Published online before print December 15, 2006

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(Journal of Leukocyte Biology. 2007;81:825-834.)
© 2007 by Society for Leukocyte Biology

Modulation of the IL-12/IFN- axis by IFN- therapy for hepatitis C

Adriana A. Byrnes^*,1,2, Ding-You Li^,1,3, Kiwon Park^*, Douglas Thompson, Cathleen Mocilnikar, Parvathi Mohan, Jean P. Molleston^||, Michael Narkewicz^¶, Huanfang Zhou^#, Stanley F. Wolf^#, Kathleen B. Schwarz and Christopher L. Karp^*,**,4

Departments of
^* Medicine and Molecular Microbiology and Immunology and
Pediatrics, Johns Hopkins University, Baltimore, Maryland, USA;
Maryland Medical Research Institute, Baltimore, Maryland, USA;
Departments of Pediatrics and Pathology and Laboratory Medicine, Children’s National Medical Center, George Washington University School of Medicine, Washington, DC, USA;
^|| Division of Gastroenterology, Riley Hospital for Children, Indiana University Medical Center, Indianapolis, Indiana, USA;
^¶ Department of Pediatrics, University of Colorado Health Sciences Center, and The Pediatric Liver Center, The Children’s Hospital, Denver, Colorado, USA;
^# Wyeth Research, Cambridge, Massachusetts, USA; and
^** Division of Molecular Immunology, Cincinnati Children’s Hospital Research Foundation, and the University of Cincinnati, Cincinnati, Ohio, USA

⁴ Correspondence: Division of Molecular Immunology, Cincinnati Children’s Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. E-mail: chris.karp{at}chmcc.org

Although IFN- forms the foundation of therapy for chronic hepatitis C, only a minority of patients has a sustained response to IFN- alone. The antiviral activities of IFN- formed the rationale for its use in viral hepatitis. However, IFN- and the other Type I IFNs are also pleiotropic immune regulators. Type I IFNs can promote IFN- production by activating STAT4 but can also inhibit production of IL-12, a potent activator of STAT4 and IFN- production. The efficacy of IFN- in the treatment of hepatitis C may therefore depend in part on the balance of IFN--inducing and IL-12-suppressing effects. We characterized the effects of pegylated IFN- therapy for hepatitis C on the capacity of patients’ PBMC to produce IL-12 and IFN- ex vivo. Cells from patients with a sustained virological response to therapy had significantly greater levels of IFN--driven IFN- production prior to treatment than those from nonresponding patients. No differences in pretreatment IL-12 productive capacity were seen between patient groups. However, therapy with IFN- led to suppression of inducible IL-12 production throughout the course of therapy in both groups of patients.

Key Words: immunomodulation • cytokine • memory T cell • IFN-ß