A promising therapeutic approach for multiple sclerosis: recombinant T-cell receptor ligands modulate experimental autoimmune encephalomyelitis by reducing interleukin-17 production and inhibiting migration of encephalitogenic cells into the CNS
A promising therapeutic approach for multiple sclerosis: recombinant T-cell receptor ligands modulate experimental autoimmune encephalomyelitis by reducing interleukin-17 production and inhibiting migration of encephalitogenic cells into the CNS
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DOI：
10.1523/jneurosci.3599-07.2007
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发表时间：
2007-11-14
影响因子：
5.3
通讯作者：
Offner, Halina
中科院分区：
文献类型：
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作者：
Sinha, Sushmita;Subramanian, Sandhya;Offner, Halina
重组T细胞受体配体（RTL）可以以抗原特异性的方式预防和逆转实验性自身免疫性脑脊髓炎（EAE）的临床和组织学体征，并且目前正在临床试验中用于治疗患有多发性硬化（MS）的受试者。为了评估调节机制，我们设计并测试了RTL 551，其含有与C57 BL/6小鼠中致脑炎MOG-35-55肽共价连接的I-A（B）II类分子的α 1和β 1结构域。在疾病发作后用RTL 551治疗主动或被动EAE显著减少临床体征和脊髓病变。此外，RTL 551处理强烈地和选择性地减少了转移的绿色荧光蛋白阳性（GFP+）MOG-35-55反应性T细胞的白细胞介素-17和肿瘤坏死因子α的分泌，并且几乎完全消除了受影响的脊髓切片中存在的GFP+细胞浸润。RTL 551处理的小鼠脊髓中的炎症减少伴随着趋化因子及其受体的高度显著下调以及内皮细胞对VCAM-1（血管细胞粘附分子-1）和ICAM-1（细胞间粘附分子-1）表达的抑制。因此，RTL治疗不仅可以抑制由靶向髓鞘少突胶质细胞糖蛋白反应性T细胞引起的致脑炎细胞因子的全身性产生，而且还可以阻碍CNS中炎性细胞的下游局部募集和保留。这些发现表明，抗原特异性T细胞的靶向免疫治疗可以逆转CNS病变的形成，并为RTL方法在MS治疗中的应用提供了强有力的支持。
Recombinant T-cell receptor ligands (RTLs) can prevent and reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in an antigen-specific manner and are currently in clinical trials for treatment of subjects with multiple sclerosis (MS). To evaluate regulatory mechanisms, we designed and tested RTL551, containing the alpha 1 and beta 1 domains of the I-A(b) class II molecule covalently linked to the encephalitogenic MOG-35-55 peptide in C57BL/6 mice. Treatment of active or passive EAE with RTL551 after disease onset significantly reduced clinical signs and spinal cord lesions. Moreover, RTL551 treatment strongly and selectively reduced secretion of interleukin-17 and tumor necrosis factor alpha by transferred green fluorescent protein-positive (GFP+) MOG-35-55-reactive T-cells and almost completely abrogated existent GFP+ cellular infiltrates in affected spinal cord sections. Reduced inflammation in spinal cords of RTL551-treated mice was accompanied by a highly significant downregulation of chemokines and their receptors and inhibition of VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) expression by endothelial cells. Thus, RTL therapy cannot only inhibit systemic production of encephalitogenic cytokines by the targeted myelin oligodendrocyte glycoprotein-reactive T-cells but also impedes downstream local recruitment and retention of inflammatory cells in the CNS. These findings indicate that targeted immunotherapy of antigen-specific T-cells can result in a reversal of CNS lesion formation and lend strong support to the application of the RTL approach for therapy in MS.