Study on individual immunosuppressive therapy based on peripheral-blood lymphocyte-sensitivity to immunosuppressive drugs and the mechanisms on drug resistance

本研究旨在为免疫抑制药物在各种免疫疾病中的有效和安全使用建立药效学指标。为了评估个体对免疫抑制药物的反应，我们使用来自自身免疫性疾病患者的外周血淋巴细胞，在体外检测了糖皮质激素(强的松龙和甲基强的松龙)和免疫抑制剂(环孢素A和他克莫司)的淋巴细胞抑制能力，这些患者包括哮喘、类风湿关节炎、肾病、溃疡性结肠炎和肾移植受者。我们还检查了淋巴细胞对免疫抑制药物的抗药性的分子基础。淋巴细胞对免疫抑制剂的体外敏感性与每种疾病患者的临床疗效相关。这些疾病之间可能存在一些不同的淋巴细胞抵抗机制。我们的结论是，可以通过测量患者淋巴细胞对药物的体外反应来预测免疫抑制剂的临床疗效。淋巴细胞对药物高度敏感的患者可能会接受较短的疗程或剂量的药物治疗，而对药物有淋巴细胞耐药性的患者可能对治疗无效。体外药敏数据可作为选择适合患者的免疫抑制剂的指标。

This study was carried out to establish pharmacodynamic indices for effective and safety use of immunosuppressive drugs in various immunological disorders. To evaluate individual response to immunosuppressive drugs, we examined lymphocyte suppressive potency of glucocorticoids (prednisolone and methylprednisolone) and immunosuppressants (cyclosporine and tacrolimus) in vitro by use of peripheral-blood lymphocytes obtained from patients with autoimmune disorders including bronchial asthma, rheumatoid arthritis, nephrosis, ulcerative colitis, and renal transplant recipients. We also examined molecular basis for lymphocyte-resistance to immunosuppressive drugs. Lymphocyte sensitivity to immunosuppressants in vitro correlated with clinical efficacy of the drugs in patients of each disease. There may be some different mechanisms for lymphocyte-resistance between these diseases. We concluded that clinical efficacy of immunosuppressants can be predicted by measuring in vitro response of patient's lymphocytes to the drugs. The patients with lymphocytes exhibiting high-sensitivity to the drug might be treated with shorter periods or amounts of the drug, whereas the patients showing lymphocyte resistance to the drug might be refractory to the therapy. The data of in vitro sensitivity to the drugs could be an index for selection of appropriate immunosuppressant to individual patient.