Kivisäkk P, Healy B C, Viglietta V, Quintana F J, Hootstein M A, Weiner H L, Khoury S J
Center for Neurological Diseases, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Neurology. 2009 Jun 2;72(22):1922-30. doi: 10.1212/WNL.0b013e3181a8266f.
Natalizumab is an antibody directed against integrin alpha4 that reduces disease activity in patients with multiple sclerosis (MS) by blocking migration of T and B cells into the CNS. The goal of this study was to characterize the effects of natalizumab treatment on cytokine production and expression of activation markers, costimulatory molecules, and trafficking determinants on CD4+ and CD8+ T cells.
In a longitudinal study, we investigated the expression of surface makers and cytokine expression on peripheral blood lymphocytes from 28 patients with MS who started natalizumab treatment and were followed for 1 year. A mixed effects model was used to compare pretreatment to on-treatment measurements.
The frequency of CD4+ T cells producing interferon-gamma, tumor necrosis factor, and interleukin (IL)-17 upon anti-CD3 stimulation increased 6 months after initiation of natalizumab treatment and remained elevated throughout the follow-up. The frequency of CD4+ T cells expressing CD25, HLA-DR, and CCR6 ex vivo was increased at one or more time points during treatment. Among CD8+ T cells, the frequency of cells producing IL-2 and IL-17 after stimulation was increased during natalizumab treatment, as was the frequency of CD8+ T cells expressing CD58 and CCR5 ex vivo. The increase in the frequency of activated cells could not be replicated by in vitro exposure to natalizumab.
Natalizumab treatment increases the percentage of activated leukocytes producing proinflammatory cytokines in blood, presumably due to sequestration of activated cells in the peripheral circulation.
那他珠单抗是一种针对整合素α4的抗体，通过阻断T和B细胞向中枢神经系统的迁移来降低多发性硬化症（MS）患者的疾病活动度。本研究的目的是描述那他珠单抗治疗对细胞因子产生以及CD4+和CD8+T细胞上激活标志物、共刺激分子和转运决定因素表达的影响。
在一项纵向研究中，我们调查了28例开始接受那他珠单抗治疗并随访1年的MS患者外周血淋巴细胞表面标志物的表达和细胞因子表达。使用混合效应模型比较治疗前和治疗期间的测量值。
抗CD3刺激后产生干扰素-γ、肿瘤坏死因子和白细胞介素（IL）-17的CD4+T细胞频率在那他珠单抗治疗开始6个月后增加，并在整个随访期间保持升高。治疗期间的一个或多个时间点，体外表达CD25、HLA-DR和CCR6的CD4+T细胞频率增加。在CD8+T细胞中，那他珠单抗治疗期间刺激后产生IL-2和IL-17的细胞频率增加，体外表达CD58和CCR5的CD8+T细胞频率也增加。体外暴露于那他珠单抗无法复制激活细胞频率的增加。
那他珠单抗治疗增加了血液中产生促炎细胞因子的活化白细胞百分比，可能是由于活化细胞在外周循环中被隔离。
