Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation.
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.
Choi
Je-Min
JM
Department of Biotechnology, College of Engineering, Yonsei University, Seoul 120-749, Republic of Korea.
Ahn
Mi-Hyun
MH
Chae
Wook-Jin
WJ
Jung
Yung-Gook
YG
Park
Jae-Chul
JC
Song
Hyun-Mi
HM
Kim
Young-Eun
YE
Shin
Jung-Ah
JA
Park
Choon-Sik
CS
Park
Jung-Won
JW
Park
Tae-Kwann
TK
Lee
Jung-Hoon
JH
Seo
Byung-Fhy
BF
Kim
Kyun-Do
KD
Kim
Eun-Sung
ES
Lee
Dong-Ho
DH
Lee
Seung-Kyou
SK
Lee
Sang-Kyou
SK
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
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