[Up-to-date understanding of tuberculosis immunity]

This symposium was organized to provide the up-to-date knowledge on tuberculosis immunity, especially on the understanding of cytokines or Th1 cells involved in pathophysiology/protective immunity and vaccine development. Dr. Kazuo Kobayashi (Osaka City Univ.) reported their findings on the immune response to bioactive lipid component from M. tuberculosis, trehalose-dimycolate (TDM) and sulfolipid (SL) in mice. Their unique and novel finding was that TDM is capable of inducing T-dependent immune response in euthymic mice. The specific immune response in TDM-immune mice was consisting of CD4+ cell response and expression of chemokines, inflammatory cytokines and then TH1-related cytokines. In contrast, SL did not show such an activity. TDM may be one of the protective antigens and may modulate the specific immune response of the host. Dr. Isamu Sugawara's group (JATA) has examined the involvement of various cytokines in the host response to aerosolic infection with virulent strain of M. tuberculosis by using cytokine-knockout mice. The single deletion of IFN-gamma or TNF alpha resulted in a severe lesion of multiple necrosis without granuloma, and cytokine mRNA level other than knocked out cytokine was normal, suggesting that IFN-gamma and TNF alpha are principally important cytokines. In knockout mice for IL-12 or IL-18, necrotic lesion was not induced after infection and the pathological change was not so significant as in IFN-gamma/TNF alpha knockout mice. By using IFN-gamma knockout mice, it became possible to generate a granulomatous lesion with central necrosis and cavity resembling the lesion in humans. These mouse model appeared to be useful in the analysis of pathophysiology of human tuberculosis. Dr. Kazuyoshi Kawakami (Ryukyu Univ.) reported the importance of TH1 cytokines in anti-tuberculous immunity. By using IL-12, IL-18 knockout mice or double knockout mice, it was shown that IL-12 exhibits more important role than IL-18 in the protection. A possible contribution of IL-23 was also suggested. In most of the clinical cases of tuberculosis, the production of IL-12, IL-18 and IFN-gamma is increased, however, the group of relatively lower cytokine production did not respond well to the treatment. In addition, the plasma level of one of the chemokines, IP-10, was shown to be an indicator for the severity of the disease. Thus, some cytokines appear to be employable for the novel treatment in the near future. Dr. Saburo Yamamoto (NIH) summarized the recent advance in the understanding of biological function of CpG motifs. Immunostimulatory DNA is effective in the modulation of TH1/TH2 polarity and the enhancement of protective immunity to M. tuberulosis in animals. CpG motif (immunostimulatory DNA) appears to exert its activity by signaling cascade via TLR9 resulting in NF-kappa B activation and cytokine gene expression. Analysis of basic mechanism of action by CpG motif should pave the way to the clinical application in the future. Dr. Masaji Okada (Kinki Chuo Hospital) reported the current situation in the development of novel vaccines against tuberculosis. They have extensively constructed and examined the efficacy of various types of vaccines including subunit, DNA and recombinant BCG vaccines. Various vector systems have been tested for DNA vaccine. As immunizing antigens, a-Ag, ESAT-6, HSP65, 38kD-lipoprotein and so on have been employed. A large body of experimental data are accumulating for final evaluation, and among them, it is noteworthy to mention that HSP65DNA + IL-12DNA was 100 times more effective than conventional BCG in animal model. Among subunit vaccines, Mtb72f vaccine appears to be one of the promising candidates. In addition to the trial with various candidates, they have established a new mouse model, SCID/human PBL. This model animal has been employed for the development of vaccine effective for the induction of ESAT-6-specific human T cells.