Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation
Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation
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DOI：
10.1038/nm1385
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发表时间：
2006-05-01
期刊：
影响因子：
82.9
通讯作者：
Lee, Sang-Kyou
中科院分区：
文献类型：
--
作者：
Choi, Je-Min;Ahn, Mi-Hyun;Lee, Sang-Kyou
CTLA-4是T细胞活化的负调节因子，其抑制作用可以通过与CD28竞争或通过其胞内结构域传递负信号来实现。为了利用 CTLA-4 的胞质结构域抑制过敏性炎症，我们将其与人类转录因子 Hph-1 中的新型蛋白质转导结构域融合。经眼部、鼻内和皮内给药后，在体外和体内验证了转导效率。转导至 T 细胞后，Hph-1 ctCTLA-4 融合蛋白抑制白细胞介素 (IL)-2 的产生，并下调 CD69 和 CD25。在过敏性气道炎症小鼠模型中，鼻内施用 Hph-1-ctCTLA-4 可显着减少炎症细胞的浸润、2 型辅助 T (T(H)2) 细胞因子的分泌、血清 IgE 水平和气道高反应性。这些结果表明，Hph-1-ctCTLA-4 构成了一种有效的免疫抑制蛋白药物，可通过鼻腔给药用于治疗过敏性哮喘。
CTLA-4 is a negative regulator of T-cell activation, and its inhibitory effects can be accomplished either by competition with CD28 or by transmitting negative signals through its intracellular domain. To utilize the cytoplasmic domain of CTLA-4 to suppress allergic inflammation, we fused it to a novel protein-transduction domain in the human transcriptional factor Hph-1. Transduction efficiency was verified in vitro and in vivo after ocular, intranasal and intradermal administration. After transduction into T cells, the Hph-1 ctCTLA-4 fusion protein inhibited the production of interleukin (IL)-2, and downregulated CD69 and CD25. Intranasal administration of Hph-1-ctCTLA-4 resulted in markedly reduced infiltration of inflammatory cells, secretion of T helper type 2 (T(H)2) cytokines, serum IgE levels and airway hyper-responsiveness in a mouse model of allergic airway inflammation. These results indicated that Hph-1-ctCTLA-4 constitutes an effective immunosuppressive protein drug for potential use in the treatment of allergic asthma, via nasal administration.