Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients
Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients
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DOI：
10.1172/jci21759
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发表时间：
2006-01-01
影响因子：
15.9
通讯作者：
Hawrylowicz, CM
中科院分区：
文献类型：
--
作者：
Xystrakis, E;Kusumakar, S;Hawrylowicz, CM
我们之前报道过，在地塞米松和骨化三醇（维生素 D3）的刺激下，人类 CD4+ Tregs 会分泌高水平的 IL-10。我们现在表明，在受到过敏原刺激后，分泌 IL-10 的 Tregs 以 IL-10 依赖性方式抑制过敏原特异性 Th2 细胞的细胞因子分泌。一部分患有严重哮喘的患者在糖皮质激素治疗后未能表现出临床改善，他们的哮喘被描述为糖皮质激素抵抗（SR，源自“类固醇抵抗”的缩写）。地塞米松不会增强 CD4(+) T 细胞分泌 IL-10。在SR CD4(+) T细胞培养物中添加维生素D3和地塞米松可增强IL-10的合成，达到在单独使用地塞米松培养的糖皮质激素敏感患者的细胞中观察到的水平。此外，用 IL-10 预处理可完全恢复这些细胞对地塞米松的反应而合成 IL-10。维生素D3显着克服了地塞米松对糖皮质激素受体表达的抑制，而IL-10上调了CD4+T细胞的糖皮质激素受体表达，这表明这些治疗可能克服糖皮质激素反应性差的潜在机制。我们在此表明，对健康个体和 SR 哮喘患者施用维生素 D3 增强了随后对地塞米松诱导 IL-10 的反应。这强烈表明维生素 D3 可能会增加 SR 患者对糖皮质激素的治疗反应。
We previously reported that human CD4(+) Tregs secrete high levels of IL-10 when stimulated in the presence of dexamethasone and calcitriol (vitamin D3). We now show that following stimulation by allergen, IL-10-secreting Tregs inhibit cytokine secretion by allergen-specific Th2 cells in an IL-10-dependent manner. A proportion of patients with severe asthma fail to demonstrate clinical improvement upon glucocorticoid therapy, and their asthma is characterized as glucocorticoid resistant (SR, abbreviation derived from "steroid resistant"). Dexamethasone does not enhance secretion of IL-10 by their CD4(+) T cells. Addition of vitamin D3 with dexamethasone to cultures of SR CD4(+) T cells enhanced IL-10 synthesis to levels observed in cells from glucocorticoid-sensitive patients cultured with dexamethasone alone. Furthermore, pretreatment with IL-10 fully restored IL-10 synthesis in these cells in response to dexamethasone. Vitamin D3 significantly overcame the inhibition of glucocorticoid-receptor expression by dexamethasone while IL-10 upregulated glucocorticoid-receptor expression by CD4(+) T cells, suggesting potential mechanisms whereby these treatments may overcome poor glucocorticoid responsiveness. We show here that administration of vitamin D3 to healthy individuals and SR asthmatic patients enhanced subsequent responsiveness to dexamethasone for induction of IL-10. This strongly suggests that vitamin D3 could potentially increase the therapeutic response to glucocorticoids in SR patients.