| Budget Amount *help |
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1996: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1995: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Research Abstract |
This study has deatl with the roles of immunosuppressive cytokines including IL-10 and TGF-beta in the initiation and the progression of bacterial regrowth at the sites of infection due to Mycobacterium avium complex (MAC), one of the representative atypical mycobacteria, induced in mice and, moreover, the roles of immunosuppressor macrophages (Mphis) induced in the relatively early phase (weeks 2 to 3) of infection in the establishment of persistent MAC infected mice in host mice. The following results were obtained. (1) In MAC infection in which the bacterial regrowth was initiated from weeks 2 to 4 after infection, the tissue levels of TNF-alpha, IL-10, and IFN-gamma in the lungs and spleens were temporarily elevated around weeks 2 to 4, while the TGF-beta levels in the spleen remained high during weeks 4 to 8. The transient increase in the cytokine levels was blocked by rifamycin-treatment of host mice. (2) When murine peritoneal or splenic Mphis were infected with the MAC organism
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s, the increase in Mphi production of TNF-alpha, IL-6, and IL-10 was seen during the first 3-day cultivation, whereas TGF-beta production was observed in much later phase of cultivation such as during days 7 to 14. The expression of mRNA encoding these cytokines was observed during 2 to 6 h after Mphi stimulation with the MAC.(3) TNF-alpha and IFN-gamma were found to participate in the in-vivo induction of the immunosuppressive Mphis in MAC-infected mice and play an important role in the experssion of their suppressor function against T cell mitogenesis, by enhancing Mphi production of certain effector molecules including prostaglandin E,reactive nitrogen intermediates, and phospholipids. (4) The blocking experiments using anti-IL-10 and anti-TGF-beta antibodies showed that the TNF-alpha-mediated expression of an adhesion molecule ICAM-1 in MAC-infected Mphis observed during days 1 to 3 after the initiation of Mphi cultivation was down-regulated by IL-10 and TGF-beta produced by the Mphis themselves in an autocrine fashion. These findings indicate important roles of immunosuppressive cytokines in progression of MAC infection in hosts. Less
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