Is there a Role for Cyclophilin Inhibitors in the Management of Primary Biliary Cirrhosis?

Abstract

Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are poorly understood autoimmune liver diseases. Immunosuppression is used to treat AIH and ursodeoxycholic acid is used to slow the progression of PBC. Nevertheless, a proportion of patients with both disorders progress to liver failure. Following liver transplantation, up to a third of patients with PBC experience recurrent disease. Moreover a syndrome referred to as “de novo AIH” occurs in a proportion of patients regardless of maintenance immunosuppression, who have been transplanted for disorders unrelated to AIH. Of note, the use of cyclosporine A appears to protect against the development of recurrent PBC and de novo AIH even though it is a less potent immunosuppressive compared to tacrolimus. The reason why cyclosporine A is protective has not been determined. However, a virus resembling mouse mammary tumor virus (MMTV) has been characterized in patients with PBC and AIH. Accordingly, we hypothesized that the protective effect of cyclosporine A in liver transplant recipients may be mediated by the antiviral activity of this cyclophilin inhibitor. Treatment of the MMTV producing MM5MT cells with different antivirals and immunosuppressive agents showed that both cyclosporine A and the analogue NIM811 inhibited MMTV production from the producer cells. Herein, we discuss the evidence supporting the role of MMTV-like human betaretrovirus in the development of PBC and de novo AIH and speculate on the possibility that the agent may be associated with disease following transplantation. We also review the mechanisms of how both cyclosporine A and NIM811 may inhibit betaretrovirus production in vitro.

Modelling Recurrent Primary Biliary Cholangitis and Primary Sclerosing Cholangitis as Infectious Diseases Following Liver Transplantation

“…Because of our interest in the retroviral hypothesis for the development of PBC, we evaluated whether cyclosporine had antiviral activity against HBRV and observed reduced betaretrovirus production from infected cells treated with cyclosporine but not tacrolimus in vitro [50]. These data were consistent with prior studies showing that cyclosporine inhibited cyclophilin activity required for assembly of many viral agents [50,51]. This observation may partially explain the effects of reduced frequency of rPBC post-LT with cyclosporine therapy.…”

Primary Biliary Cholangitis in British Columbia First Nations: Clinical features and discovery of novel genetic susceptibility loci

“…We hypothesize that variations in PIN1 affecting its interactions with any of these proteins may lead to alterations in hepatic inflammation and cell protection. Of note, treatment with cyclosporine A following liver transplantation for PBC has been shown to decrease the incidence of recurrent disease and cyclosporine has been shown to inhibit Pin1 . DNMT1 has been shown previously to be associated with global methylation in autoimmune diseases such as RA and SLE as well as in the maintenance of CpG methylation in hepatocarcinoma cells, suggesting alteration of epigenetic signalling .…”

New perspectives on the complexity of genetic predisposition to autoimmune liver disease in indigenous Canadians

“…Among the candidate genes that were identified, PIN1 is of particular interest as it encodes a peptidyl-prolyl isomerase belonging to a highly conserved protein family of immunophilins that includes cyclophilin A, the target of cyclosporine. 10 These isomerases catalyze proline peptide bonds and alter the configuration of proteins such as kinases and phosphatases that play a key role in cell cycle, immune response, gene expression, cell signalling and many other cellular processes. The relevance to PBC is that patients undergoing liver transplantation have repeatedly been shown to be protected against the development of recurrent disease by the use of cyclosporine.…”

“…In contrast with past PBC GWAS data, immune‐related genes were not highlighted as candidates in this study of FN PBC families. Among the candidate genes that were identified, PIN1 is of particular interest as it encodes a peptidyl‐prolyl isomerase belonging to a highly conserved protein family of immunophilins that includes cyclophilin A, the target of cyclosporine . These isomerases catalyze proline peptide bonds and alter the configuration of proteins such as kinases and phosphatases that play a key role in cell cycle, immune response, gene expression, cell signalling and many other cellular processes.…”

“…Notably, both cyclophilin A and PIN1 are also required by various intracellular pathogens to promote key conformational changes in viral proteins needed for replication or assembly. For example, cyclophilin A is required for the production of several DNA and RNA viruses and its inhibitor, cyclosporine, has been found to have broad antiviral activity against the betaretrovirus linked with PBC, HIV and hepatitis C virus . Similarly, various modalities that inhibit PIN1 have been shown to suppresses retroviral reverse transcription, EBV replication and the hepatitis B virus HBx protein activity in virally infected cells .…”