Atherosclerosis Deteriorates Liver Ischemia/Reperfusion Injury Via Interferon Regulatory Factor-1 Overexpression in a Murine Model.

BACKGROUND: Abdominal aortic calcification (AAC) is associated with cardiovascular-related mortality, along with an elevated risk of coronary, cerebrovascular, and cardiovascular events. Notably, AAC is strongly associated with poor overall and recurrence free survival posthepatectomy for hepatocellular carcinoma. Despite the acknowledged significance of atherosclerosis in systemic inflammation, its response to ischemia/reperfusion injury (IRI) remains poorly elucidated. In this study, we aimed to clarify the impact of atherosclerosis on the liver immune system using a warm IRI mouse model. METHODS: Injury was induced in an atherosclerotic mouse model (ApoE-/-) or C57BL/6J wild-type (WT) mice through 70% clamping for 1 hour and analyzed after 6 hours of reperfusion. RESULTS: Elevated serum levels of aspartate and alanine aminotransferase, along with histological assessment, indicated considerable damage in the livers of ApoE-/- mice than that in WT mice. This indicates a substantial contribution of atherosclerosis to IRI. Furthermore, T and natural killer (NK) cells in ApoE-/- mouse livers displayed a more inflammatory phenotype than those in WT mouse livers. Reverse transcription-polymerase chain reaction analysis revealed a significant upregulation of interleukin (IL)-15 and its transcriptional regulator, interferon regulatory factor-1 (IRF-1) in ApoE-/- mouse livers compared with that in WT mouse livers. CONCLUSIONS: These findings suggest that in an atherosclerotic mouse model, atherosclerosis can mirror intrahepatic immunity, particularly activating liver NK and T cells through IL-15 production, thereby exacerbating hepatic damage. The upregulation of IL-15 expression is associated with IRF-1 overexpression.

Successful Treatment of Chronic Myeloid Leukemia With Dasatinib After Kidney Transplantation: A Case Report.

OBJECTIVE: Chronic myeloid leukemia (CML) is a rare malignancy in kidney transplant (KT) recipients. Although dasatinib is the first-line treatment for CML, it has inhibitory activity against CYP3A4; this might increase the blood concentration of tacrolimus (administered to KT patients for immune suppression). Furthermore, tacrolimus can also increase blood concentrations of dasatinib through P-glycoprotein inhibition. METHODS: Here, we report a case of sustained molecular remission of CML with prolonged first-line dasatinib therapy in a KT recipient being treated with tacrolimus. A 61-year-old woman developed CML-chronic phase (CML-CP) 38 months post KT. Her maintenance immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil, and methylprednisolone. Considering the potential drug interaction with tacrolimus, dasatinib was administered at a low dose of 50 mg/day. Her immune status was evaluated regularly by assessing the mixed lymphocyte reaction (MLR) using an intracellular carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeling technique; immunosuppressive therapy was adjusted accordingly. RESULTS: The patient achieved complete hematologic remission (CHR) after 1 month of dasatinib treatment. Six months after dasatinib treatment, she achieved a major molecular response. During the observation period, neither antibody-mediated nor acute cellular rejection were encountered in the patient. She remained in CHR with a major molecular response 12 months after the diagnosis of CML-CP. CONCLUSION: Data obtained from immune monitoring assays using CFSE-MLR helped us to successfully manage a KT recipient with CML-CP being treated with dasatinib. Drug-drug interactions are a key consideration while designing treatment regimens; such strategies would ensure that drug-drug interactions do not negatively affect the treatment outcomes.