Th2 cells and GATA-3 in asthma: new insights into the regulation of airway inflammation
Th2 cells and GATA-3 in asthma: new insights into the regulation of airway inflammation
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DOI：
10.1172/jci8204
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发表时间：
1999-10-01
影响因子：
15.9
通讯作者：
Cohn, L
中科院分区：
文献类型：
--
作者：
Ray, A;Cohn, L
前景研究。尽管对人类的研究强调了Th 2细胞与哮喘的关联，但动物研究显示了因果关系。许多研究表明，嗜酸性气道炎症和AHR依赖于CD 4 + T细胞（1，12）。此外，从抗原诱导的AHR动物中过继转移CD 4 + T细胞导致气溶胶激发的受体小鼠的气道炎症和高反应性（20）。最近显示了Th 2细胞刺激哮喘特征的能力。当抗原特异性Th 1或Th 2细胞在体外产生，转移到受体小鼠中，并在呼吸道中被吸入抗原激活时，Th 2细胞诱导气道嗜酸性粒细胞增多、粘液分泌过多和AHR（2，21）。Th 1细胞导致嗜中性粒细胞占主导地位的炎症反应，而没有任何哮喘的特征。因此，Th 2细胞可以激活炎症途径，导致气道炎症和AHR后，短期暴露于抗原。还发现个体Th 2细胞因子的组成性产生诱导哮喘样综合征。在气道上皮中过表达Th 2细胞因子-IL-4、IL-5、IL-13和IL-9的转基因小鼠在气道中表现出常见的炎症特征，包括嗜酸性粒细胞增多和粘液过度产生。过表达IL-13、IL-9和IL-5的转基因小鼠在气道中显示AHR和胶原沉积，表明长期暴露于Th 2细胞因子也可诱导气道重塑（参见Elias等人在本系列中的文章）。因此，似乎Th 2细胞的活化足以诱导炎症和与哮喘相关的慢性病理变化。动物研究已经证明了单个Th 2细胞因子如何控制哮喘炎症反应的不同特征。IL-5的产生对于气道嗜酸性粒细胞增多是必不可少的（12），在某些情况下，AHR依赖于嗜酸性粒细胞增多（1）。最近的研究表明，Th 2细胞诱导AHR、嗜酸性粒细胞增多和粘液产生需要通过IL-4 R进行信号传导（1）。这似乎主要反映了IL-13在这些过程中的作用（22，23），因为在不存在IL-4的情况下，AHR、肺嗜酸性粒细胞增多和粘液产生仍然可以被诱导（2，21）。在没有IL-13的情况下，IL-4是否也能刺激这些哮喘现象尚未显示。IL-4对于Th 2细胞诱导至关重要，并且IL-4可能是Th 2细胞在肺中体内持续存在所必需的（24）。Th 2细胞因子可以在动物中诱导一系列类似于人类哮喘的病理生理变化。但是，IL-4、IL-5和IL-13的产生并不限于CD 4 + T细胞。事实上，CD 8+和γ/δ T细胞、嗜酸性粒细胞、肥大细胞和嗜碱性粒细胞都显示出产生这些细胞因子。在所有这些炎性细胞中，CD 4 + T细胞通常在呼吸道中以较高的数量存在，从而解释了为什么在许多哮喘动物模型中病理生理异常依赖于CD 4 + T细胞。但是，在某些动物系统中，嗜酸性粒细胞、肥大细胞和CD 8或γ/δ T细胞已被证明有助于气道炎症和AHR（25，26）。不同的动物品系或诱导气道炎症的方法的变化可能会加重一种细胞类型或另一种细胞类型的影响。因此，这些不同的结果可能表明，在一个特定的动物模型中的炎症的后果取决于一个非CD 4 + T细胞，是贡献Th 2细胞因子。目前似乎清楚的是，Th 2细胞因子的分泌对于哮喘动物模型中特征性气道炎症的诱导至关重要。
Perspective studies. Whereas investigations in humans highlight an association of Th2 cells and asthma, animal studies show cause and effect. Many studies have shown that eosinophilic airway inflammation and AHR are dependent upon CD4+ T cells (1, 12). In addition, adoptive transfer of CD4+ T cells from animals with antigeninduced AHR resulted in airway inflammation and hyperresponsiveness in aerosol-challenged recipient mice (20). The ability of Th2 cells to stimulate the characteristic features of asthma was recently shown. When antigen-specific Th1 or Th2 cells were generated in vitro, transferred into recipient mice, and activated in the respiratory tract with inhaled antigen, Th2 cells induced airway eosinophilia, mucus hypersecretion, and AHR (2, 21). Th1 cells resulted in a neutrophil-predominant inflammatory response without any of the characteristic features of asthma. Thus, Th2 cells can activate inflammatory pathways that result in airway inflammation and AHR after short-term exposure to antigen. Constitutive production of individual Th2 cytokines has also been found to induce an asthma-like syndrome. Transgenic mice that overexpress the Th2 cytokines—IL-4, IL-5, IL-13, and IL-9—in the airway epithelium exhibit common inflammatory features in the airways, including eosinophilia and mucus overproduction. Transgenic mice that overexpress IL-13, IL-9, and IL-5 showed AHR and collagen deposition in the airways, indicating that chronic exposure to Th2 cytokines can also induce airway remodeling (see article by Elias et al. in this series). Therefore, it appears that activation of Th2 cells is sufficient for the induction of inflammation and the chronic pathologic changes associated with asthma. Animal studies have now demonstrated how individual Th2 cytokines control different features of the inflammatory response in asthma. IL-5 production is essential for airway eosinophilia (12), and, in some cases, AHR depends on eosinophilia (1). Recent studies have shown that the induction of AHR, eosinophilia, and mucus production by Th2 cells requires signaling through IL-4R (1). This appears predominantly to reflect the role of IL-13 in these processes (22, 23), because in the absence of IL-4, AHR, lung eosinophilia, and mucus production can still be induced (2, 21). Whether IL-4 can also stimulate these asthmatic phenomena in the absence of IL-13 has not yet been shown. IL-4 is critical for Th2 cell induction, and IL-4 may be required for the persistence of Th2 cells in vivo in the lung (24). Th2 cytokines can induce a constellation of pathophysiologic changes in animals that resemble human asthma. But, the production of IL-4, IL-5, and IL-13 is not exclusive to CD4+ T cells. In fact, CD8+ and γ/δ T cells, and eosinophils, mast cells, and basophils have all been shown to produce these cytokines. Of all of these inflammatory cells, CD4+ T cells are typically present in higher numbers in the respiratory tract, thus explaining why the pathophysiologic abnormalities depend on CD4+ T cells in many animal models of asthma. But, in certain animal systems, eosinophils, mast cells, and CD8 or γ/δ T cells have been shown to contribute to airway inflammation and AHR (25, 26). Different animal strains or variations in methods for induction of airway inflammation may accentuate the effects of one cell type or another. Thus, these divergent results may indicate that the consequences of inflammation in a particular animal model depend on a non-CD4+ T cell that is contributing Th2 cytokines. What appears to be clear at present is that the secretion of Th2 cytokines is critical for the induction of the characteristic airway inflammation in animal models of asthma …