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

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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.

Original languageEnglish
Pages (from-to)574-579
Number of pages6
JournalNature Medicine
Volume12
Issue number5
DOIs
Publication statusPublished - 2006 May 1

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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