Establishment of Novel (DNA-recombinant BCG-, and fusion protein-)vaccination against Tuberculosis and analysis of novel differentiation mechanism of cytotoxic T cell

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〔Abstract〕1.The production of cytotoxic T cell differentiation factors (IL-6,IL-2,and IFN-Y,) were inhibited in the culture supernatants from patients with tuberculosis. Furthermore, it was demonstrated that the expression of granulysin (cytotoxic protein against tuberculosis) protein in CD3^+ CD8^+ CTL from TB patients was suppressed in comparison with the granulysin expression on CD8^+ CTL from healthy volunteers.2.Two novel TB vaccines ; a DNA vaccine combination expressing mycobacterial heat shock protein 65(HSP65) and interleukin-12(IL-12) by using the hemagglutinating virus of Japan(HVJ)-liposome (HSP65+IL-12/HVJ), have been developed. These vaccines provide remarkable protective efficacy in mouse and guinea pig models, as compared to the current by available BCG vaccine.HSPGS DNA+IL-12 DNA vaccination were 100 fold more efficient than parental BCG Tokyo vaccination, on the elimination of M. TB in lungs, liver, and spleen of BALB/c mice. In the present study, our studies were extended to a cynomolgus monkey model, which is currently the best animal model of human tuberculosis, to evaluate the HSP65+IL-12 vaccine. Vaccination with HSP65+IL-12 DNA provided better protective efficacy as assessed by the Erythrocyte Sedimentation Rate, chest X-ray findings, body weight and immune responses (IFN-y, IL-2, IL-6 production, and lymphocyte proliferation of cynomolgus monkey), than BCG. Most importantly, HSP65+IL-12 DNA vaccine resulted in an increased survival for over a year. This is the first report of successful DNA vaccination against M. tuberculosis in the monkey model.