FK506 in liver transplantation for chronic hepatitis B: in vitro studies on lymphocyte activation and virus replication.
Recurrence of hepatitis B virus (HBV) in the graft is the major problem for patients with chronic HBV infection undergoing liver transplantation, which could be potentiated by the immunosuppression. In the present study, we used lymphocytes and hepatocytes isolated from patients with chronic HBV infection to investigate in vitro the effects of FK506 with and without methylprednisolone (25 ng/mL) on mitogen-induced lymphocyte proliferation, T-cell activation marker expression, and HBV replication in human hepatocytes. Increasing concentrations of FK506 (0.1, 0.5, and 5 ng/mL) resulted in a dose-dependent inhibition of lymphocyte proliferation with a reduction of the stimulation index by 9.2%, 39.0%, and 55.1%, respectively, with no difference between 25 chronic HBV carriers and normal controls. Methylprednisolone alone had no effect but potentiated the inhibitory effect of all three FK506 concentrations, such that the stimulation index was decreased by 20%, 56.2%, and 65.7%, respectively. FK506 (0.5 ng/ mL) reduced both the percentage of interleukin-2 receptor expressing T cells and the cell surface density of this receptor by 7.1% and 8.7% (P < .01), whereas it only reduced the proportion of HLA-DR expressing T cells by 6.8%. FK506 did not change significantly the intracellular HBV DNA or the hepatic expression of hepatitis B surface antigen (HBsAg) in short-term culture of human hepatocytes, whereas methylprednisolone increased the percentage of HBsAg-positive hepatocytes in all 5 patients with active viral replication. These results indicate that the effects of FK506 on T-cell activation in chronic HBV carriers are identical to normal subjects, resulting in marked suppression of T-lymphocyte function but only modest reduction in the expression of cell surface activation markers. The drug showed no direct stimulatory effect on viral replication, suggesting that FK506 can be a useful, steroid-sparing immunosuppressive agent for liver graft recipients with chronic HBV infection.
Wong
P Y
PY
Institute of Liver Studies, King's College School of Medicine and Dentistry, London, England.
Marinos
G
G
Peakman
M
M
Tredger
J M
JM
Lau
J Y
JY
Vergani
D
D
Naoumov
N V
NV
Williams
R
R
D000328:Adult; D018929:Cell Culture Techniques; D002455:Cell Division / Q000187:drug effects; D004279:DNA, Viral / Q000032:analysis; D004357:Drug Synergism; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006684:HLA-DR Antigens / Q000378:metabolism; D006510:Hepatitis B Antibodies / Q000032:analysis; D006514:Hepatitis B Surface Antigens / Q000378:metabolism; D006515:Hepatitis B virus / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000150:complications* / Q000601:surgery; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016031:Liver Transplantation; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D008875:Middle Aged; D013601:T-Lymphocytes / Q000502:physiology*; D016559:Tacrolimus / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
D004279:DNA, Viral; D005938:Glucocorticoids; D006684:HLA-DR Antigens; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D007166:Immunosuppressive Agents; D016559:Tacrolimus; D008775:Methylprednisolone