title: [Development of a novel recombinant BCG for tuberculosis vaccine].
abstract: A novel recombinant BCG (BCG-DHTM), that was deficient in urease, expressed with gene encoding the fusion of BCG-derived HSP70 and M. tuberculosis-derived major membrane protein (MMP)-II, was constructed for use as a vaccine against tuberculosis. BCG-DHTM efficiently activated dendritic cells (DC) to induce cytokine production, including IL-12, TNFalpha and IL-1beta and phenotypic changes. The DC infected BCG-DHTM was more potent in activation of native T cells of CD4 and CD8 subsets than those infected vector control BCG. The activation of naïve T cells by BCG-DHTM was closely associated with phagomal maturation, and that of naïve CD8+ T cells by BCG-DHTM was induced by the activation of cytosolic cross-presentation pathway. Further, BCG-DHTM seemed to activate native CD4+ T cells and native CD8+ T cells by antigen-specific fashion. The primary infection of BCG-DHTM in C57BL/6 mice for 12 weeks efficiently produced T cells responsive to in vitro secondary stimulation with MMP-II, HSP70 and H37Rv-derived cytosolic protein and inhibited with multiplication of subsequently challenged M. tuberculosis in lungs at least partially. The effect of BCG-DHTM as a vaccine for tuberculosis is not fully convincing and need the improvement, however, our strategy in the development of new recombinant BCG for tuberculosis seems to provide useful tool.
authors.affiliation: Department of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, Tokyo, Japan. mmaki@nih.go.jp
authors.forename: Masahiko
authors.initials: M
authors.lastname: Makino
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000235:genetics* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D015195:Drug Design; D050939:Gene Fusion; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D007918:Leprosy / Q000517:prevention & control; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000235:genetics*; D009169:Mycobacterium tuberculosis / Q000235:genetics*; D011995:Recombination, Genetic; D014376:Tuberculosis / Q000517:prevention & control*; D014614:Vaccines, Synthetic
chemical_list: D001500:BCG Vaccine; D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D014614:Vaccines, Synthetic; C500901:major membrane protein II, Mycobacterium leprae