Reduced Ceramides Are Associated with Acute Rejection in Liver Transplant Patients and Skin Graft and Hepatocyte Transplant Mice, Reducing Tolerogenic Dendritic Cells.
Hyun Ju YooYeogyeong YiYoorha KangSu-Jung KimYoung-In YoonPhuc Huu TranTaewook KangMin Kyung KimJaeseok HanEunyoung TakChul-Soo AhnGi-Won SongGil-Chun ParkSung Gyu LeeJae-Joong KimDong Hwan JungShin HwangNayoung KimPublished in: Molecules and cells (2023)
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 B 1 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.
Keyphrases
- dendritic cells
- immune response
- regulatory t cells
- tandem mass spectrometry
- liquid chromatography
- end stage renal disease
- high fat diet induced
- lymph node
- newly diagnosed
- ejection fraction
- soft tissue
- stem cell transplantation
- prognostic factors
- high performance liquid chromatography
- liver injury
- wound healing
- drug induced
- mass spectrometry
- chronic kidney disease
- ultra high performance liquid chromatography
- heart failure
- bone marrow
- peritoneal dialysis
- simultaneous determination
- early stage
- toll like receptor
- type diabetes
- patient reported outcomes
- insulin resistance
- respiratory failure
- metabolic syndrome
- high resolution mass spectrometry
- high dose
- gas chromatography
- ms ms
- low dose
- solid phase extraction