Transduction of the cytoplasmic domain of CTLA-4 inhibits TcR-specific activation signals and prevents collagen-induced arthritis.
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-1beta, IL-6, TNF-alpha, 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.
Choi
Je-Min
JM
Department of Immunobiology, Yale University, School of Medicine, New Haven, CT 06520, USA.
Kim
Seung-Hyung
SH
Shin
Jae-Hoon
JH
Gibson
Thomas
T
Yoon
Byoung-Seok
BS
Lee
Dong-Ho
DH
Lee
Seung-Kyou
SK
Bothwell
Alfred L M
AL
Lim
Jong-Soon
JS
Lee
Sang-Kyou
SK
D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D001169:Arthritis, Experimental / Q000473:pathology / Q000517:prevention & control*; D060908:CTLA-4 Antigen; D002352:Carrier Proteins / Q000235:genetics*; D002358:Cartilage, Articular / Q000276:immunology / Q000473:pathology; D003593:Cytoplasm / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D007596:Joints / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D063150:Polycomb Repressive Complex 1; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D002352:Carrier Proteins; C556707:Ctla4 protein, mouse; C491239:PHC1 protein, human; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D063150:Polycomb Repressive Complex 1