This project is focused on the use of interleukin 2 (IL2) as a therapeutic to improve the immune response to Hepatitis C Virus (HCV). As in most viral infections, recovery from HCV infection depends upon a vigorous cellular immune response, mediated by T lymphocytes (T cells), Natural Killer (NK) cells and macrophages. Standard therapy of HCV infection, comprised of interferon-alpha and Ribavirin results in a sustained viral response rate of only approximately 40 percent. Those who respond to standard antiviral therapy have readily detectable immune responses HCV, whereas those who fail to respond or relapse have low undetectable HCV immune reactivity. Therefore, we propose to determine whether IL2 immunotherapy adds benefit to standard therapy (Specific Aim 1), and to determine the effect of IL2 immunotherapy on T cell immune reactivity to HCV (Specific Aim 2). A randomized, controlled trial of 72 subjects who are therapy-naive and have contracted genotype 1 HCV will receive either 48 weeks of IFN/Ribavirin alone, or 12 weeks of low-dose daily IL2 therapy, followed by 48 weeks of combined IL2 and IFN/Ribavirin. The primary endpoint will be the proportion of subjects who remain free of detectable virus 24 weeks after the cessation of therapy. These subjects will be tested for CD4+ and CD8+ polyclonal T cell immune responses, and CD4+ HCV antigen- specific immune responses using short-term in vitro activation followed by analysis with monoclonal antibodies reactive with surface molecules and intracellular accumulation of cytokines (IL2, IFN, TNF) by flow cytometry. HCV antigen peptide-specific CD8+ T cells will be enumerated via peptide-MHC tetramers, and CD8+ functional recognition of HCV peptides will be assayed by intracellular cytokine production after a short-term activation with the peptide-MHC tetramers. If successful, this project will provide for a new approach to the treatment of HCV infection, using a combination of antiviral agents with IL2 immuno- stimulation. This approach should prove beneficial in improving the proportion of patients who recover from HCV infection, and as well, introduce immunologic tests that may be predictive of responsiveness to therapy.
|Joyce, Sebastian; Girardi, Enrico; Zajonc, Dirk M (2011) NKT cell ligand recognition logic: molecular basis for a synaptic duet and transmission of inflammatory effectors. J Immunol 187:1081-9|
|Florence, William C; Xia, Chengfeng; Gordy, Laura E et al. (2009) Adaptability of the semi-invariant natural killer T-cell receptor towards structurally diverse CD1d-restricted ligands. EMBO J 28:3579-90|