Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation

被引:121
作者
Choi, Je-Min
Ahn, Mi-Hyun
Chae, Wook-Jin
Jung, Yung-Gook
Park, Jae-Chul
Song, Hyun-Mi
Kim, Young-Eun
Shin, Jung-Ah
Park, Choon-Sik
Park, Jung-Won
Park, Tae-Kwann
Lee, Jung-Hoon
Seo, Byung-Fhy
Kim, Kyun-Do
Kim, Eun-Sung
Lee, Dong-Ho
Lee, Seung-Kyou [1 ]
Lee, Sang-Kyou
机构
[1] Yonsei Univ, Coll Engn, Dept Biotechnol, Seoul 120749, South Korea
[2] Soonchunhyang Univ Hosp, Genome Res Ctr Allergy & Resp Dis, Puchon 420767, South Korea
[3] Yonsei Univ, Sch Med, Dept Internal Med, Div Allergy & Immunol, Seoul 120749, South Korea
[4] Soonchunhyang Univ Hosp, Dept Ophthalmol, Puchon 420767, South Korea
[5] Chungnam Natl Univ Hosp, Dept Dermatol, Taejon 301721, South Korea
[6] Amorepacific Co, R&D Ctr, Skin Res Inst, Yongin 449729, South Korea
[7] ForHumanTech Co Ltd, Suwon, South Korea
关键词
D O I
10.1038/nm1385
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:574 / 579
页数:6
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