INTRAOPERATIVE COURSE AND PROGNOSTIC-SIGNIFICANCE OF ENDOTOXIN, TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-6 IN LIVER-TRANSPLANT RECIPIENTS

Early events in reaction of the host immune system to an allograft were studied by intraoperative measurements of endotoxin (ET), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in human liver transplantation. Blood samples were collected prior to operation, before clamping of the liver vessels, at the beginning and end of the anhepatic phase, and 5 and 30 min after recirculation. Diagnosis of rejection and infection in the graft recipients was established by assessment of spontaneous blastogenesis and T-lymphocyte subpopulations in addition to clinical symptoms and results from biopsies and blood chemistry. Of the 27 unmatched liver transplantations included in this study, 8 patients had infections in the first two postoperative weeks and 6 patients showed rejection of their grafts under antithymocyte globulin immunoprophylaxis. Endotoxin was transiently elevated in plasma in the anhepatic phase (2-fold in comparison to normal values) as expected for an accumulation of intestine-derived endotoxin during clamping of liver vessels, but no correlation was found with TNF-alpha levels and specific post-transplant complications. All patients with rejections had high plasma levels of TNF-alpha immediately after recirculation (mean value 240 pg TNF-alpha/ml), in contrast to low TNF-alpha levels in graft recipients without complications or infections. These results indicate that the initiation of rejection in liver transplantation is associated with increased plasma concentrations of TNF-alpha. The measured TNF-alpha concentrations are adequate to promote the binding of lymphocytes to allograft endothelial tissue and/or to induce expression of MHC antigens in the graft. Subsequent viral or bacterial infections were preceded by high intraoperative plasma concentrations of interleukin-6 (mean value 1400 pg IL-6/ml). The correlations of rejection with high intraoperative TNF-alpha levels and of infection with those of IL-6 are statistically significant in Wilcoxon tests for the direct measurements and in Fisher's exact tests for positive test values, with limits of 90 pg/ml for TNF-alpha and 800 pg/ml for IL-6.