Gilt required for RTL550-CYS-MOG to treat experimental autoimmune encephalomyelitis.
Gilt required for RTL550-CYS-MOG to treat experimental autoimmune encephalomyelitis.
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RTL550-CYS-MOG 治疗实验性自身免疫性脑脊髓炎所需的后备母猪。
DOI：
10.1007/s11011-012-9289-7
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发表时间：
2012
影响因子：
3.6
通讯作者：
Offner,Halina
中科院分区：
文献类型：
--
作者：
Burrows,GregoryG;Meza-Romero,Roberto;Huan,Jianya;Sinha,Sushmita;Mooney,JeffreyL;Vandenbark,ArthurA;Offner,Halina
MHC II 类衍生的重组 T 细胞受体配体 (RTL) 调节致病性 T 细胞的行为，可以逆转实验性自身免疫性脑脊髓炎 (EAE)、实验性自身免疫性葡萄膜炎 (EAU) 和胶原诱导性关节炎 (CIA) 中自身免疫性疾病的临床和组织学体征，目前正在进行治疗多发性硬化症 (MS) 的临床试验。为了扩展这些合理设计的生物制剂的效用并探索其体内活性机制，我们设计了带有半胱氨酸束缚抗原肽的 RTL 构建体，并证明适当的半胱氨酸束缚 RTL 可以有效治疗 EAE。这里提供的数据表明，体内带有半胱氨酸栓系抗原肽的 RTL 诱导抗原特异性耐受的机制涉及将 RTL/抗原递送至内体区室，以由全长 MHC II 类进行加工和重新呈递，其中带有半胱氨酸栓系抗原肽的 RTL 需要γ-干扰素诱导型溶酶体硫醇还原酶 (GILT) 来发挥治疗活性。
MHC class II-derived recombinant T cell receptor ligands (RTLs) modulate the behavior of pathogenic T cells and can reverse clinical and histological signs of autoimmune disease in experimental autoimmune encephalomyelitis (EAE), experimental autoimmune uveitis (EAU) and collagen-induced arthritis (CIA), and are currently in clinical trials for treatment of multiple sclerosis (MS). To expand the utility of these rationally-designed biologics and explore their mechanism(s) of activity in vivo, we have engineered RTL constructs bearing cysteine-tethered antigenic peptides and demonstrate that the appropriate cysteine-tethered RTLs effectively treat EAE. The data presented here suggests that the mechanism by which antigen-specific tolerance induction by RTLs bearing cysteine-tethered antigenic peptides in vivo involves delivery of RTL/antigen to endosomal compartments for processing and re-presentation by full-length MHC class II, with RTLs bearing cysteine-tethered antigenic peptides requiring gamma-interferon-inducible lysosomal thiol-reductase (GILT) for therapeutic activity.