title: Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation.
abstract: 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.
authors.affiliation: Department of Biotechnology, College of Engineering, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Je-Min
authors.initials: JM
authors.lastname: Choi
authors.forename: Mi-Hyun
authors.initials: MH
authors.lastname: Ahn
authors.forename: Wook-Jin
authors.initials: WJ
authors.lastname: Chae
authors.forename: Yung-Gook
authors.initials: YG
authors.lastname: Jung
authors.forename: Jae-Chul
authors.initials: JC
authors.lastname: Park
authors.forename: Hyun-Mi
authors.initials: HM
authors.lastname: Song
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Kim
authors.forename: Jung-Ah
authors.initials: JA
authors.lastname: Shin
authors.forename: Choon-Sik
authors.initials: CS
authors.lastname: Park
authors.forename: Jung-Won
authors.initials: JW
authors.lastname: Park
authors.forename: Tae-Kwann
authors.initials: TK
authors.lastname: Park
authors.forename: Jung-Hoon
authors.initials: JH
authors.lastname: Lee
authors.forename: Byung-Fhy
authors.initials: BF
authors.lastname: Seo
authors.forename: Kyun-Do
authors.initials: KD
authors.lastname: Kim
authors.forename: Eun-Sung
authors.initials: ES
authors.lastname: Kim
authors.forename: Dong-Ho
authors.initials: DH
authors.lastname: Lee
authors.forename: Seung-Kyou
authors.initials: SK
authors.lastname: Lee
authors.forename: Sang-Kyou
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D001249:Asthma / Q000276:immunology / Q000517:prevention & control; D016535:Bronchial Hyperreactivity; D060908:CTLA-4 Antigen; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D063150:Polycomb Repressive Complex 1; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014161:Transduction, Genetic
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D002352:Carrier Proteins; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; C491239:PHC1 protein, human; D011993:Recombinant Fusion Proteins; D010047:Ovalbumin; D063150:Polycomb Repressive Complex 1