[Analysis of host defense mechanism against mycobacterial infection and its application to therapy with biological response modifiers].

Recently, tuberculosis have been increasing among the immunocompromised patients. In patients with acquired immunodeficiency syndrome (AIDS), multi-drug resistant mycobacteria are often detected, which make the therapy difficult. In these patients, chemotherapy alone is often insufficient and some treatment to augment their host defense activity has been desired. Therefore, to know the host defense mechanism against mycobacterial infection will be helpful to develop an adjuvant therapy for intractable tuberculosis. In this study, IFN-gamma mRNA was induced in murine lungs after mycobacterial infection, and anti-IFN-gamma monoclonal antibody (mAb) prevented the activation of pulmonary intraparenchymal macrophages by M. bovis BCG and the elimination of M. tuberculosis from lungs. In addition, this mAb inhibited the activation of Mac1+CD4-CD8- T cells bearing alpha beta antigen receptor by BCG, which were found in murine lungs and might be involved in the host defense mechanism against mycobacterial infection, and administration of IFN-gamma significantly increased this population in lungs. Thus, IFN-gamma was suggested to be a candidate cytokine for the treatment of intractable tuberculosis. Next, CD4+ T cell-depleted mice were prepared by injecting anti-CD4 mAb and used as an immunocompromised model. When infected with M. tuberculosis, the multiplication of the bacilli within the lungs of such immunocompromised mice was much more enhanced in comparison with the control mice with intact CD4+ T cells. Administration of IFN-gamma significantly reduced the number of the bacilli in lungs. Further, in an in vitro study with human lung macrophages, IFN-gamma enhanced the killing activity of macrophages against M. tuberculosis in a dose dependent manner, and suboptimal dose of 1 alpha, 25-dihydroxyvitamin D3 synergistically augmented the effect of IFN-gamma.