A putative immunotherapy with biological response modifiers (BRM) against intractable pulmonary tuberculosis

Abstract

The problem of tuberculosis is emerging again with increase in the population of aged people and immunocompromised patients in Japan. It has been well documented that cell-mediated immunity play a central role in host resistance to infection with Mycobacterium tuberculosis. Many recent studies have provided evidences suggesting that the Th1-Th2 cytokine balance may determine the outcome of some diseases: predominant production of Th1 cytokines may prevent the occurrence of infectious diseases caused by intracellularly growing pathogens and Th2 cytokines may be involved in the exacerbation of allergic diseases. On the other hand, IL-12 plays an essential role in the differentiation of Th1 cells from naive T cells, and IL-18 potentiates this effect although it does not show such effect by itself. In previous investigations using gene-disrupted mice, the essential roles for IFN-gamma, IL-12 and IL-18 have been demonstrated. There are several host factors which determines the outcome of mycobacterial infection. Among them, steroid treatment and AIDS are important factors. In this lecture, I addressed the effect of these pathological conditions on Th1-Th2 cytokine balance and outcome of mycobacterial infection using murine models. In both conditions, the exacerbated infection was well correlated with the reduced production of IFN-gamma. Furthermore, I also talked about the relationship between other host factors and balance in the production of Th1 and Th2 cytokines. Using a murine model of fatal infection with M. tuberculosis, we demonstrated the therapeutic effect of Th1-type cytokines against this infection and suggested that immunotherapy with these cytokines may be clinically effective in the intractable infection. We tried a combined therapy with anti-tuberculous agents and IFN-gamma in intractable pulmonary tuberculosis caused by multidrug-resistant pathogen in a patient with insulin-dependent diabetes mellitus. Although no report showing the clinical use of IL-12 in infectious diseases has been seen, clinical trials already commenced for the therapy of malignant neoplastic diseases. It may not be in far future that this cytokine is clinically used for the treatment of infectious diseases. IL-18 has not yet been under the clinical trials.