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

Je Min Choi; Mi Hyun Ahn; Wook Jin Chae; Yung Gook Jung; Jae Chul Park; Hyun Mi Song; Young Eun Kim; Jung Ah Shin; Choon Sik Park; Jung Won Park; Tae Kwann Park; Jung Hoon Lee; Byung Fhy Seo; Kyun Do Kim; Eun Sung Kim; Dong Ho Lee; Seung Kyou Lee; Sang Kyou Lee

doi:10.1038/nm1385

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

Je Min Choi, Mi Hyun Ahn, Wook Jin Chae, Yung Gook Jung, Jae Chul Park, Hyun Mi Song, Young Eun Kim, Jung Ah Shin, Choon Sik Park, Jung Won Park, Tae Kwann Park, Jung Hoon Lee, Byung Fhy Seo, Kyun Do Kim, Eun Sung Kim, Dong Ho Lee, Seung Kyou Lee, Sang Kyou Lee

Research output: Contribution to journal › Article › peer-review

120 Citations (Scopus)

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_H2) 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.

Original language	English
Pages (from-to)	574-579
Number of pages	6
Journal	Nature Medicine
Volume	12
Issue number	5
DOIs	https://doi.org/10.1038/nm1385
Publication status	Published - 2006 May

Bibliographical note

Funding Information:
We thank A. Bothwell and T. Morio for the comments on the manuscript and all members of Immune Cell Engineering Laboratory, Department of Biotechnology, Yonsei University for their spiritual help. This work was supported in part by research grants to S.K.L. from Korea Institute of Industrial Technology Evaluation and Planning (M1-0310-40-0000), Korea Health Industry Development Institute (0412-DB00-0101-0011), Korea Science and Engineering Foundation (2005-00117) and Korea Rural Economic Institute (204081-3). This work was also supported in part by research grants to C.S.P. from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (01-PJ3-PG6-01GN04-003).

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

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10.1038/nm1385

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Choi, J. M., Ahn, M. H., Chae, W. J., Jung, Y. G., Park, J. C., Song, H. M., Kim, Y. E., Shin, J. A., Park, C. S., Park, J. W., Park, T. K., Lee, J. H., Seo, B. F., Kim, K. D., Kim, E. S., Lee, D. H., Lee, S. K., & Lee, S. K. (2006). Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation. Nature Medicine, 12(5), 574-579. https://doi.org/10.1038/nm1385

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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 (TH2) 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.",

author = "Choi, {Je Min} and Ahn, {Mi Hyun} and Chae, {Wook Jin} and Jung, {Yung Gook} and Park, {Jae Chul} and Song, {Hyun Mi} and Kim, {Young Eun} and Shin, {Jung Ah} and Park, {Choon Sik} and Park, {Jung Won} and Park, {Tae Kwann} and Lee, {Jung Hoon} and Seo, {Byung Fhy} and Kim, {Kyun Do} and Kim, {Eun Sung} and Lee, {Dong Ho} and Lee, {Seung Kyou} and Lee, {Sang Kyou}",

note = "Funding Information: We thank A. Bothwell and T. Morio for the comments on the manuscript and all members of Immune Cell Engineering Laboratory, Department of Biotechnology, Yonsei University for their spiritual help. This work was supported in part by research grants to S.K.L. from Korea Institute of Industrial Technology Evaluation and Planning (M1-0310-40-0000), Korea Health Industry Development Institute (0412-DB00-0101-0011), Korea Science and Engineering Foundation (2005-00117) and Korea Rural Economic Institute (204081-3). This work was also supported in part by research grants to C.S.P. from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (01-PJ3-PG6-01GN04-003).",

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month = may,

doi = "10.1038/nm1385",

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Choi, JM, Ahn, MH, Chae, WJ, Jung, YG, Park, JC, Song, HM, Kim, YE, Shin, JA, Park, CS, Park, JW, Park, TK, Lee, JH, Seo, BF, Kim, KD, Kim, ES, Lee, DH, Lee, SK & Lee, SK 2006, 'Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation', Nature Medicine, vol. 12, no. 5, pp. 574-579. https://doi.org/10.1038/nm1385

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AU - Choi, Je Min

AU - Ahn, Mi Hyun

AU - Chae, Wook Jin

AU - Jung, Yung Gook

AU - Park, Jae Chul

AU - Song, Hyun Mi

AU - Kim, Young Eun

AU - Shin, Jung Ah

AU - Park, Choon Sik

AU - Park, Jung Won

AU - Park, Tae Kwann

AU - Lee, Jung Hoon

AU - Seo, Byung Fhy

AU - Kim, Kyun Do

AU - Kim, Eun Sung

AU - Lee, Dong Ho

AU - Lee, Seung Kyou

AU - Lee, Sang Kyou

N1 - Funding Information: We thank A. Bothwell and T. Morio for the comments on the manuscript and all members of Immune Cell Engineering Laboratory, Department of Biotechnology, Yonsei University for their spiritual help. This work was supported in part by research grants to S.K.L. from Korea Institute of Industrial Technology Evaluation and Planning (M1-0310-40-0000), Korea Health Industry Development Institute (0412-DB00-0101-0011), Korea Science and Engineering Foundation (2005-00117) and Korea Rural Economic Institute (204081-3). This work was also supported in part by research grants to C.S.P. from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (01-PJ3-PG6-01GN04-003).

PY - 2006/5

Y1 - 2006/5

N2 - 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 (TH2) 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.

AB - 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 (TH2) 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.

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

Abstract

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