Ghadiri Mahtab, Rezk Ayman, Li Rui, Evans Ashley, Luessi Felix, Zipp Frauke, Giacomini Paul S, Antel Jack, Bar-Or Amit
Montreal Neurological Institute (M.G., A.R., R.L., P.S.G., J.A., A.B.-O.), McGill University, Montreal, QC, Canada; Brain and Mind Centre (M.G.), University of Sydney, NSW, Australia; Institute of Actuaries of Australia (A.E.); Department of Neurology (F.L., F.Z.), University Medical Center Mainz, Germany; and Department of Neurology (A.R., R.L., A.B.-O.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Neurol Neuroimmunol Neuroinflamm. 2017 Mar 23;4(3):e340. doi: 10.1212/NXI.0000000000000340. eCollection 2017 May.
To examine the mechanism underlying the preferential CD8 vs CD4 T-cell lymphopenia induced by dimethyl fumarate (DMF) treatment of MS.
Total lymphocyte counts and comprehensive T-cell subset analyses were performed in high-quality samples obtained from patients with MS prior to and serially following DMF treatment initiation. Random coefficient mixed-effects analysis was used to model the trajectory of T-cell subset losses in vivo. Survival and apoptosis of distinct T-cell subsets were assessed following in vitro exposure to DMF.
Best-fit modeling indicated that the DMF-induced preferential reductions in CD8 vs CD4 T-cell counts nonetheless followed similar depletion kinetics, suggesting a similar rather than distinct mechanism involved in losses of both the CD8 and CD4 T cells. In vitro, DMF exposure resulted in dose-dependent reductions in T-cell survival, which were found to reflect apoptotic cell death. This DMF-induced apoptosis was greater for CD8 vs CD4, as well as for memory vs naive, and conventional vs regulatory T-cell subsets, a pattern which mirrored preferential T-cell subset losses that we observed during in vivo treatment of patients.
Differential apoptosis mediated by DMF may underlie the preferential lymphopenia of distinct T-cell subsets, including CD8 and memory T-cell subsets, seen in treated patients with MS. This differential susceptibility of distinct T-cell subsets to DMF-induced apoptosis may contribute to both the safety and efficacy profiles of DMF in patients with MS.
研究富马酸二甲酯（DMF）治疗多发性硬化症（MS）诱导CD8与CD4 T细胞优先淋巴细胞减少的潜在机制。
在DMF治疗开始前及治疗过程中连续采集的高质量样本中，对MS患者进行全淋巴细胞计数和全面的T细胞亚群分析。采用随机系数混合效应分析对体内T细胞亚群损失轨迹进行建模。体外暴露于DMF后，评估不同T细胞亚群的存活和凋亡情况。
最佳拟合模型表明，DMF诱导的CD8与CD4 T细胞计数优先减少，但遵循相似的耗竭动力学，提示CD8和CD4 T细胞损失涉及相似而非不同的机制。在体外，DMF暴露导致T细胞存活率呈剂量依赖性降低，这被发现反映了凋亡性细胞死亡。DMF诱导的这种凋亡在CD8与CD4、记忆性与初始性以及传统与调节性T细胞亚群中更为明显，这一模式与我们在患者体内治疗期间观察到的T细胞亚群优先损失情况相符。
DMF介导的差异性凋亡可能是MS患者接受治疗后出现包括CD8和记忆性T细胞亚群在内的不同T细胞亚群优先淋巴细胞减少的原因。不同T细胞亚群对DMF诱导凋亡的这种差异性易感性可能有助于解释DMF在MS患者中的安全性和有效性。
