Transduction of the cytoplasmic domain of CTLA-4 inhibits TcR-specific activation signals and prevents collagen-induced arthritis

Je Min Choi, Seung Hyung Kim, Jae Hoon Shin, Thomas Gibson, Byoung Seok Yoon, Dong Ho Lee, Seung Kyou Lee, Alfred L.M. Bothwell, Jong Soon Lim, Sang Kyou Lee

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32 Citations (Scopus)

Abstract

CTLA-4 (CD152) negatively regulates T cell activation signaling, and the cytoplasmic domain of CTLA-4 (ctCTLA-4) itself has the capacity to inhibit T cell activation in vitro and in vivo. In this study, the inhibitory mechanisms of the cell-permeable recombinant protein Hph-1-ctCTLA-4 on T cell activation and its ability to prevent collagen-induced arthritis were analyzed. Hph-1-ctCTLA-4 prevented human and mouse T cell activation and proliferation by inhibition of T cell receptor-proximal signaling and the arrest of the cell cycle. Furthermore, Hph-1-ctCTLA-4 protected human umbilical vein endothelial cells (HUVEC) from the human CTL allo-response. The incidence and severity of collagen-induced arthritis were significantly reduced and the erosion of cartilage and bone was effectively prevented by i.v. injection and transdermal administration of Hph-1-ctCTLA-4. Inflammatory cytokine production (IL-1β, IL-6, TNF-α, IL-17A) and collagen-specific antibody levels were significantly reduced, and the numbers of activated T cells and infiltrating granulocytes were substantially decreased. These results demonstrate that systemic or transdermal application of a cell-permeable form of the cytoplasmic domain of CTLA-4 offers an effective therapeutic approach for autoimmune diseases such as rheumatoid arthritis.

Original languageEnglish
Pages (from-to)19875-19880
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number50
DOIs
Publication statusPublished - 2008 Dec 16

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Experimental Arthritis
T-Lymphocytes
Cutaneous Administration
Interleukin-17
Human Umbilical Vein Endothelial Cells
T-Cell Antigen Receptor
Cell Cycle Checkpoints
Interleukin-1
Recombinant Proteins
Granulocytes
Autoimmune Diseases
Cartilage
Interleukin-6
Rheumatoid Arthritis
Collagen
Cell Proliferation
Cytokines
Bone and Bones
Injections
Antibodies

All Science Journal Classification (ASJC) codes

  • General

Cite this

Choi, Je Min ; Kim, Seung Hyung ; Shin, Jae Hoon ; Gibson, Thomas ; Yoon, Byoung Seok ; Lee, Dong Ho ; Lee, Seung Kyou ; Bothwell, Alfred L.M. ; Lim, Jong Soon ; Lee, Sang Kyou. / Transduction of the cytoplasmic domain of CTLA-4 inhibits TcR-specific activation signals and prevents collagen-induced arthritis. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 50. pp. 19875-19880.
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abstract = "CTLA-4 (CD152) negatively regulates T cell activation signaling, and the cytoplasmic domain of CTLA-4 (ctCTLA-4) itself has the capacity to inhibit T cell activation in vitro and in vivo. In this study, the inhibitory mechanisms of the cell-permeable recombinant protein Hph-1-ctCTLA-4 on T cell activation and its ability to prevent collagen-induced arthritis were analyzed. Hph-1-ctCTLA-4 prevented human and mouse T cell activation and proliferation by inhibition of T cell receptor-proximal signaling and the arrest of the cell cycle. Furthermore, Hph-1-ctCTLA-4 protected human umbilical vein endothelial cells (HUVEC) from the human CTL allo-response. The incidence and severity of collagen-induced arthritis were significantly reduced and the erosion of cartilage and bone was effectively prevented by i.v. injection and transdermal administration of Hph-1-ctCTLA-4. Inflammatory cytokine production (IL-1β, IL-6, TNF-α, IL-17A) and collagen-specific antibody levels were significantly reduced, and the numbers of activated T cells and infiltrating granulocytes were substantially decreased. These results demonstrate that systemic or transdermal application of a cell-permeable form of the cytoplasmic domain of CTLA-4 offers an effective therapeutic approach for autoimmune diseases such as rheumatoid arthritis.",
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Transduction of the cytoplasmic domain of CTLA-4 inhibits TcR-specific activation signals and prevents collagen-induced arthritis. / Choi, Je Min; Kim, Seung Hyung; Shin, Jae Hoon; Gibson, Thomas; Yoon, Byoung Seok; Lee, Dong Ho; Lee, Seung Kyou; Bothwell, Alfred L.M.; Lim, Jong Soon; Lee, Sang Kyou.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 50, 16.12.2008, p. 19875-19880.

Research output: Contribution to journalArticle

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AU - Choi, Je Min

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AU - Shin, Jae Hoon

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AU - Yoon, Byoung Seok

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AU - Lee, Sang Kyou

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