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Murine models of pulmonary diseases induced by adoptive transfer of T cell clones.

T 细胞克隆过继转移诱导的肺部疾病小鼠模型。

基本信息

批准号：
05807053
负责人：
YOKOYAMA Akihito
金额：
$ 1.22万
依托单位：
Ehime University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

项目摘要

We could not complete the experiments of above theme, because of some difficulties concerning maintenance of T cell clones. Instead, we report herein the results of fundamental experiments of the study. We have successfully made a murine model of antigen-driven pulmonary eosinophilia. Primed mice (BALB/c, 6-8wk old) with ovualbumin (OVA) and alum (three times, 2-wk interval) were challenged with OVA by inhalation (50mg/ml for 20min, 6 days) , yielded 9x10^5/ml Eo in bronchoalveolar lavage fluids (BALF) at 24-hours after the last challenge. Histological analysis revieled peribronchiolar and perivascular cell infiltration of lymphocytes and eosinophils. Recently, thromboxane A2 (TxA2) synthetase inhibitor (Sl) and receptor antagonist (RA) have been developed for the prophylaxis of bronchoconstriction. These compounds can improve pronchial hyperreactivity, indicating that the points of their action seem to be more than bronchoconstriction. To explore their influence on eosinophil (Eo) infiltration, we treated this model mice with OKY-046 (TxA2 Sl ; 100,10,1mg/kg) and S-1452 (TxA2 RA ; 25,2.5,0.25 mg/kg). Treatment with either compound significantly reduced Eo number in BALF in a dose-dependent manner up to-70% at the highest dose. Although we could detect IL-5 neither in BALF nor serum from untreated mice, the production of IL-5 decreased in culture supernatants of OVA plus spleen cells from treated mice with either compound in a dose-dependent manner up to-75% at the highest dose. The production of both interferon-gamma and IL-2 also significantly decreased. The cell differentials and percentages of CD3,4 or 8-positive splenocytes from treated mice were not significantly different from untreated mice. These results suggest that inhibition of TxA2 may reduce not only bronchoconstrictive response but also pulmonary infiltration of eosinophils by inhibiting cytokines production in vivo.

由于T细胞克隆维持方面的困难，我们未能完成上述主题的实验。相反，我们在此报告的研究基础实验的结果。我们已经成功地建立了抗原驱动的肺嗜酸性粒细胞增多症的小鼠模型。用卵清蛋白（OVA）和明矾（3次，间隔2周）致敏BALB/c小鼠（6- 8周龄），通过吸入OVA（50 mg/ml，持续20 min，6天）进行激发，在最后一次激发后24小时，支气管肺泡灌洗液（BALF）中产生9 × 10^5/ml Eo。组织学分析显示细支气管周围和血管周围有淋巴细胞和嗜酸性粒细胞浸润。近年来，血栓素A2（TxA 2）合成酶抑制剂（S1）和受体拮抗剂（RA）已被开发用于预防支气管收缩。这些化合物可以改善支气管高反应性，表明它们的作用点似乎不仅仅是支气管收缩。为探讨OKY-046（TxA_2S_1; 100、10、1 mg/kg）和S-1452（TxA_2RA; 25、2.5、0.25mg/kg）对Eo浸润的影响。用任一化合物治疗以剂量依赖性方式显著降低BALF中的Eo数量，在最高剂量下高达约70%。尽管我们在BALF和未处理小鼠的血清中均不能检测到IL-5，但在用任一化合物处理的小鼠的OVA加脾细胞的培养上清液中IL-5的产生以剂量依赖性方式降低，在最高剂量下高达~ 75%。干扰素-γ和IL-2的产生也显著降低。处理小鼠的细胞分化和CD 3、4或8阳性脾细胞百分比与未处理小鼠无显著差异。这些结果表明，抑制TxA 2不仅可以减少支气管收缩反应，而且可以通过抑制细胞因子的产生来减少嗜酸性粒细胞的肺浸润。