KMID : 0578320230460110688
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Molecules and Cells 2023 Volume.46 No. 11 p.688 ~ p.699
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Reduced Ceramides Are Associated with Acute Rejection in Liver Transplant Patients and Skin Graft and Hepatocyte Transplant Mice, Reducing Tolerogenic Dendritic Cells
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Yoo Hyun-Ju
Yi Yeog-Yeong Kang Yoo-Rha Kim Su-Jung Yoon Young-In Phuc Huu Tran Kang Tae-Wook Kim Min-Kyung Han Jae-Seok Tak Eun-Young Ahn Chul-Soo Song Gi-Won Park Gil-Chun Lee Sung-Gyu Kim Jae-Joong Jung Dong-Hwan Hwang Shin Kim Na-Young
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Abstract
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We set up this study to understand the underlying mechanisms of reduced ceramides on immune cells in acute rejection (AR). The concentrations of ceramides and sphingomyelins were measured in the sera from hepatic transplant patients, skin graft mice and hepatocyte transplant mice by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Serum concentrations of C24 ceramide, C24:1 ceramide, C16:0 sphingomyelin, and C18:1 sphingomyelin were lower in liver transplantation (LT) recipients with than without AR. Comparisons with the results of LT patients with infection and cardiac transplant patients with cardiac allograft vasculopathy in humans and in mouse skin graft and hepatocyte transplant models suggested that the reduced C24 and C24:1 ceramides were specifically involved in AR. A ceramide synthase inhibitor, fumonisin B1 exacerbated allogeneic immune responses in vitro and in vivo, and reduced tolerogenic dendritic cells (tDCs), while increased P3-like plasmacytoid DCs (pDCs) in the draining lymph nodes from allogeneic skin graft mice. The results of mixed lymphocyte reactions with ceranib-2, an inhibitor of ceramidase, and C24 ceramide also support that increasing ceramide concentrations could benefit transplant recipients with AR. The results suggest increasing ceramides as novel therapeutic target for AR, where reduced ceramides were associated with the changes in DC subsets, in particular tDCs.
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KEYWORD
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acute rejection, ceramide, human, mice, tolerogenic dendritic cells, transplantation
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