Laurence Dubel

High incidence of antitissue antibodies in patients experiencing chronic liver allograft rejection

BACKGROUND The precise immunologic mechanisms responsible for chronic rejection of liver allografts are unknown. We have recently shown in a rodent model that recipients of liver allografts developed non-major histocompatibility complex antitissue antibodies. The aim of the present study was to test this hypothesis in the clinical setting. METHODS Posttransplant sera of 14 patients undergoing chronic rejection and of 48 control patients (12 liver transplant patients with chronic active hepatitis or liver cirrhosis related to hepatitis C virus [HCV] infection and without chronic rejection, 10 with sclerosing cholangitis, and 26 with normal liver function tests and liver biopsy) were tested for the presence of antitissue antibodies by indirect immunofluorescence. Pretransplant sera of all these patients lacked antitissue antibodies. RESULTS Antitissue antibodies were detected in 71% of patients who developed chronic rejection (before or at the time of chronic rejection). This incidence was significantly greater than that observed in patients not undergoing rejection (HCV-related chronic active hepatitis, 16%; sclerosing cholangitis, 0%; normal liver biopsy, 7%). All these autoantibodies were directed against the smooth muscle and/or the nucleus. In two patients, anti-smooth muscle antibodies had an antiactin or antivimentin specificity. CONCLUSIONS These results show a strong association between chronic allograft rejection and the development of antitissue antibodies and suggest that these antibodies could be used to identify patients at high risk of developing chronic rejection after liver transplantation.

Histological features predictive of recurrence of primary biliary cirrhosis after liver transplantation.

BACKGROUND Recurrence of primary biliary cirrhosis (PBC) within liver allografts remains a controversial issue. The aims of this study were to evaluate this risk and to determine the presence, if any, of a predictive histological feature. METHODS We reviewed the most recent and the 1-year protocol liver biopsies of 69 patients who received transplants for PBC and of 53 control patients. Histological features consistent with PBC recurrence included nonsuppurative destructive cholangitis, mixed portal infiltrate, fibrosis, and ductopenia. A complete evaluation was undertaken in each patient with these histological features. RESULTS These histological features were present in six patients who received transplants for PBC (8.7% vs. 0% in the control group) and occurred between 1 and 8 years after transplant. In five of the six patients, anti-mitochondrial antibody-2 (anti-M2) antibodies remained at high titers. Cholestasis was present in four patients, and clinical symptoms in two patients. All six patients were negative for hepatitis C antibodies and hepatitis C RNA in their serum. None had bile duct obstruction. The presence of plasma cells in the portal infiltrate at 1 year after transplant was predictive of this risk of recurrence. CONCLUSION The risk of PBC recurrence is real (8.7%). The presence of plasma cells in the portal infiltrate seems to be an early marker of recurrence of PBC in patients transplanted for this indication.

Kinetics of anti-M2 antibodies after liver transplantation for primary biliary cirrhosis

BACKGROUND/AIMS Orthotopic liver transplantation is currently considered as the treatment of choice for primary biliary cirrhosis in the terminal stage and, as for other autoimmune liver disease, the risk of recurrence of the disease within the graft has been raised. There is, however, some discrepancy about the risk of recurrence based on pathological analysis. In addition, pathological recurrence of primary biliary cirrhosis within the graft is not always associated with a rise in the serological markers of the disease. In order to clarify this situation, we have monitored antimitochondrial antibodies before and after transplantation. METHODS Antimitochondrial antibodies were detected by indirect immunofluorescence (variation in antibody titers) and the antimitochondrial antibodies-2 by western blotting (variation in the number of peptides recognized in 16 primary biliary cirrhosis patients followed for at least 4 years after transplantation. RESULTS Antimitochondrial antibody titers had normalized 1 year after transplantation in seven patients, declined in seven others and remained unchanged in two. Over the 4 years of follow up, four patients demonstrated a subsequent increase in antimitochondrial antibody titers. Western blot analysis demonstrated the loss of one or more bands in seven patients during the first operative year after transplantation and in three other patients thereafter; in six patients the western blotting profile remained identical to that obtained before transplantation. The important changes generally occurred during the first year post-transplantation, without significant changes thereafter, except for three patients who demonstrated a secondary reappearance of the initially lost band. Disappearance of all bands was never observed. There was no concordance between the normalization of antimitochondrial antibody titers (indirect immunofluorescence) and the reduction in the number of peptides recognized (western blotting). Serum bilirubin and alkaline phosphatase levels had normalized by 1 year after transplantation, and remained normal thereafter. Routine liver biopsies performed on a yearly basis did not disclose any pattern suggestive of primary biliary cirrhosis recurrence. CONCLUSIONS Antimitochondrial antibody titers decreased in primary biliary cirrhosis patients after liver transplantation, although antimitochondrial antibodies-2 never disappeared as assessed by western blotting. In the present study these features were not associated with biochemical or histological (correction of histoclogical) evidence of primary biliary cirrhosis recurrence.

