Analysis of costimulation by 4-1BBL, CD40L, and B7 in graft rejection by gene expression profiles

DeFina, Rachel; Christopher, Kenneth B.; He, Hongzhen; Mandelbrot, Didier A.; YongPing, Gu; Perkins, David L.

doi:10.1007/s00109-003-0468-1

Cited by 6 publications

(2 citation statements)

References 16 publications

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“…10 Furthermore, CD40 -CD40L interaction plays an essential role in autoimmunity and transplant rejection. 11 Blocking of CD40L may become a promising therapeutic approach in autoimmune processes and in transplantation medicine. 12,13 Recently, the potency of blocking the CD40 -CD40L interaction by CD40 antisense oligonucleotides was elucidated to treat experimental colitis.…”

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confidence: 99%

Induction of murine liver damage by overexpression of CD40 ligand provides an experimental model to study fulminant hepatic failure

et al. 2006

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Previously, we demonstrated that intrahepatic upregulation of the immunoactivating molecules CD40 and CD40 ligand (CD40L) are early mechanisms for liver cell damage in human and murine fulminant hepatic failure (FHF). In the present study, we investigated the functional effects of intrahepatic overexpression of CD40L by adenoviral-mediated gene transfer (AdCD40L) in mice. AdCD40L injection induced severe liver cell damage, which was associated with increased alanine aminotransferase (ALT) levels peaking at day 5 after vector administration (AdCD40L, 1,707 ؎ 279 U/L; AdLacZ, 213 ؎ 25 U/L) and with lethality in half of the mice. Except for mild splenomegaly, no organs other than the liver were involved in inflammatory reactions. CD40 -CD40L interaction was mandatory for liver damage, because CD40 ؊/؊ mice were completely protected. F ulminant hepatic failure (FHF) is a life-threatening condition induced by pathogens such as hepatitis B virus infection and drug toxicity. The underlying pathophysiological mechanisms are not fully understood. This renders a causal therapeutic approach difficult. 1,2 Uncontrolled hepatic immunoactivation is discussed as a pivotal pathomechanism of FHF. 3-5 Recently, we described significant intrahepatic upregulation of the immunoactivating molecules CD40 and its ligand (CD40L/ CD154) in patients with FHF. 3 In human FHF, CD40 was upregulated in hepatocytes, sinusoidal and vascular endothelial cells, and macrophages/Kupffer cells, whereas CD40L was expressed in an increased number of intrahepatic lymphocytes. Taking into account our observation of strongly enhanced hepatic CD40 and CD40L expression in FHF and the potent immunoactivating properties of the CD40 -CD40L interaction, we hypothesized that the interaction of CD40 with CD40L is a pivotal trigger of immune cascade-inducing FHF.CD40L is a member of the tumor necrosis factor receptor superfamily and is expressed on activated CD4 ϩ T cells and platelets. 6,7 The CD40 -CD40L interaction induces strong immunoactivation at different levels of the immune system, including T cells, B cells, macrophages, and dendritic cells. Interaction of CD40 -CD40L on dendritic cells and other antigen-presenting cells such as monocytes/macrophages and B lymphocytes upregulates Abbreviations: FHF, fulminant hepatic failure; CD40L, CD40 ligand; AdCD40L, adenoviral CD40 ligand; ALT, alanine aminotransferase; NKT cell, natural killer T cell; pfu,

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confidence: 99%

Induction of murine liver damage by overexpression of CD40 ligand provides an experimental model to study fulminant hepatic failure

et al. 2006

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“…15) Also, 4-1BB-deficient or 4-1BBL-deficient recipient mice showed prolongation of allograft survival time. 15,16) However, the involvement of the 4-1BB pathway in the development of GAD has not been reported to date.…”

Section: Saiki Et Almentioning

confidence: 99%

Blockade of the 4-1BB Pathway Attenuates Graft Arterial Disease in Cardiac Allografts

et al. 2008

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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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Gene therapy using adenoviral vector encoding 4-1BBIg gene significantly prolonged murine cardiac allograft survival

Huang

Yin

Huang

et al. 2006

Transplant Immunology

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Analysis of costimulation by 4-1BBL, CD40L, and B7 in graft rejection by gene expression profiles

Cited by 6 publications

References 16 publications

Induction of murine liver damage by overexpression of CD40 ligand provides an experimental model to study fulminant hepatic failure

Induction of murine liver damage by overexpression of CD40 ligand provides an experimental model to study fulminant hepatic failure

Blockade of the 4-1BB Pathway Attenuates Graft Arterial Disease in Cardiac Allografts

Gene therapy using adenoviral vector encoding 4-1BBIg gene significantly prolonged murine cardiac allograft survival

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