クリプトコッカス感染とＴｈ １‐Ｔｈ ２サイトカインバランス

Abstract

Cryptococcus neoformans, a ubiquitous fungal pathogen, causes a life-threatening infection in patients with AIDS. Host defense to this pathogen is mediated by cellular immunity, which receives a critical regulation by a balance between Th 1 cytokines, such as IFN-γ, and Th 2 cytokines, including IL-4 and IL-10. Overproduction of Th 1 cytokines relative to Th 2 cytokines protects host against this microbe, while shifted balance toward Th 2 cytokines is related to exacerbation of this infection. This balance is controled by IL-12 secreted by macrophages. In the present study, using a murine model of pulmonary and disseminated infection with C. neoformans, we demonstrated the shifted balance between these two categories of cytokines toward Th 2-dominant state in lung, which resulted in the uncontroled infection. Interestingly, IL-12 treatment altered this balance toward Th 1-dominant condition and protected animals from the fatal infection. We also demonstrated the failure of mononuclear leukocytes-trafficking chemokines, including RANTES, MCP-1, MIP-1 α, β and IP-10, to be produced, which resulted in poor infiltration of protective inflammatory leukocytes in lung after infection with C. neoformans. IL-12 treatment induced marked accumulation of these cells through production of the above chemokines. Finally we showed the suppressive effects of C. neoformans on IL-12 production by macrophages stimulated with LPS and IFN-γ. These results suggested that C. neoformans may suppress the induction of Th 1 responses by inhibiting macrophage IL-12 production. This mechanism may allow the fungal pathogen to evade the host defense system.