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SUMMARY4-1BB, 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-γ , 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. (Int Heart J 2008; 49: 105-118)

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The F 1 hybrid of autoimmune hemolytic anemia-prone NZB and nonautoimmune NZW strains of mice has been studied as a murine model of systemic lupus erythematosus. Both NZB and F 1 hybrid mice show age-dependent spontaneous activation of peripheral CD4 þ T cells as reflected by the elevated frequencies of CD4 þ T cells positive for CD69 early activation marker. Both strains also show age-dependent abnormal decrease of the frequencies of CD62L þ naive CD4 þ T cells and/or NTA260 þ memory CD4 þ T cells in the spleen. We studied the multigenic control of these abnormal features of peripheral CD4 þ T cells in (NZB Â NZW) F 1 Â NZW backcross mice by quantitative trait loci mapping and by association rule analysis. The abnormally elevated frequencies of CD69 þ CD4 þ T cells and decreased frequencies of CD62L þ naive and/or NTA260 þ memory CD4 þ T cells were under the common genetic control, in which the interaction between MHC and a hitherto unknown locus, designated Sta-1 (spontaneous T-cell activation) on chromosome 12, plays a major role. The allelic effects of these loci likely predispose CD4 þ T cells to the loss of self-tolerance, and are responsible for the accelerated autoimmune phenotypes of (NZB Â NZW) F 1 hybrid mice.

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