FIBRINOGEN-LIKE 2/FIBROLEUKIN (FGL2), AN EFFECTOR MOLECULE OF REGULATORY T-CELLS (Tregs), HAS PROGNOSTIC AND POTENTIAL THERAPEUTIC ROLES IN CHRONIC HEPATITIS C (HCV) TRANSPLANT PATIENTS

O.A. Adeyi^{1, 2}, N. Selzner², A. Helmy, I. Shalev², Y. Zhu², G.A. Levy²
Department of Pathology, University Health Network¹and Multiorgan Transplant², University of Toronto, Toronto, Ontario, Canada

Objectives: CD4+/CD25+/FoxP3+ T regulatory cells (Tregs) a subset of T cells are known to promote viral persistence and more aggressive HCV disease in humans. Recent data suggests  that FoxP3  expression  may not be as specific for Tregs as previously believed, making it necessary to identify other markers and/or effector molecules  of Treg which could be more useful diagnostic and/or therapeutic targets.. Our laboratory has recently demonstrated in experimental murine models of viral hepatitis that FGL2 may serve as a specific and sensitive marker of Tregs activity. In this study we present data showing that FGL2-positive cells in liver explants correlated with post-transplant HCV recurrence.

Methods: We measured plasma levels of human FGL2 using a highly sensitive and reproducible ELISA developed in our laboratory  in healthy individuals (controls) and post-transplant HCV patients and conducted studies to  determine if plasma levels  of FGL2 correlated with other known prognostic factors, including response to treatment and HCV genotype. We then identified three groups of post-transplant HCV patients with documented recurrent disease as follows: 1. recurrence with aggressive course (5 patients); 2. recurrence, treated, with sustained virological response SVR (6 patients); and 3. recurrence, low grade activity , untreated (4 patients). The explanted livers of these patients were retrieved and stained with a mouse monoclonal anti-human FGL2 antibody.
Results: Plasma levels of FGL2 were significantly higher in HCV patients (13.1+4.7ng/ml) than in normal healthy controls (5.8+1.3 ng/ml p=0.007). HCV genotype 1 infected patients had higher levels of FGL2 (13.11+2.4ng/ml) than genotype 2/3 patients (6.1+1.4ng/ml) (p=0.04). FGL2 levels were lower in patients with SVR than in non-responders and were similar to non infected controls. FGL2 immunostaining demonstrated more positive cells within the portal and lobular infiltrates in the explants of all 5 HCV patients with aggressive HCV recurrence compared to those patients with SVR or low-grade recurrence. Conclusions: These data suggest that high levels of FGL2 predict poor response to treatment, correlate with severity of disease, and expression of FGL2 in explanted livers appears to predict the post-transplant course of HCV. These findings have potential prognostic and therapeutic implications in the management of post-transplant recurrence of HCV.  

Supported by Grant the Physicians Services Incorporated foundation (PSI).