| Co-Investigator(Kenkyū-buntansha) |
HYODOH Fuminori KAWASAKI MEDICAL SCHOOL, SCHOOL OF MEDICINE, DEPARMENT OF HYGINE, ASSISTANT PROFESSOR, 医学部, 講師 (80069070)
NISHIMURA Yasumitsu KAWASAKI MEDICAL SCHOOL, SCHOOL OF MEDICINE, DEPARMENT OF HYGINE, ASSISTANT PROFESSOR, 医学部, 講師 (90360271)
MIURA Yoshie KAWASAKI MEDICAL SCHOOL, SCHOOL OF MEDICINE, DEPARMENT OF HYGINE, RESEARCH FELLOW, 医学部, 助手 (00388935)
高田 晶子 川崎医科大学, 医学部, 助手 (30278957)
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| Budget Amount *help |
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2005: ¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 2004: ¥7,700,000 (Direct Cost: ¥7,700,000)
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| Research Abstract |
Silicosis patients suffer not only from respiratory disorders but also from autoimmune diseases. To clarify the mechanisms involved in the of autoimmunity found in silicosis patients, we have been focusing on Fas and Fas-related molecules in the Fas-mediated apoptotic pathway, since Fas is one of the most important molecules regulating autoimmunity involving T cells. Our findings showed that silicosis patients exhibited elevated serum soluble Fas levels, an increased relative expression of the soluble fas and dcr3 genes in peripheral blood mononuclear cells, high levels if other variant messages of the fas transcript, relatively decreased expression of several physiological inhibitors (survivin and toso), and dominancy of lower membrane Fas expressers in lymphocytes, which transcribe soluble fas dominantly, in comparison with healthy donors. These findings are consistent with known features regarding immunological factors such as serum immunoglobulin G levels and the titer of anti-nucl
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ear autoantibodies in silicosis. In addition, anti-caspase 8 autoantibody and anti-Fas autoantibody were detected in serum from silicosis patients, and a functional assay showed that anti-Fas antibody stimulated Fas-mediated apoptosis. We hypothesize that there are two subpopulations of silicosis lymphocytes. One is a long-term fraction that includes self-recognizing clones showing lower levels of membrane Fas and inhibition of Fas/Fas ligand binding in extracellular spaces. The other is a fraction that exhibits apoptosis caused by silica/silicates, is recruited from bone marrow, shows higher levels of membrane Fas, and is sensitive to anti-Fas autoantibody. Further investigation should be performed to comfirm the effects of silica/silcates on the human immune system.
In addition, too analyze the possibility of immunological alteration in asbestos-related diseases (ARD) such as asbestosis (ASB) and malignant mesothelioma (MM) may affect the progression of cancers, a human adult T cell leukemia virus-immortalized T cell line (MT-2Org) was continuously exposed to 10 10μg/ml of chrysotile-B (CB), an asbestos. After at least 8 months exposure, the apoptosis in the cells became very low and this subline was designated MT-2Rst). The MT-2Rst cells were characterized (i)enhanced expression of bcl-2 with regain of apoptotis-sensitivity by reduction of bcl-2 by siRNA, (ii)excess IL-10 secretion and expression, and (iii)activation of STAT3 with inhibition by PP2, a specific inhibitor of Src family kinases. These results suggested that the contact between cells and asbestos affect human immune system and trigger the cascade ob biological events such as activation of Src family kinases, enhancement of IL-10, STAT3 activation and Bcl-2 overexpression. This supeculation was partially confirmed by elevated bcl-2 expression levels in CD4+ peripheral blood T cells from patients with MM compared with those of ASB or healthy donors. Future study are required to ensure the role of T cells with enhanced bcl-2 expression in tumor progression induced by asbestos exposure. Less
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