Seki M, Ushiyama C, Seta N, Abe K, Fukazawa T, Asakawa J, Takasaki Y, Hashimoto H
Juntendo University School of Medicine, Tokyo, Japan.
Arthritis Rheum. 1998 May;41(5):823-30. doi: 10.1002/1529-0131(199805)41:5<823::AID-ART8>3.0.CO;2-#.
Glucocorticoids (GCs) are the drugs of first choice for treatment of systemic lupus erythematosus (SLE). However, the disease in some patients is resistant to these agents. This study evaluated the possibility of a relationship between response to GC treatment and the rate of apoptosis in vitro, and also analyzed Bcl-2 and Fas expression on peripheral blood mononuclear cells (PBMC) from patients with SLE in relation to GC-induced apoptosis.
Twenty-seven SLE patients and 13 normal controls were studied. Disease activity scores were determined before and after treatment and used to divide patients into 2 groups: GC-resistant and GC-responsive. Isolated PBMC were stimulated with anti-CD3 monoclonal antibodies, cultured with various concentrations of GC, and analyzed by alamar blue assay to determine the LC50, defined as the concentration of GC lethal to 50% of the cells. We measured the expression of CD4, CD8, Fas, and Bcl-2 by FACStar plus flow cytometry.
Lymphocytes in the GC-resistant group of SLE patients showed a significantly lower percentage of GC-induced apoptotic cells than did lymphocytes from the responsive group or from normal controls. The LC50 in the resistant group was significantly higher than that in normal controls or the responsive group. The lymphocytes remaining in the resistant group after GC treatment were mainly CD8+, with a high expression of Bcl-2. There was no significant difference in Fas expression between the GC-responsive and GC-resistant groups.
Determination of the LC50 may be useful in predicting the efficacy of GC treatment in SLE patients, and may be of use in considering other treatment options. CD8 and Bcl-2 double-positive lymphocytes that are insensitive to the apoptotic effect of GCs may play a role in the resistance to these agents in SLE patients.
糖皮质激素（GCs）是治疗系统性红斑狼疮（SLE）的首选药物。然而，部分患者的疾病对这些药物耐药。本研究评估了体外GC治疗反应与凋亡率之间存在关联的可能性，并分析了SLE患者外周血单个核细胞（PBMC）上Bcl-2和Fas表达与GC诱导凋亡的关系。
对27例SLE患者和13名正常对照者进行研究。在治疗前后测定疾病活动评分，并用于将患者分为两组：GC耐药组和GC反应组。分离的PBMC用抗CD3单克隆抗体刺激，用不同浓度的GC培养，并通过alamar蓝分析法进行分析，以确定LC50，即对50%细胞具有致死性的GC浓度。我们通过FACStar plus流式细胞术测量CD4、CD8、Fas和Bcl-2的表达。
SLE患者GC耐药组淋巴细胞中GC诱导的凋亡细胞百分比显著低于反应组或正常对照组的淋巴细胞。耐药组的LC50显著高于正常对照组或反应组。GC治疗后耐药组中剩余的淋巴细胞主要是CD8+，Bcl-2表达较高。GC反应组和GC耐药组之间Fas表达无显著差异。
测定LC50可能有助于预测GC治疗SLE患者的疗效，并可能有助于考虑其他治疗方案。对GC凋亡作用不敏感的CD8和Bcl-2双阳性淋巴细胞可能在SLE患者对这些药物的耐药中起作用。
