| Co-Investigator(Kenkyū-buntansha) |
INOUE Yoshitsugu Tottori University, Faculty of Medicine, Professor, 医学部, 教授 (10213183)
BABA Takashi Tottori University, Faculty of Medicine, Research Associate, 医学部, 助手 (40304216)
KAKIMARU Akiko Tottori University, Faculty of Medicine, Research Associate, 医学部, 助手 (50379624)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2004: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
The immune response is regulated, in part, by effector cells whose activation requires multiple signals. For example, T cells require signals emanating from the T-cell antigen receptor and costimulatory molecules for full activation. We present evidences indicating that immunoglobulin E (IgE)-mediated hypersensitivity reactions in vivo also require cognate signals to activate mast cells, and explored the signaling cascades to search for therapeutic targets.
First, we evaluated contribution of mast cells in immediate hypersensitivity reactions of allergic conjunctivitis model by adoptive transfer approaches. Second, we established isolation/culture condition of conjunctiva-derived connective tissue type mast cells expressing relevant maturation markers, and found associated expression of CCR1, CCR2, CCR3, CCR5, and CXCR3. Of these markers, we found CCR3 as well as CCR1 are critical as cognate signals in vitro and in vivo. Immediate hypersensitivity reactions in the conjunctiva are ablate
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d in mice deficient in eotaxin-1 or MIP-1α, despite normal numbers of tissue mast cells and levels of IgE. To further define the co-stimulatory signals mediated by CCR3, an eotaxin-1 receptor, effects of CCR3 blockade were tested with an allergic conjunctivitis model, and in ex vivo isolated connective tissue type mast cells. CCR3 blockade significantly suppressed allergen-mediated hypersensitivity reactions as well as IgE-mediated mast cell degranulation. Our results suggested that a costimulatory axis by CCR3, mainly stimulated by eotaxin-1, is pivotal in mast cell-mediated hypersensitivity reactions. Third, using small molecular antagonist of CCR3, molecular events in acute phase reactions were analyzed by whole genome scanning. Network analysis showed that early signaling events are summarized in pathways of MAPK, PI3Kinase, and NFκB pathways. Using isolated connective tissue type mast cells, therapeutic candidate genes, predicted by these analyses, have currently been examined for contribution to IgE-mediated degranulation or cytokines induction. Less
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