|Budget Amount *help
¥2,500,000 (Direct Cost : ¥2,500,000)
Fiscal Year 1999 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1998 : ¥1,000,000 (Direct Cost : ¥1,000,000)
Fiscal Year 1997 : ¥1,000,000 (Direct Cost : ¥1,000,000)
We have studied on the mechanism of cytokine-based regulation for host defense against cryptococcosis using a murine model of pulmonary and disseminated infection. We demonstrated that imbalance of Th1-Th2 cytokine production was well associated with the fatal outcome of infection: that is, in infection with a highly virulent strain of C. neoformans, Th2 cytokine production was dominant over Th1 in the primary infection site and these mice all died with 6 weeks post-infection, while IL-12 treatment saved them by converting the imbalanced cytokine synthesis to Th1-dominant condition. Interestingly, this strain suppressed the IL-12 production but did not or rather enhanced the synthesis of IL-10 by macrophages, which may suggest the involvement of this mechanism in the shifted cytokine balance toward Th2 predominant condition.
Furthermore, in the fatal infection model, CC chemokines, such as MCP-1, RANTES, MIP-1α and MIP-1β, and IP-10, a CXC chemokine, all of which are important for the t
rafficking of lymphocytes and macrophages were poorly produced in lungs. Compatibly, the accumulation of inflammatory leukocytes composing of lymphocytes and macrophages was found very poor. IL- 12 treatment induced the marked accumulation of lymphocytes and macrophages and formation of multinuclear giant cells in the lungs, which was well consistent with the production of these mononuclear leukocyte-trafficking chemokines.
In our recent study, we have demonstrated the essential role for IL-12 and IL-18 in host defense against cryptococcal infection using IL-12, IL-18 and IL-12/IL-18KO mice. In these mice, IFN-γ synthesis and host resistance and DTH response to the microorganism were impaired compared to those in wild-type mice. The impairment was more profound in IL-12KO mice than in IL-18KO mice. In IL12/IL-18KO mice, IFN-γ production was almost completely abrogated and host defense was as profoundly impaired as in IFN-γKO mice. Compatibly with these results, treatment with either IL-12 or IL-18 increased the host protection against fatal infection with C. neoformans. Such activity was greater in the former cytokine than in the latter. Combined treatment with these two IFN-γ-inducing cytokines synergistically induced the production of IFN-γ and potentiated the host resistance to this pathogen both in in vitro and in vivo studies.
In our other studies, we firstly demonstrated that host defense to Penicillium infection was mediated by cellular immunity. We showed that nude mice were highly susceptible to the infection with P. marneffei and that adoptive transfer of T cell-enriched spleen cells from normal mice rendered nude mice resistant to this infection. Furthermore, we demonstrated that fungicidal activity of murine macrophages was mediated by nitric oxide, not by superoxide anion and that such activity of human neutrophils was potentiated by various cytokines, such as GM-CSF, G-CSF, IL-8. TNF-γ and IFN-γ and the GM-CSF effect, which was most potent, was mediated by granular enzymes, not by oxygen radicals. Less