Correlation between bioassayed plasma levels of FK 506 and lymphocyte growth from liver transplant biopsies with histological evidence of rejection.

FK 506, a novel immunosuppressive agent, was first used to reverse rejection in liver recipients who had failed to respond to conventional therapy.' The successful outcome of the initial study has led to clinical trials of FK 506 as the primary immunosuppressive agent for liver allografts and other organ transplants. 2-4 Ongoing studies include dosage protocols for optimal immunosuppression without significant side effects. Monitoring plasma levels of FK 506 in the transplant patient is performed using an enzyme-linked immunosorbent assay (ELISA) in the presence of anti-FK 506 monoclonal antibody. S FK 506 exhibits strong immunosuppressive effect on in vitro models of T-cell activation including mixed lymphocyte reaction and secondary proliferative responses (PLT) of alloreactive T cells. 6 .7 Recently we have developed another method to monitor plasma levels of FK 506, a bioassay based on the inhibition of the PL T response of an alloreactive T-cell c1one. 8 Our results indicate that the levels of active FK 506 determined by the bioassay are consistently lower than those measured by ELISA. Histologic examination of needle core biopsies differentiate acute cellular rejection from other causes of liver allograft dysfunction. The major histologic signs of hepatic allograft rejection are: a predominantly mononuclear portal infiltrate and evidence of bile duel damage.9 Immunophenotypic analysis of this inflammatory infiltrate reveals the presence of CD4+ and CD8+ T cells. macrophages. monocytes. neutrophils. eosinophils. and B cells. lu Graft infiltrating lymphocytes can be propagated in vitro in the presence of tissue culture media supplemented with recombinant Interleukin 2 (rIL2). II In vitro propagation of lymphocytes from transplant biopsies has increased our understanding of the immunological events in rejection. We have shown that in cyclosporine (CyAHreated patients increased lymphocyte growth occurs in biopsies with proven histologic rejection. 12 In the present study we investigated the frequency of lymphocyte growth from liver allograft biopsies in FK 506-treated patients. We also examined the relationship between lymphocyte growth from biopsies with different histologic diagnoses and the plasma levels of FK 506 as determined by ELISA and bioassay.