Plasmacytoid dendritic cells induce efficient stimulation... : Hepatology (original) (raw)

Viral Hepatitis

Plasmacytoid dendritic cells induce efficient stimulation of antiviral immunity in the context of chronic hepatitis B virus infection

Martinet, Jeremie1,2,4; Leroy, Vincent2,3; Dufeu-Duchesne, Tania2,3; Larrat, Sylvie5; Richard, Marie-Jeanne2,4; Zoulim, Fabien6; Plumas, Joel1,2,7; Aspord, Caroline1,2*

1 EFS Rhone-Alpes, R&D Laboratory, La Tronche, France

2 University Joseph Fourier, Grenoble, France; INSERM U823, Immunobiology & Immunotherapy of Cancers, La Tronche, France

3 Hepato-gastroenterology Unit, CHU Grenoble, Michallon Hospital, Grenoble, France

4 Department of Cancerology and Biotherapy, CHU Grenoble, Michallon Hospital, Grenoble, France

5 Virological Laboratory/UMI 3265 CNRS-UJF-EMBL, CHU Grenoble, Michallon Hospital, Grenoble, France

6 INSERM U871, Molecular Pathobiology and New Treatments of Viral Hepatitis, Lyon, France

7 University College London, Cancer Institute, London, UK

* Address reprint requests to: R&D Laboratory, EFS Rhone-Alpes, 29 Avenue du Maquis Gresivaudan, 38701 La Tronche, France

Email:[email protected]

Received 20 February 2012; Accepted 21 May 2012

Potential conflict of interest: Dr. Leroy consults for, is on speakers' bureau of, and received grants from Bristol-Myers Squibb, Gilead, and Roche.

Supported by the French Blood Service and the French National Agency for Research on AIDS and Viral Hepatitis.

fax: (33)-4-76-54-69-18

Abstract

The immune control of hepatitis B virus (HBV) infection is essential for viral clearance. Therefore, restoring functional anti–HBV immunity is a promising immunotherapeutic approach to treatment of chronic infection. Plasmacytoid dendritic cells (pDCs) play a crucial role in triggering antiviral immunity through their ability to capture and process viral antigens and subsequently induce adaptive immune responses. We investigated the potential of pDCs to trigger antiviral cellular immunity against HBV. We used a human leukocyte antigen A (HLA–A)*0201+ pDC line loaded with HLA–A*0201-restricted peptides derived from hepatitis B core/hepatitis B surface (HBc/HBs) antigens to amplify specific CD8 T cells ex vivo from chronic HBV patients and established a Hepato-HuPBL mouse model to address the therapeutic potential of the strategy in vivo . Stimulation of PBMCs or liver-infiltrating lymphocytes from HLA–A*0201+ chronic HBV patients by HBc peptide-loaded pDCs elicited up to 23.1% and 76.1% HBV-specific CD8 T cells in 45.8% of cases. The specific T cells from the “responder” group secreted interferon-γ, expressed CD107 upon restimulation, and efficiently lysed HBV antigen-expressing hepatocytes. Circulating hepatitis B e antigen (HBeAg) was found to distinguish the group of patients not responding to the pDC stimulation. The therapeutic efficacy of the pDC vaccine was evaluated in immunodeficient NOD-SCID β2m−/− mice reconstituted with HBV patients' PBMCs and xenotransplanted with human HBV-transfected hepatocytes. Vaccination of Hepato–HuPBL mice with the HBc/HBs peptide–loaded pDCs elicited HBV-specific T cells able to specifically lyse the transfected hepatocytes and reduce the systemic viral load.

Conclusion:

pDCs loaded with HBV–derived peptides can elicit functional virus-specific T cells. HBeAg appears to be critical in determining the outcome of immunotherapies in chronic HBV patients. A pDC-based immunotherapeutic approach could be of interest in attempts to restore functional antiviral immunity, which is critical for the control of the virus in chronic HBV patients.

Abbreviations: ALT, alanine aminotransferase; CFSE, carboxyfluorescein succinimidyl ester; CTL, cytotoxic T lymphocyte; HBcAg, hepatitis B core antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen, HBV, hepatitis B virus; HLA-A, human leukocyte antigen A; IFN, interferon; LIL, liver-infiltrating lymphocyte; mDC, myeloid dendritic cell; PBMC, peripheral blood mononuclear cell; pDC, plasmacytoid dendritic cell; TCR, T cell receptor.