UPREGULATION OF PD-1 EXPRESSION ON CIRCULATING AND INTRAHEPATIC HCV-SPECIFIC CD8+ T CELLS ASSOCIATED WITH REVERSIBLE IMMUNE DYSFUNCTION.
J Virol. 2007 Jun 13;
Golden-Mason L, Palmer B, Klarquist J, Mengshol JA, Castelblanco N, Rosen HR.
Division of Gastroenterology & Hepatology, Hepatitis C Center, and Integrated Program in Immunology; Department of Medicine, Division of Clinical Immunology; University of Colorado Health Sciences Center & National Jewish Hospital.
Infection with hepatitis C virus (HCV) is associated with persistence in the majority of individuals. Here, we demonstrate that the inhibitory molecule programmed death-1 (PD-1) is significantly up-regulated on total and HCV-specific CD8+ cytotoxic T cells (CTLs) in peripheral blood and livers of patients with chronic infection as compared to subjects with spontaneous HCV resolution, patients with non-viral liver disease, and normal controls. PD-1 expression on cytomegalovirus (CMV)-specific CTLs also varies according to HCV status and is highest in patients with chronic infection. HCV-specific CTLs that are PD-1(high) express higher levels of the senescence marker CD57 than PD-1(low) CTLs, and CD57 expression is greater in chronic than in resolved infection.
In vitro blockade of PD-1 by monoclonal antibodies specific to its ligands (PDL-1 and PDL-2) results in restoration of functional competence (proliferation and IFN-gamma, IL-2 secretion) of HCV-specific CTLs, including those residing in the liver. This reversal of CTL exhaustion is evident even in those individuals who lack HCV-specific CD4+ T cell help.
Our data indicate that the PD-1/PD-L pathway is critical in persistent HCV infection in humans and represents a potential novel target for restoring function of exhausted HCV-specific CTLs.
[At the Citibank conference in May, MEDX said, that they are expecting to file an IND (presumably HCV-related) for MDX-1106 (anti-PD1) at mid-year] |
