Posttransplantation: future therapies

Recent advances in prophylaxis and treatment of hepatitis B virus (HBV) infection after liver transplantation have improved the outcome of liver transplantation for hepatitis B. Currently, the long-term use of hepatitis B immune globulin (HBIG) and/or nucleoside analogues are the only effective therapies to prevent or ameliorate HBV recurrence in liver transplant patients. However, they are very expensive, and breakthrough infections due to resistant HBV mutants are not infrequent. New strategies are being sought to decrease the risks of breakthrough infection and to increase the cost-effectiveness of liver transplantation for hepatitis B. Vaccination to prevent de novo infection is strongly recommended before transplantation, despite a decreased response in this immunosuppressed population. Adoptive transfer of immunity with such therapies as bone marrow or cytotoxic T lymphocyte transplants or xenotransplantation of an organ from a donor, which is not susceptible to infection by HBV may be effective in preventing or treating recurrent HBV posttransplantation. In addition, gene therapies and use of nucleoside and nucleotide analogues to disrupt various stages of the HBV life cycle may prevent or slow viral replication or assembly of the virus. Ultimately, the most effective therapy for the prevention of recurrent hepatitis B after liver transplantation will involve a combination of HBIG with one or more of the new antiviral agents.     

Selecting binding and complement-mediated lysis of human hepatoma cells (PLC/PRF/5) in culture by monoclonal antibodies to hepatitis B surface antigen.

High-affinity 125I-labelled monoclonal antibodies to hepatitis B virus surface antigen (HBsAg) bind to human hepatocellular carcinoma cell line, PLC/PRF/5, which synthesizes and secretes HBsAg. These monoclonal antibodies of the IgG1, IgG2a, and IgM isotypes are directed against different antigenic determinants on HBsAg and, in the presence of complement, both anti-HBs IgG2a and IgM, but not anti-HBs IgG1, lyse PLC/PRF/5 cells in culture. Although there is a low level of anti-HBs binding (especially with anti-HBs IgM) to human hepatoma cell lines which do not synthesize HBsAg (SK-Hep 1 and Mahlavu cells), this interaction does not lead to complement-mediated cell lysis and is thought to be nonspecific. Minimal binding of 125I-labeled anti-influenza HA antigen IgM binding to PLC/PRF/5 cells was also detected, but this likewise did not lead to complement-mediated cell lysis. These results indicate that a human hepatocellular carcinoma cell line, persistently infected with hepatitis B virus, can be recognized and lysed by monoclonal antibodies directed against specific determinants of HBsAg. Monoclonal antibodies to this viral envelope protein may prove to be useful immunodiagnostic and immunotherapeutic agents when such viral epitopes are expressed on the surface of infected cells.     

IL-1 is required for tumor invasiveness and angiogenesis

Here, we describe that microenvironmental IL-1 beta and, to a lesser extent, IL-1 alpha are required for in vivo angiogenesis and invasiveness of different tumor cells. In IL-1 beta knockout (KO) mice, local tumor or lung metastases of B16 melanoma cells were not observed compared with WT mice. Angiogenesis was assessed by the recruitment of blood vessel networks into Matrigel plugs containing B16 melanoma cells; vascularization of the plugs was present in WT mice, but was absent in IL-1 beta KO mice. The addition of exogenous IL-1 into B16-containing Matrigel plugs in IL-1 beta KO mice partially restored the angiogenic response. Moreover, the incorporation of IL-1 receptor antagonist to B16-containing plugs in WT mice inhibited the ingrowth of blood vessel networks into Matrigel plugs. In IL-1 alpha KO mice, local tumor development and induction of an angiogenic response in Matrigel plugs was less pronounced than in WT mice, but significantly higher than in IL-1 beta KO mice. These effects of host-derived IL-1 alpha and IL-1 beta were not restricted to the melanoma model, but were also observed in DA/3 mammary and prostate cancer cell models. In addition to the in vivo findings, IL-1 contributed to the production of vascular endothelial cell growth factor and tumor necrosis factor in cocultures of peritoneal macrophages and tumor cells. Host-derived IL-1 seems to control tumor angiogenesis and invasiveness. Furthermore, the anti-angiogenic effects of IL-1 receptor antagonist, shown here, suggest a possible therapeutic role in cancer, in addition to its current use in rheumatoid arthritis.     

Wilson's disease with severe hepatic insufficiency: beneficial effects of early administration of D-penicillamine

BACKGROUND: Wilson's disease, heralded by severe hepatic insufficiency, is a rare disorder for which emergency liver transplantation is considered to be the only effective therapy. AIMS: To report the features of Wilson's disease with severe hepatic insufficiency in a series of 17 patients and, during the second period of the study, to assess the efficacy of a policy consisting of early administration of D-penicillamine. PATIENTS: Seventeen consecutive patients with Wilson's disease were studied. During the first period of the study (up to 1979), none of the patients received D-penicillamine. During the second period (after 1979), all patients without encephalopathy at admission received D-penicillamine. RESULTS: The four patients observed during the first period who did not have encephalopathy at admission and did not receive D-penicillamine progressed to encephalopathy and died. Among the 13 consecutive patients observed during the second period, two patients with encephalopathy at admission did not receive D-penicillamine and were transplanted. The 11 remaining patients all received D-penicillamine. Ten of these patients survived without the need for transplantation and returned to compensated liver disease without liver insufficiency. In one patient, liver insufficiency progressed and transplantation had to be performed. CONCLUSIONS: In most patients with Wilson's disease heralded by severe hepatic insufficiency and without encephalopathy at admission, early administration of D-penicillamine was associated with survival without transplantation. These results suggest the importance of early diagnosis of this form of Wilson's disease before the onset of encephalopathy, and favour early administration of D-penicillamine which could avoid the need for transplantation in most cases.     

Mononeuritis multiplex: a rare complication of acute hepatitis A

Abstract: A 28-year-old man suffered from acute severe hepatitis A virus infection, documented by serologic diagnosis. During the clinical and enzymatic recovery phase, mononeuritis multiplex that involved the left ulnar and right lateral cutaneous nerves developed. It presented by sensorimotor disturbances in left arm and right thigh. Mononeuritis multiplex has been frequently described in patients with chronic hepatitis B, either isolated or associated with periarteritis nodosa. However, it has not been reported in association with hepatitis A infection.