Mathias Amandine, Perriot Sylvain, Canales Mathieu, Blatti Claudia, Gaubicher Coline, Schluep Myriam, Engelhardt Britta, Du Pasquier Renaud
Laboratory of Neuroimmunology (A.M., S.P., M.C., C.G., R.D.P.), Center of Research in Neurosciences, Service of Neurology (M.S., R.D.P.), Department of Clinical Neurosciences, CHUV, Lausanne, Switzerland; and Theodor Kocher Institute (C.B., B.E.), University of Bern, Switzerland.
Neurol Neuroimmunol Neuroinflamm. 2017 Oct 11;4(6):e401. doi: 10.1212/NXI.0000000000000401. eCollection 2017 Nov.
To evaluate the long-term effects of treatments used in MS on the T-cell trafficking profile.
We enrolled 83 patients with MS under fingolimod (FTY), natalizumab (NTZ), dimethyl fumarate (DMF), or other disease-modifying treatments (DMTs). Blood was drawn before treatment onset and up to 36-48 months. The ex vivo expression of CNS-related integrins (α4β1 and α subunit of LFA-1) and the gut-related integrin (α4β7) was assessed using flow cytometry on CD4 and CD8 T cells. The adhesion profiles of CD3 T cells to specific integrin ligands (vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule-1 [ICAM-1], and mucosal vascular addressin cell adhesion molecule-1 [MAdCAM-1]) were measured in vitro before and after 12 and 36-48 months.
NTZ decreased the frequency of α4β1 and α4β7 integrin expressing T cells and the binding of these cells to VCAM-1 and MAdCAM-1, respectively. After 12 months, DMF induced a decreased frequency of αCD4 T cells combined with reduced binding to ICAM-1. By contrast, with FTY, there was a doubling of the frequency of α4β1 and α, but a decreased frequency of α4β7 T cells. Strikingly, the binding of α4β1, α4β7, and to a lesser extent of α T cells to VCAM-1, MAdCAM-1, and ICAM-1, respectively, was decreased at month 12 under FTY treatment. The presence of manganese partially restored the binding of these T cells to VCAM-1 in vitro, suggesting that FTY interferes with integrin activation.
In addition to NTZ, DMF and FTY but not other tested DMTs may also decrease T-cell-mediated immune surveillance of the CNS. Whether this mechanism may contribute to the onset of CNS opportunistic infections remains to be shown.
评估用于治疗多发性硬化症（MS）的药物对T细胞迁移谱的长期影响。
我们纳入了83例接受芬戈莫德（FTY）、那他珠单抗（NTZ）、富马酸二甲酯（DMF）或其他疾病修饰治疗（DMTs）的MS患者。在治疗开始前及长达36 - 48个月期间采集血液。使用流式细胞术评估CD4和CD8 T细胞上中枢神经系统相关整合素（α4β1和淋巴细胞功能相关抗原-1的α亚基）及肠道相关整合素（α4β7）的体外表达。在12个月以及36 - 48个月前后，体外测量CD3 T细胞与特定整合素配体（血管细胞黏附分子-1 [VCAM-1]、细胞间黏附分子-1 [ICAM-1]和黏膜血管地址素细胞黏附分子-1 [MAdCAM-1]）的黏附情况。
NTZ分别降低了表达α4β1和α4β7整合素的T细胞频率以及这些细胞与VCAM-1和MAdCAM-1的结合。12个月后，DMF导致αCD4 T细胞频率降低，同时与ICAM-1的结合减少。相比之下，使用FTY时，α4β1和α的频率翻倍，但α4β7 T细胞频率降低。引人注目的是，在FTY治疗12个月时，α4β1、α4β7以及程度较轻的α T细胞与VCAM-1、MAdCAM-1和ICAM-1的结合分别减少。锰的存在部分恢复了这些T细胞在体外与VCAM-1的结合，表明FTY干扰整合素激活。
除NTZ外，DMF和FTY而非其他测试的DMTs也可能降低T细胞介导的对中枢神经系统的免疫监视。这种机制是否可能导致中枢神经系统机会性感染的发生仍有待证实。
