Rudick R A, Carpenter C S, Cookfair D L, Tuohy V K, Ransohoff R M
Department of Neurology, Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, OH 44195.
Neurology. 1993 Oct;43(10):2080-7. doi: 10.1212/wnl.43.10.2080.
Recombinant interferon beta (rIFN beta) is being tested as experimental immunotherapy for exacerbating-remitting MS. To clarify the possible mechanisms of a therapeutic response to rIFN beta in MS patients, we conducted studies on the effects of rIFN beta on mitogen-driven T-cell activation by stimulating peripheral blood mononuclear cells (PBMC) with concanavalin A (ConA) or with anti-CD3 monoclonal antibodies in the presence or absence of rIFN beta. We monitored T-cell activation using proliferation assays or by expression of surface activation markers detected by flow cytometry. In vitro rIFN beta, in concentrations > or = 10 U/ml, inhibited PBMC proliferation or surface expression of interleukin-2 receptor (IL-2R), transferrin receptor, or CD2. In contrast, rIFN gamma augmented mitogen-driven IL-2R expression. PBMC isolated from normal volunteers or MS patients responded to ConA and rIFN beta in a similar manner. We conducted pilot in vivo studies in exacerbating-remitting MS patients participating in a double-blind placebo-controlled clinical trial of rIFN beta. PBMC were isolated from study participants immediately before and 24 hours after a weekly study injection. IL-2R expression by T cells was determined following a ConA stimulus. While there was no significant change following placebo injection, rIFN beta recipients showed significantly reduced ConA-driven IL-2R expression following study injection. The results document in vitro and in vivo inhibition of mitogen-driven T-cell activation by rIFN beta. This suggests a possible mechanism underlying a therapeutic response to rIFN beta in MS patients.
重组干扰素β（rIFNβ）正在作为缓解复发型多发性硬化症（MS）的实验性免疫疗法进行测试。为了阐明MS患者对rIFNβ治疗反应的可能机制，我们通过在有或无rIFNβ的情况下用伴刀豆球蛋白A（ConA）或抗CD3单克隆抗体刺激外周血单个核细胞（PBMC），研究了rIFNβ对丝裂原驱动的T细胞活化的影响。我们使用增殖测定法或通过流式细胞术检测的表面活化标志物的表达来监测T细胞活化。体外rIFNβ浓度≥10 U/ml时，可抑制PBMC增殖或白细胞介素2受体（IL-2R）、转铁蛋白受体或CD2的表面表达。相比之下，rIFNγ增强了丝裂原驱动的IL-2R表达。从正常志愿者或MS患者分离的PBMC对ConA和rIFNβ的反应方式相似。我们对参与rIFNβ双盲安慰剂对照临床试验的缓解复发型MS患者进行了体内初步研究。在每周一次的研究注射前和注射后24小时立即从研究参与者中分离PBMC。在ConA刺激后测定T细胞的IL-2R表达。安慰剂注射后无显著变化，而rIFNβ接受者在研究注射后ConA驱动的IL-2R表达显著降低。结果证明了rIFNβ在体外和体内对丝裂原驱动的T细胞活化的抑制作用。这提示了MS患者对rIFNβ治疗反应的一种可能机制。
