Fox R J, Kivisakk P, Fisher E, Tucky B, Lee J C, Rudick R A, Ransohoff R M
Department of Neurology, Mellen Center, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Mult Scler. 2008 Sep;14(8):1036-43. doi: 10.1177/1352458508092261. Epub 2008 Aug 13.
Leukocytes expressing inflammatory chemokine receptors (CKRs), most consistently CCR2, CCR5, and CXCR3, have been identified in multiple sclerosis (MS) tissue lesions and provide attractive therapeutic targets. Our previous studies found large inter-individual differences in expression of these CKRs but stable levels over time within subjects. This observation suggests a CKR "set-point" within individuals, which might relate to inflammatory injury in MS. We evaluated the correlation between CKR levels and magnetic resonance imaging (MRI) measures of disease activity.
Fifty-five relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) patients were prospectively followed with annual CKR and MRI studies. Multiparameter flow cytometry was used to determine CCR2, CCR5, and CXCR3 expression on CD4 and CD8 cells. Simultaneous cranial MRIs were performed, and quantitative measures of T2, T1, and gadolinium lesions, brain parenchymal fraction (BPF), and whole brain and fractionated magnetization transfer ratio (MTR) were performed using automated software. Spearman's rank correlations evaluated the relationship between CKR levels and MRI measures.
Significant correlations were observed between CXCR3 expression on CD8 cells and measures of new (T1) and total (T1, T2) lesion volumes, lesion MTR, and BPF; higher levels of CXCR3 expression were correlated with greater injury on MRI (|r| = 0.27-0.42). In contrast, CD4 cell CKR expression was only minimally correlated with MRI measures.
Over 2 years, we observed significant correlations between the percent of CD8 cells expressing CXCR3 and MRI measures of MS inflammatory activity and tissue destruction. These observations are consistent with a pathogenic role for cytotoxic T cells in MS brain and have significant implications regarding T-cell targeted therapeutic strategies.
在多发性硬化症（MS）组织病变中已鉴定出表达炎症趋化因子受体（CKR）的白细胞，其中最常见的是CCR2、CCR5和CXCR3，这些受体是有吸引力的治疗靶点。我们之前的研究发现，这些CKR的表达存在较大的个体间差异，但在个体内部随时间保持稳定。这一观察结果提示个体内存在CKR“设定点”，这可能与MS中的炎症损伤有关。我们评估了CKR水平与疾病活动的磁共振成像（MRI）测量值之间的相关性。
对55例复发缓解型MS（RRMS）和继发进展型MS（SPMS）患者进行前瞻性随访，每年进行CKR和MRI研究。采用多参数流式细胞术测定CD4和CD8细胞上CCR2、CCR5和CXCR3的表达。同时进行头颅MRI检查，并使用自动化软件对T2、T1和钆增强病变、脑实质分数（BPF）以及全脑和分数化磁化传递率（MTR）进行定量测量。采用Spearman等级相关性分析评估CKR水平与MRI测量值之间的关系。
观察到CD8细胞上CXCR3的表达与新发病变（T1）和总病变（T1、T2）体积、病变MTR及BPF测量值之间存在显著相关性；CXCR3表达水平越高，与MRI上更严重的损伤相关（|r| = 0.27 - 0.42）。相比之下，CD4细胞CKR表达与MRI测量值的相关性极小。
在2年的时间里，我们观察到表达CXCR3的CD8细胞百分比与MS炎症活动和组织破坏的MRI测量值之间存在显著相关性。这些观察结果与细胞毒性T细胞在MS脑内的致病作用一致，对T细胞靶向治疗策略具有重要意义。
