, Seung-Hyung Kimb
, Jae-Hoon Shinc
, Thomas Gibsona
, Byoung-Seok Yoonc
, Dong-Ho Leed
, Seung-Kyou Leed
, Alfred L. M. Bothwella
, Jong-Soon Limb,c,1
, and Sang-Kyou Leec,d,1
Department of Immunobiology, Yale University, School of Medicine, New Haven, CT 06520; b
Institute of Traditional Medicine and Bioscience, Daejeon University, Daejeon 300-716, Republic of Korea; c
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea; and d
ForHumanTech Co., Ltd., 706, Suwon University Go-un Technology Center, Suwon 445-890, Republic of Korea
Edited by Peter Cresswell, Yale University School of Medicine, New Haven, CT, and approved October 16, 2008 (received for review May 28, 2008)
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.
autoimmune disease, costimulatory molecule
To whom correspondence may be addressed.
Author contributions: J.-M.C., A.L.M.B., J.-S.L., and Sang-Kyou Lee designed research; J.-M.C., S.-H.K., J.-H.S., T.G., and B.-S.Y. performed research; D.-H.L., Seung-Kyou Lee, and J.-S.L. contributed new reagents/analytic tools; J.-M.C., S.-H.K., A.L.M.B., and J.-S.L. analyzed data; and J.-M.C., A.L.M.B., and Sang-Kyou Lee wrote the paper.
Conflict of interest statement: The authors have pending patent applications.
This article is a PNAS Direct Submission.
This article contains supporting information online atwww.pnas.org/cgi/content/full/0805198105/DCSupplemental