Assessing renal function with daclizumab induction and delayed tacrolimus introduction in liver transplant recipients.

Background. Calcineurin inhibitor-induced renal dysfunction is a major problem in liver transplantation. Interleukin-2 receptor antagonist induction followed by delayed tacrolimus (Tac) administration may minimize the renal insult without compromising immunoprotection. Methods. This open, randomized, multicenter trial evaluated the benefit of daclizumab induction with delayed Tac on renal function at 6 months; an observational study was continued for 18 months. Liver transplant patients with a 12-hr serum creatinine (SrC) level less than 180 &mgr;mol/L received either delayed Tac with daclizumab induction (n=98) or standard Tac (n=101) both combined with mycophenolate mofetil and steroids. The primary endpoint was the incidence of SrC level more than 130 &mgr;mmol/L at 6 months. Results. The incidence was 22.4% with delayed Tac and 29.7% with standard Tac (P=ns), which remained unchanged at 12 months (21.6% and 23.9%) but increasing slightly at 24 months (29.0% and 32.9%), respectively. A post hoc analysis of renal function was done based on patients stratification by SrC at 12 hr (≤100&mgr;mol/L or >100 &mgr;mol/L) showing no difference in SrC values at 6 months regardless of the 12-hr values despite a trend toward better estimated glomerular filtration rate for patients with 12-hr value less than 100 &mgr;mol/L in the delayed Tac group. Biopsy-proven acute rejection was similar at 6 months (17.5% and 18.75%), 12 months (23.5% and 23.8%), and 24 months (24.5% and 25.7%), respectively. Patient and graft survival in both groups were comparable and good. Similar types and incidences of adverse events were reported in both groups at all time. Conclusions. Delay of Tac does not benefit renal function in liver transplant recipients with a good renal function at baseline.

Polyspecificity of antimicrosomal thyroid antibodies in hepatitis C virus-related infection.

OBJECTIVES:The outcome of dysthyroidism and the presence of antithyroid antibodies in patients with chronic hepatitis C virus (HCV) infection receiving interferon-α therapy is clearly established. However, the prevalence and the specificity of antithyroid antibodies in HCV patients before interferon-α therapy remain controversial. The aim of the present study is to clarify within a large population of HCV patients the prevalence of antithyroid antibodies before interferon-α therapy and to determine whether their immunodominant antigen is the same as described in autoimmune thyroiditis.METHODS:Sera from 99 patients with chronic hepatitis C before (n = 99) and after (n = 37) interferon-α treatment were investigated for the presence of antimicrosomal and antithyroperoxidase antibodies assessed by indirect immunofluorescence and ELISA, respectively. Dot blotting on human thyroid lysate was designed to further characterize these autoantibodies. Data were compared to those obtained with sera of patients with autoimmune thyroiditis (n = 75) and healthy subjects (n = 96).RESULTS:In HCV patients, antimicrosomal antibodies were found with a higher proportion before interferon-α therapy (12.1%) than after therapy (8%). Thyroperoxidase constitutes the main antigen in only 4% before treatment, a prevalence similar to that observed in healthy controls.CONCLUSIONS:The prevalence of antithyroid antibodies is low in patients with chronic hepatitis C before interferon-α therapy. Thyroperoxidase may not be their main target. Further studies are required to determine whether HCV infection leads to a breakdown of tolerance to a thyroid self-protein other than thyroperoxidase.

Development of anti-tissue antibodies in the rat liver transplant model.

BACKGROUND The aim of this study was to analyze the humoral immune response associated with orthotopic liver transplantation in the rat liver transplant model, and in particular to test the presence of anti-tissue antibodies. METHODS Rearterialized liver transplantations were performed in the Dark Agouti (DA)-to-Lewis (LEW) and the LEW-to-DA rat strain combinations. Sera of recipients were analyzed by immunofluorescence (on DA and LEW organ sections) and by western blotting (with DA and LEW liver proteins). RESULTS We have shown that liver (but not heart or skin) recipients develop a humoral response against non-MHC tissue antigens as evidenced (1) by a pattern of staining comparable to that described in human patients harboring anti-smooth muscle antibodies and (2) by the presence of donor liver peptides recognized in the sera of the recipient by Western blotting. CONCLUSIONS These experiments indicate that orthotopic transplantation of a nonacutely rejected liver allograft is associated with the development of a previously undescribed anti-tissue antibody response that seems to be neither organ nor MHC restricted.

A new type of antithyroid antibodies in untreated patients with chronic hepatitis C infection

Abstract The aim of this study was to test the hypothesis that antimicrosomal antibodies, found in patients with hepatitis C virus infection (HCV) before interferon (INF) therapy, are directed against a microsomal protein distinct from the thyroperoxidase. Sera from 99 HCV patients were analysed, before INF therapy, by ELISA and indirect immunofluorescence (IF). We confirm that antithyroid microsomal antibodies (TMA) detected in HCV patients before INF therapy are directed against a thyroid protein other than the usual thyroperoxidase autoantigen of autoimmune thyroiditis.