Costimulatory blockade prevents early rejection, promotes lymphocyte apoptosis, and inhibits the upregulation of intragraft interleukin-6 in an orthotopic liver transplant model in the rat

Bartlett, Adam; McCall, John L.; Ameratunga, Rohan; Howden, B O; Yeong, Mee Ling; Benjamin, Christopher D.; Hess, Donna M.; Peach, Robert; Munn, Stephen

doi:10.1053/jlts.2002.32979

Cited by 11 publications

(7 citation statements)

References 60 publications

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“…Off-label use of nivolumab in two young patients with posttransplant recurrent, refractory fibrolamellar HCC was followed by a rapid and irreversible acute liver rejection that resulted in a fatal outcome (31). The role of CTLA-4 in liver allograft rejection is not so well understood, but treatment with a CTLA-4/Ig fusion protein prevents early rejection in an animal model of liver transplantation (32). Off-label use of ipilimumab in two patients who developed melanoma after liver transplantation was not followed by organ rejection or immune-related AEs (33,34).…”

Section: The Hopesmentioning

confidence: 99%

Immunotherapy of Hepatocellular Carcinoma: Facts and Hopes

Iñarrairaegui

Melero

Sangro

2018

Clinical Cancer Research

206

164

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Treatment of patients with hepatocellular carcinoma (HCC) in the advanced stage remains a great challenge, with very few drugs approved. After decades of failure of immune therapies, immune checkpoint inhibitors have emerged as potentially effective treatments for patients with HCC in the advanced stage. Immune checkpoints, including human cancer, cytotoxic T-lymphocyte protein 4 (CTLA-4), and programmed cell death protein 1 (PD-1), are surface proteins expressed in a variety of immune cells and mostly provide immunosuppressive signals. Monoclonal antibodies able to block these molecules have shown antitumor activity against a wide spectrum of human cancers. Clinical experience with checkpoint inhibitors in HCC includes early trials with the anti-CTLA-4 agent tremelimumab and a large phase II trial with the anti-PD-1 agent nivolumab. The latter has shown strong activity particularly as second-line therapy, both in terms of tumor response and patient survival. At least three topics should be the focus of future research: (i) the search for activity in patients at less-advanced stages, including the adjuvant treatment of patients with resectable or ablatable tumors; (ii) the enhanced efficacy of combination therapies, including particularly the combination with those targeted and locoregional therapies that may have a synergistic effect or act upon mechanisms of primary or acquired resistance to checkpoint inhibitors; and (iii) the identification of clinical features and serum or tissue biomarkers that would allow a better patient selection for individual treatments. Hopefully, ongoing trials will help to design better treatments in the future. .

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Section: The Hopesmentioning

confidence: 99%

Immunotherapy of Hepatocellular Carcinoma: Facts and Hopes

Iñarrairaegui

Melero

Sangro

2018

Clinical Cancer Research

206

164

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“…The efficacy of anti‐CD154 and CTLA4‐Ig were compared in a rearterialized rat liver allograft model 44. Both treatments lead to prolonged allograft survival but treatment with anti‐CD154 was associated with less biliary and endothelial cell injury compared with CTLA4‐Ig.…”

Section: Costimulatory Pathways and Transplantationmentioning

confidence: 99%

Basic concepts in transplant immunology

Martinez

Rosen

2005

Liver Transpl

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“…Similarly, in a murine cardiac model, intragraft CD154 transcripts were virtually undetectable in syngeneic grafts, but were strongly expressed by day 5 in fully allogeneic strain combinations (6). We have demonstrated increased CD154 gene expression in untreated recipients at day 8 in a high responder rat OLT model (27). Recipients treated with cyclosporin (20 mg/kg/day) did not show an increase in CD154 mRNA expression following transplantation (27).…”

Section: Discussionmentioning

confidence: 62%

“…We have demonstrated increased CD154 gene expression in untreated recipients at day 8 in a high responder rat OLT model (27). Recipients treated with cyclosporin (20 mg/kg/day) did not show an increase in CD154 mRNA expression following transplantation (27). Whether this is the result of CyA inhibiting CD154 mRNA transcription, owing to an absence of intragraft alloreactivity, or an organ-specific phenomenon is not known.…”

Section: Discussionmentioning

confidence: 91%

Analysis of Intragraft Gene and Protein Expression of the Costimulatory Molecules, CD80, CD86 and CD154, in Orthotopic Liver Transplant Recipients

Bartlett¹,

McCall²,

Ameratunga³

et al. 2003

American Journal of Transplantation

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CD40-CD154 and/or CD28-CD80/86 costimulatory blockade induces long-term allograft survival in numerous animal models. Studies examining the expression of costimulatory molecules during acute cellular rejection (ACR) have been limited to renal and cardiac allografts.The aim of this study was to describe the relationship between intragraft costimulatory molecule expression in OLT recipients and ACR. Forty-five liver biopsies were obtained at reperfusion and day 7. Gene and protein expression of CD80, CD86 and CD154 were analyzed by RT-PCR and immunohistochemistry. CD154 protein expression was present in 13 of 18 patients with a RAI score of 4, but in only two of 14 patients with a RAI score of <4. There was a strong association between the RAI score and the presence of CD80 and CD154 immunoreactivity. CD86 protein expression did not correlate with the severity of ACR. In reperfusion biopsies CD154, but not CD80 or CD86, protein expression correlated with the total ischaemic time. There was no association between expression of costimulatory molecule genes and ACR.In conclusion, we have demonstrated an association between CD154 and CD80 protein expression and ACR in orthotopic liver allografts.

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Costimulatory blockade prevents early rejection, promotes lymphocyte apoptosis, and inhibits the upregulation of intragraft interleukin-6 in an orthotopic liver transplant model in the rat

Cited by 11 publications

References 60 publications

Immunotherapy of Hepatocellular Carcinoma: Facts and Hopes

Immunotherapy of Hepatocellular Carcinoma: Facts and Hopes

Basic concepts in transplant immunology

Analysis of Intragraft Gene and Protein Expression of the Costimulatory Molecules, CD80, CD86 and CD154, in Orthotopic Liver Transplant Recipients

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