GLUCOCORTICOID RESISTANCE IN CHRONIC ASTHMA - PERIPHERAL-BLOOD LYMPHOCYTE-T ACTIVATION AND COMPARISON OF THE LYMPHOCYTE-T INHIBITORY EFFECTS OF GLUCOCORTICOIDS AND CYCLOSPORINE-A
GLUCOCORTICOID RESISTANCE IN CHRONIC ASTHMA - PERIPHERAL-BLOOD LYMPHOCYTE-T ACTIVATION AND COMPARISON OF THE LYMPHOCYTE-T INHIBITORY EFFECTS OF GLUCOCORTICOIDS AND CYCLOSPORINE-A
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DOI：
10.1164/ajrccm/144.5.page
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发表时间：
1991-11-01
期刊：
影响因子：
--
通讯作者：
KAY, AB
中科院分区：
文献类型：
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作者：
CORRIGAN, CJ;BROWN, PH;KAY, AB
根据口服泼尼松龙后FEV 1的变化，将37例有可逆性气道阻塞记录的慢性重度哮喘患者分为糖皮质激素敏感型和抵抗型。应用流式细胞术研究了泼尼松龙治疗前患者外周血T淋巴细胞表型和活化分子的表达。与敏感患者相比，耐药患者表达活化分子IL-2 R和HLA-DR的T淋巴细胞百分比显著升高。两组患者外周血T淋巴细胞表达表型标志物CD 4和CD 8的百分比无差异。用T淋巴细胞有丝分裂原PHA在地塞米松或环孢菌素A存在或不存在的情况下，对29例患者的外周血单个核细胞（PBMC）进行体外培养。地塞米松（10（-7）mol/L）可显著抑制敏感性哮喘患者T淋巴细胞的增殖，但对抵抗性哮喘患者无明显影响。与此相反，环孢素A（500 ng/ml）抑制T淋巴细胞增殖的敏感性和抵抗性哮喘患者，虽然效果不太明显，在后者组。我们还研究了丝裂原刺激的哮喘患者敏感和抵抗的T淋巴细胞对白细胞介素-2和干扰素-γ的抑制作用。地塞米松（10（-7）mol/L）可显著抑制激素敏感型慢性哮喘患者T淋巴细胞增殖产生IL-2和IFN-γ，但对激素抵抗型慢性哮喘患者无明显影响。环孢菌素A（500 ng/ml）抑制两个淋巴因子的制作由T淋巴细胞来自两个患者组。这些观察结果表明，正在进行的T淋巴细胞活化可以在接受糖皮质激素治疗但未表现出临床改善的慢性哮喘患者的外周血中检测到。他们还提供了进一步的证据表明，哮喘的临床糖皮质激素敏感性与糖皮质激素体外抑制T淋巴细胞功能的程度相关。这表明，活化的T淋巴细胞可能是糖皮质激素治疗这种疾病的一个目标，这意味着替代抗T淋巴细胞药物，如环孢素A，可能是糖皮质激素抵抗的哮喘患者的治疗价值。
A total of 37 chronic severe asthmatic patients with documented reversible airways obstruction were classified as glucocorticoid sensitive or resistant according to changes in the FEV1 following a course of oral prednisolone. The phenotype and expression of activation molecules on peripheral blood T lymphocytes from these patients just before the course of prednisolone were studied using flow cytometry. The resistant patients had significantly elevated percentages of T lymphocytes expressing the activation molecules IL-2R and HLA-DR compared to the sensitive patients. There were no differences between the patient groups in the percentages of peripheral blood T lymphocytes expressing the phenotypic markers CD4 and CD8. Peripheral blood mononuclear cells (PBMC) from 29 patients were cultured in vitro with the T lymphocyte mitogen PHA in the presence or absence of dexamethasone or cyclosporin A. Dexamethasone (10(-7) mol/L) significantly inhibited the proliferation of T lymphocytes from the sensitive but not the resistant asthmatic subjects. In contrast, cyclosporin A (500 ng/ml) inhibited proliferation of T lymphocytes from both the sensitive and the resistant asthmatic subjects, although the effect was less marked in the latter group. Inhibition of elaboration of interleukin-2 and interferon-gamma by mitogen-stimulated T lymphocytes from sensitive and resistant asthmatic patients was also studied. Dexamethasone (10(-7) mol/L) significantly inhibited the production of interleukin-2 and interferon-gamma by proliferating T lymphocytes isolated from the glucocorticoid-sensitive but not the resistant chronic asthmatic patients. Cyclosporin A (500 ng/ml) inhibited the elaboration of both lymphokines by T lymphocytes derived from both patient groups. These observations demonstrate that ongoing T lymphocyte activation can be detected in the peripheral blood of chronic asthmatic patients who are receiving glucocorticoids but not demonstrating clinical improvement. They also provide further evidence that clinical glucocorticoid sensitivity in asthma correlates with the degree of inhibition of T lymphocyte function by glucocorticoids in vitro. This suggests that activated T lymphocytes may be one target for glucocorticoid therapy in this disease, with the implication that alternative anti-T lymphocyte drugs, such as cyclosporin A, may be of therapeutic value in glucocorticoid-resistant asthmatic patients.