| Budget Amount *help |
¥14,100,000 (Direct Cost: ¥14,100,000)
Fiscal Year 2005: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 2004: ¥9,200,000 (Direct Cost: ¥9,200,000)
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| Research Abstract |
Based on the finding that leukotriene B_4 receptor 1 (BLT1) is expressed highly in Th2 lymphocytes, we analyzed the roles of BLT1 using an ovalbumin-induced bronchial asthma model. BLT1-null mice did not develop airway hyperresponsiveness, eosinophilic inflammation and hyperplasia of goblet cells. Attenuated symptoms were accompanied by reduced IgE production, and accumulation of IL-5 and IL-13 in bronchoalveolar lavage fluid, suggesting attenuated Th2-type immune response in BLT1-null mice. Peribronchial lymph node cells of sensitized BLT1-null mice showed much attenuated proliferation and production of Th2 cytokines upon re-stimulation with antigen in vitro. Thus, LTB_4-BLT1 axis is required for the development of Th2-type immune response, and blockade of LTB_4 functions through BLT1 would be novel and useful in the effort to ameliorate bronchial asthma and related Th2-biased immune disorders.
Dendritic cells (DCs) are important antigen-presenting cells that control Th1- and Th2-type
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immunological reactions by releasing cytokines and interacting directly with T cells. We found that BLT1 is expressed in human monocyte-derived DCs and mouse bone marrow-derived DCs (BMDCs). Detailed analyses using BMDCs revealed that BLT1-deficient DCs produced less IL-l2 p70 than WT DCs, leading to attenuated IFN-□ production in an allogeneic mixed lymphocyte reaction. Adoptive transfer of BLT1-deficient DCs into naive WT mice induced a weakened. Th1 response and an enhanced Th2 response in vivo compared to WT DCs. BLT1-deficient mice consistently showed much attenuated delayed-type hypersensitivity (DTH), in which Th1-type cellular responses play a key role, and popliteal lymph node cells of BLT1-deficient mice showed reduced production of Th1 cytokines after DTH induction compared to cells from WT mice. Thus, in addition to its role in inflammation, the LTB4-BLT1 axis is important in initiating Th1-type immunological reactions mediated by DCs.
We characterized G2A receptor, which was reported as a lysophospholipid receptor, as a proton-sensing GPCR. Less
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