Approach to Fingolimod-Induced Lymphopenia in Multiple Sclerosis Patients: Do We Have a Roadmap?
Approach to Fingolimod-Induced Lymphopenia in Multiple Sclerosis Patients: Do We Have a Roadmap?
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DOI：
10.1002/jcph.945
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发表时间：
2017-11-01
影响因子：
2.9
通讯作者：
Urrea-Mendoza, Enrique
中科院分区：
文献类型：
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作者：
Avasarala, Jagannadha;Jain, Sandip;Urrea-Mendoza, Enrique
2010年9月由食品和药物管理局（FDA）批准用于复发形式的多发性硬化症（MS）的第一类口服药物疗法芬戈莫德（FTY）以商标名Gilenya（Novartis Pharmaceuticals，巴塞尔，瑞士）销售。它是一种鞘氨醇1-磷酸（S1 P）受体调节剂，可抑制幼稚和中枢记忆淋巴细胞从淋巴结中流出，淋巴结被认为在MS的发病机制中起核心作用。在外周血中，FTY可导致CD 4+和CD 8 + T细胞可逆地保留在淋巴结中，减少淋巴细胞浸润到中枢神经系统（CNS）中，在那里它们被认为是引发和促进炎症。FTY给药可阻止淋巴细胞从原发性和继发性淋巴器官中流出，导致淋巴细胞减少症。1在体内，FTY被磷酸化形成磷酸芬戈莫德，其类似于天然存在的S1 P，一种细胞外脂质介质，其主要作用由同源G蛋白偶联受体介导。2在5种S1 P受体亚型（称为S1 P1 -5）中，有4种与磷酸芬戈莫德结合;受体在MS生物学的核心细胞上表达。2淋巴细胞从淋巴组织进入循环的调节通过S1 P1介导。芬戈莫德磷酸盐最初通过高亲和力受体结合激活淋巴细胞S1 P1，但诱导S1 P1下调，阻止淋巴细胞从淋巴组织中排出。2这有助于减少自身反应性淋巴细胞进入中枢神经系统CNS。S1 P受体定位于星形胶质细胞3中，并且也由许多CNS细胞类型表达，并且已显示影响细胞增殖、形态和迁移。2芬戈莫德可穿过血脑屏障4，因此可能具有直接的中枢神经系统作用，与其他免疫靶向MS疗法不同。
The first-in-class oral drug therapy approved by the Food and Drug Administration (FDA) for use in relapsing forms of multiple sclerosis (MS) in September 2010, fingolimod (FTY), is marketed under the brand name Gilenya (Novartis Pharmaceuticals, Basel, Switzerland). It is a sphingosine 1-phosphate (S1P) receptor modulator that inhibits egress of naive and central memory lymphocytes from lymph nodes, which are thought to play a central role in the pathogenesis of MS. In the peripheral blood, FTY causes CD4+ and CD8+ T cells to be reversibly retained in the lymph nodes, reducing the infiltration of lymphocytes into the central nervous system (CNS), where they are thought to initiate and promote inflammation. Administration of FTY prevents the egress of lymphocytes from primary and secondary lymph organs, causing lymphopenia. 1In vivo, FTY is phosphorylated to form fingolimod phosphate, which resembles naturally occurring S1P, an extracellular lipid mediator whose major effects are mediated by cognate G protein–coupled receptors. 2 Of the 5 S1P receptor subtypes, known as S1P1-5, 4 bind to fingolimod phosphate; the receptors are expressed on cells that are central to the biology of MS. 2 Regulation of lymphocyte egress from lymphoid tissues into the circulation is mediated via S1P1. Fingolimod phosphate initially activates lymphocyte S1P1 via high-affinity receptor binding but induces S1P1 downregulation, preventing lymphocyte egress from lymphoid tissues. 2 This serves to reduce autoreactive lymphocyte trafficking into the central nervous system CNS. S1P receptors are localized in astrocytes3 and are also expressed by many CNS cell types and have been shown to influence cell proliferation, morphology, and migration. 2 Fingolimod crosses the blood-brain barrier4 and may therefore have direct CNS effects, distinguishing it from other immunologically targeted MS therapies.