Transforming growth factor-β secreted from CD4+ T cells ameliorates antigen-induced eosinophilic inflammation -: A novel high-dose tolerance in the trachea
Transforming growth factor-β secreted from CD4+ T cells ameliorates antigen-induced eosinophilic inflammation -: A novel high-dose tolerance in the trachea
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DOI：
10.1165/ajrcmb.21.2.3576
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发表时间：
1999-08-01
影响因子：
6.4
通讯作者：
Shirato, K
中科院分区：
文献类型：
--
作者：
Haneda, K;Sano, K;Shirato, K
诱导外周耐受是控制自身免疫和过敏的可行途径之一。肠道内的耐受性诱导已经得到了广泛的研究，治疗自身免疫的应用也在进行中，而呼吸道内的耐受性研究却很少。我们研究了逃避小鼠气道黏膜过度炎症反应的免疫调节机制。对气管给予最佳剂量的卵清蛋白（OVA）可引起OVA/氢氧化铝致敏BALB/c小鼠气管中的嗜酸性粒细胞炎症，而更高剂量则不能。这种失败与纵隔淋巴结（LN）T细胞产生白细胞介素-4的下调相似。这种高剂量耐受归因于抗原（Ag）特异性抑制机制，因为来自ova耐受小鼠的CD4(+) LN T细胞过继转移抑制了ova特异性，但不相关的Ag klh特异性嗜酸性反应。气管内给予抗转化生长因子(TGF)- β可中和这种抑制作用，但抗干扰素(IFN)- γ单克隆抗体不能中和这种抑制作用，这表明高剂量耐受是由分泌的TGF- β介导的，而不是由转移的辅助性T细胞（Th）1优于Th2细胞介导的。tgf - β的关键作用通过发现ova耐受小鼠的LN细胞对体外Ag刺激产生tgf - β而得到加强。这些结果证明了气道中的一种新的调节机制：T细胞分泌的tgf - β在降低对高剂量银的免疫反应中起重要作用，否则可能会引起气道粘膜组织的有害炎症。
The induction of peripheral tolerance is one of the feasible approaches for the control of autoimmunities and allergies. Tolerance induction in the intestine has been studied extensively and therapeutic applications to autoimmunities are in progress, whereas tolerance in the respiratory tract is poorly investigated. We examined the immunoregulatory mechanisms for evading exaggerated inflammatory responses in the murine airway mucosa. Administration of an optimal dose of ovalbumin (OVA) to the trachea elicited eosinophilic inflammation in the trachea of OVA/aluminum hydroxide-sensitized BALB/c mice, whereas higher doses were unable to do so. This failure paralleled the downregulation of interleukin-4 production by mediastinal lymph node (LN)T cells. This high-dose tolerance was attributable to the mechanisms of antigen (Ag)-specific suppression, because the adoptive transfer of CD4(+) LN T cells from the OVA-tolerant mice inhibited the OVA-specific, but not irrelevant Ag KLH-specific, eosinophilic responses. The inhibitory effects were neutralized by the intratracheal administration of anti-transforming growth factor (TGF)-beta, but not that of anti-interferon (IFN)-gamma, monoclonal antibodies, indicating that the high-dose tolerance was mediated by secreted TGF-beta, but not by the dominance of transferred T helper (Th)1 cells over Th2 cells. The pivotal role of TGF-beta was reinforced by the finding that the LN cells from the OVA-tolerant mice produced TGF-beta in response to the in vitro Ag stimulation. These results demonstrate a novel regulatory mechanism in the airway: that TGF-beta secreted by T cells plays an important role in the downmodulation of the immune responses to high doses of Ag which might otherwise induce deleterious inflammation in the airway mucosal tissues.