dNP2 is a blood-brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis.
dNP2 is a blood-brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis.
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DOI：
10.1038/ncomms9244
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发表时间：
2015-09-15
影响因子：
16.6
通讯作者：
Choi JM
中科院分区：
文献类型：
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作者：
Lim S;Kim WJ;Kim YH;Lee S;Koo JH;Lee JA;Yoon H;Kim DH;Park HJ;Kim HM;Lee HG;Yun Kim J;Lee JU;Hun Shin J;Kyun Kim L;Doh J;Kim H;Lee SK;Bothwell ALM;Suh M;Choi JM
中枢神经系统（CNS）浸润效应T细胞在多发性硬化（MS）的发展和进展中起着关键作用。然而，由于难以将药物递送到CNS中，目前用于MS的药物非常有限。在这里，我们确定了一种细胞渗透性肽，dNP 2，它有效地将蛋白质递送到小鼠和人类T细胞以及各种组织中。此外，它通过穿透紧密组织的血脑屏障，通过血管进入脑组织和驻留细胞。细胞毒性T淋巴细胞抗原4（dNP 2-ctCTLA-4）的dNP 2缀合的胞质结构域负调节活化的T细胞，并在预防性和治疗性小鼠模型中对实验性自身免疫性脑脊髓炎显示抑制作用，导致脱髓鞘和CNS浸润的T辅助细胞1和T辅助细胞17细胞减少。因此，这项研究表明，dNP 2是一种血脑屏障渗透肽和dNP 2-ctCTLA-4可能是一种有效的治疗剂，用于治疗中枢神经系统炎症性疾病，如MS。大多数的细胞穿透肽可以运输治疗剂穿过质膜，但几乎没有穿过血脑屏障。在这里，作者开发了一种可以进入大脑的肽，并表明其与免疫调节蛋白ctCTLA-4的融合在多发性硬化症的小鼠模型中是有效的。
Central nervous system (CNS)-infiltrating effector T cells play critical roles in the development and progression of multiple sclerosis (MS). However, current drugs for MS are very limited due to the difficulty of delivering drugs into the CNS. Here we identify a cell-permeable peptide, dNP2, which efficiently delivers proteins into mouse and human T cells, as well as various tissues. Moreover, it enters the brain tissue and resident cells through blood vessels by penetrating the tightly organized blood–brain barrier. The dNP2-conjugated cytoplasmic domain of cytotoxic T-lymphocyte antigen 4 (dNP2-ctCTLA-4) negatively regulates activated T cells and shows inhibitory effects on experimental autoimmune encephalomyelitis in both preventive and therapeutic mouse models, resulting in the reduction of demyelination and CNS-infiltrating T helper 1 and T helper 17 cells. Thus, this study demonstrates that dNP2 is a blood–brain barrier-permeable peptide and dNP2-ctCTLA-4 could be an effective agent for treating CNS inflammatory diseases such as MS. Most of the cell penetrating peptides can transport therapeutic agents across plasma membranes but barely across the blood-brain barrier. Here the authors develop a peptide that can enter the brain, and show that its fusion to immunomodulatory protein ctCTLA-4 is effective in a mouse model of multiple sclerosis.