Intragraft immune events after human liver transplantation. Correlation with clinical signs of acute rejection and influence of immunosuppression.

Abstract

Evaluation of graft morphology is regarded as a cornerstone for diagnosis of acute liver graft rejection. Here we have studied the clinical relevance of biopsy findings obtained either by aspiration cytology or by histology in the first month after human liver transplantation, and have assessed the influence of immunosuppressive induction treatment on the incidence of morphological and clinical rejection. Results of 865 aspiration biopsies (TAC) and 155 core biopsies in 141 patients were correlated with the retrospective clinical diagnosis concerning the presence or absence of acute rejection. This analysis demonstrated that there are almost no false negative findings either in cytology or in histology (less than 0.1% of negative biopsies). In contrast, with both methods a large number of positive biopsy results were obtained that were without clinical correlate ("false positive" biopsies; 46% and 41% of positive cytologies and histologies, respectively). The rates of clinical and morphological acute rejections were differently influenced by the type of immunosuppressive induction protocol used. The incidence of clinical rejection was particularly low with a quadruple drug regimen when cyclosporine therapy was started immediately after transplantation (29% vs. 62% when introduction of cyclosporine was delayed for 2-5 days). Morphological rejections were similarly frequent with immediate and delayed introduction of cyclosporine at 2 mg/kg during quadruple therapy (65-75%) and were only reduced with initial high dose cyclosporine treatment (5 mg/kg) (35%). Antirejection treatment was not required in patients with morphological evidence of rejection but without clinical symptoms. The study demonstrates that cytology and histology are similarly reliable for exclusion and similarly unreliable for diagnosis of clinical acute rejection. The clinical relevance of positive biopsy findings is strongly influenced by the basic immunosuppressive treatment. Certain types of induction treatment can obviously alter the alloresponse in a way that no graft damage occurs despite the presence of marked intragraft immune activation. "False-positive" biopsy findings, therefore, seem to represent a qualitatively modified and self-limited type of intragraft alloresponse that is without clinical consequences ("incomplete" or "subclinical" rejection).