RESUMEN
Natural killer-T (NKT) cells are rich in the liver. However, their involvement in liver injury is not fully understood. We developed here a new murine model of NKT-cell-activation-associated liver injury, and investigated a role of tumor necrosis factor alpha (TNF-alpha) and Fas in pathogenesis. We injected intraperitoneally alpha-galactosylceramide (alpha-GalCer), an NKT-cell stimulant, into D-galactosamine (GalN)-sensitized mice. Survival rate, pathological changes of the liver, and plasma concentrations of cytokines were studied. Alpha-GalCer/GalN administration gave a lethal effect within 7 h, making pathological changes such as massive parenchymal hemorrhage, hepatocyte apoptosis, sinusoidal endothelial cell injury, and close apposition of lymphocytes to apoptotic hepatocytes. Anti-NK1.1 mAb-pretreated mice and Valpha14NKT knock out (KO) mice did not develop liver injury. Tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) were elevated at 4 h in the plasma. These cytokines were produced by hepatic lymphocytes as demonstrated by in vitro stimulation with alpha-GalCer. The lethal effect was suppressed in TNF-alpha KO mice, TNF receptor-1 KO mice, and lpr/lpr (Fas deficient) mice, whereas it was not in IFN-gamma KO mice. These results indicate that the present liver injury is characterized by parenchymal hemorrhage and hepatocyte apoptosis, and mediated by TNF-alpha secretion and direct cytotoxicity of alpha-GalCer-activated NKT cells.
Asunto(s)
Galactosilceramidas/toxicidad , Células Asesinas Naturales/inmunología , Hepatopatías/inmunología , Hígado/inmunología , Hígado/lesiones , Animales , Apoptosis/fisiología , Enfermedad Hepática Inducida por Sustancias y Drogas , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Galactosamina/farmacología , Etiquetado Corte-Fin in Situ , Interferón gamma/sangre , Interferón gamma/deficiencia , Interferón gamma/genética , Hígado/patología , Hepatopatías/patología , Ratones , Ratones Noqueados , Receptores del Factor de Necrosis Tumoral/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND/AIMS: The aim of this study was to evaluate the efficacy and toxicity of a novel chemotherapeutic regimen for advanced unresectable hepatocellular carcinoma. METHODOLOGY: Seventeen patients with unresectable hepatocellular carcinoma were treated by arterial infusion once a week of low-dose cisplatin (12 mg/m2) and doxorubicin (6 mg/m2) via a subcutaneously implanted injection port and by daily oral administration of 300 mg/day of UFT comprising 5-fluorouracil prodrug tegafur (FT) and uracil (U) at a ratio of 1:4. RESULTS: The median number of chemotherapy courses was 13 (range, 5-33). All patients were evaluated for response, toxicity, and survival. As assessed by conventional imaging criteria, there were 3 (17.6%) complete responses with disappearance of the primary tumor, tumor thrombosis of the portal vein and metastatic para-aortic lymph node swelling. In addition, there were 4 (23.5%) partial responses. Among 11 patients who had initially high alpha-fetoprotein levels (> 200 ng/mL), 5 (45%) had a > 50% drop after therapy. The overall tumor response rate (complete response + partial response) was 41% and the median survival was 7.1 (range; 4.2-25.1) months. As for toxicity, there was 1 treatment-related death due to septicemia caused by catheter-related infection. Myelosuppression and renal toxicity was relatively mild and transient. CONCLUSIONS: These results suggest that our low-dose chemotherapeutic regimen may be useful for the treatment of advanced unresectable hepatocellular carcinoma without worsening the quality of life of the patient.