin therapy with the low efficacy of the latter. Tuberculin-BCG-therapy produced marked response in 52 patients against 11 responses on BCG only, increased the number of T-lymphocytes and T-helpers. It is concluded that the above combination improves regulation of an immune response by cellular mechanisms.

[Cytokines in immunopathogenesis of pulmonary tuberculosis]. / Tsitokiny v immunopatogeneze tuberkuleza legkikh.

Production of IL-1, IL-2, gamma-interferon and PNO was measured in 46 patients with various forms of pulmonary tuberculosis. Cytokins quantitation was conducted biologically, using radioimmunoassay and enzyme immunoassay in supernatants of cellular structures (blood lymphocytes). There were high levels of IL-1 and PNO, reduced production of IL-2 and gamma-IFN by stimulated blood mononuclears. In effective chemotherapy (3-4 months) production of IL-1 tented to a decline, while that of IL-2 and gamma-IFN went up.