| Co-Investigator(Kenkyū-buntansha) |
OHNISHI Tomokazu Kagoshima University, Graduate School of Medical and Dental Sciences, Associate Professor, 大学院医歯学総合研究科, 助教授 (30244247)
KAKIMOTO Kyoko Kagoshima University, Graduate School of Medical and Dental Sciences, Research Associate, 大学院医歯学総合研究科, 助手 (40274849)
BANDOW Kenjiro Kagoshima University, Graduate School of Medical and Dental Sciences, Research Associate, 大学院医歯学総合研究科, 助手 (50347093)
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| Budget Amount *help |
¥15,500,000 (Direct Cost: ¥15,500,000)
Fiscal Year 2006: ¥7,300,000 (Direct Cost: ¥7,300,000)
Fiscal Year 2005: ¥8,200,000 (Direct Cost: ¥8,200,000)
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| Research Abstract |
Elucidation of molecular mechanisms of Thl/Th2 differentiation is important for the identification of new therapeutic molecular targets for diseases such as infections, cancers, autoimmune diseases, and allergy. In this study, we mainly analyzed two regulatory mechanisms of Thl/Th2 differentiation: 1)JNK activity in helper T cells, 2)TLR signal transduction in antigen-presenting cells (APC). MKP-M, a JNK-specific MAPK phosphatase, is weakly expressed in naive Th cells, and the MKP-M expression significantly increased when they differentiate into Th2-type cells. We used T cell-specific MKP-M Tg mouse as well as in vitro experimental models such as adenoviral transduction of MKP-M, and demonstrated that MKP-M is functionally important as a driving force toward Th1-type cells. We also found that T cell-specific Tg mouse of MKP-M DN mutant is Thl-cominant in Ag-specific immune responses and may be a good animal model of primary biliary cirrhosis (PBC).
Major findings:
1. We have established
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T cell-specific Tg mice of both WT and DN MKP-M. A strain of DN MKP-M Tg showed an intrathymic T cell development arrest. We used the other DN Tg strains and WT Tg strains as well as normal C57BL/6 mice for assays. On sensitization with OVA, MKP-M WT Tg mice showed increased IL-4 and OVA-specific IgGl/IgE in their sera. In contrast, MKP-M DN Tg mice showed increased OVA-specific IgG2a and IFNy. Thus, MKP-M plays an essential role in Thl/Th2 control in vivo.
2. We immunized T cell specific DN MKP-M Tg mice, which is Thl-dominant, and control C57BL/6 mice with pyruvate dehydrogenase complex (PDC)-E2. After immunization, DN MKP-M Tg mice temporarily developed ascites. On histological analyses, non-suppurative destructive cholangitis (NSDC) was found in livers of DN MKP-M Tg mice, but not in livers of the control mice, after immunization. Furthermore, some of the DN MKP-M Tg mice spontaneously developed anti-mitochondrial antigen (AMA) in their sera. Thus, DN MKP-M Tg mice may be good animal model for PBC.
3. We have revealed important roles of TLR4 in mouse infection models of P. carinii.
4. We also found that MKP-M is expressed well in osteoblasts and that its expression changes during the course of osteoblastie differentiation. Less
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