Blockade of the 4-1BB pathway attenuates graft arterial disease in cardiac allografts.
4-1BB, a member of the tumor necrosis factor (TNF) receptor superfamily, binds the 4-1BB ligand (4-1BBL) and works as a costimulatory molecule and regulates T cell-mediated immune responses. Because T cell-mediated immunity is associated with graft arterial disease (GAD), we investigated the role of the 4-1BB pathway in the progression of GAD. Hearts from C57BL/6 mice were transplanted into Bm12 mice (class II mismatch). 4-1BB expression was induced on CD4(+) and CD8(+) splenocytes in allografts after cardiac transplantation. 4-1BBL was detected in the vessel wall of the rejecting cardiac allograft and in cultured smooth muscle cells (SMCs) stimulated with fetal calf serum. Recipients were injected intraperitoneally with 4-1BBIg every 7 days for 8 weeks. GAD was significantly attenuated by 4-1BBIg treatment (luminal occlusion, 15.4 +/- 3.1% versus control IgG treatment, 75.6 +/- 4.6%, P < 0.001). T-cell infiltration of cardiac allografts and expression of interferon-g , interleukin-6, and interleukin-15 in cardiac allografts were suppressed by 4-1BBIg treatment. Coculture of SMCs with sensitized splenocytes after transplantation induced SMC proliferation, and this was inhibited by addition of 4-1BBIg. The 4-1BB pathway regulates not only T-cell activation but also SMC proliferation. Blockade of the 4-1BB pathway is a promising strategy to prevent progression of GAD.
Saiki
Hitoshi
H
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Suzuki
Jun-Ichi
J
Kosuge
Hisanori
H
Haraguchi
Go
G
Ishihara
Takashi
T
Haga
Takaaki
T
Maejima
Yasuhiro
Y
Isobe
Mitsuaki
M
Uede
Toshimitsu
T
D053330:4-1BB Ligand / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D006086:Graft vs Host Disease / Q000517:prevention & control*; D016027:Heart Transplantation; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000032:analysis; D019409:Interleukin-15 / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000166:cytology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology / Q000502:physiology*
D053330:4-1BB Ligand; D019409:Interleukin-15; D015850:Interleukin-6; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D007371:Interferon-gamma