Discordant effects of anti-VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis
Discordant effects of anti-VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis
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DOI：
10.1172/jci11717
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发表时间：
2001-04-01
影响因子：
15.9
通讯作者：
Miller, SD
中科院分区：
文献类型：
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作者：
Theien, BE;Vanderlugt, CL;Miller, SD
复发性实验性自身免疫性脑脊髓炎（R-EAE）是多发性硬化症（MS）的动物模型，致脑炎性T细胞向中枢神经系统（CNS）的初始迁移依赖于活化T细胞上表达的α 4整合素（VLA-4）与活化脑血管内皮细胞上表达的VCAM-1的相互作用。在疾病发作后，可通过浸润炎性细胞采用替代归巢机制。因此，我们比较了在疾病发作之前或之后施用抗VLA-4调节蛋白脂质蛋白（PLP）139-151诱导的R-EAE的能力。临床前将抗VLA-4施用给致敏致脑炎T细胞的幼稚受体或肽致敏后1周的小鼠，即，在临床疾病发作前，抑制临床疾病的发作和严重程度。相反，在急性疾病高峰期或缓解期的Ab治疗加重了疾病复发并增加了CNS中CD 4（+）T细胞的积累。最显著的是，在进行中的R-EAE之前或期间的抗VLA-4治疗增强了对引发肽和继发于急性组织损伤的内源性髓鞘表位的Th 1应答。总的来说，这些结果表明，用抗VLA-4 Ah治疗对免疫系统具有多种作用，并且在治疗已建立的自身免疫性疾病如MS中可能是有问题的。
Initial migration of encephalitogenic T cells to the central nervous system (CNS) in relapsing exper imental autoimmune encephalomyelitis (R-EAE), an animal model of multiple sclerosis (MS), depends on the interaction of the alpha4 integrin (VLA-4) expressed on activated T cells with VCAM-1 expressed on activated cerebrovascular endothelial cells. Alternate homing mechanisms may be employed by infiltrating inflammatory cells after disease onset. We thus compared the ability of anti-VLA-4 to regulate proteolipid protein (PLP) 139-151-induced R-EAE when administered either before or after disease onset. Preclinical administration of anti-VLA-4 either to naive recipients of primed encephalitogenic T cells or to mice 1 week after peptide priming, i.e., before clinical disease onset, inhibited the onset and severity of clinical disease. In contrast, Ab treatment either at the peak of acute disease or during remission exacerbated disease relapses and increased the accumulation of CD4(+) T cells in the CNS, Most significantly, anti-VLA-4 treatment either before or during ongoing R-EAE enhanced Th 1 responses to both the priming peptide and endogenous myelin epitopes released secondary to acute tissue damage. Collectively, these results suggest that treatment with anti-VLA-4 Ah has multiple effects on the immune system and may be problematic in treating established autoimmune diseases such as MS.