IMMUNOMODULATORY PROPERTIES OF INTERFERON ALPHA AND RIBAVIRIN
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1 IMMUNOMODULATORY PROPERTIES OF INTERFERON ALPHA AND RIBAVIRIN Nikolai V. Naoumov UCL Institute of Hepatology University College London Chenies Mews London WC1E 6HX UK Key concepts: Interferon-alpha has a broad spectrum of immunomodulatory activities on both innate and adaptive immune responses. Ribavirin has immunomodulatory properties and both in vitro and in vivo was shown to modulate the cytokine profile. The greater efficacy of interferon-alpha plus ribavirin therapy is a result of multiple synergistic effects including antiviral activity, favourable cytokine profile, increased antiviral T-cell reactivity in fast-responders, upregulation of antiviral gene expression. In hepatitis C treatment, interferon-alpha and ribavirin appear to work mainly by direct interference with HCV life cycle, rather than by enhancement of cellular immunity to HCV. Interferon-alpha (IFN-α) has been the mainstay of treatment for hepatitis C even before the identification of the hepatitis C virus (HCV). The initial results with recombinant IFN-α or with natural, lymphoblastoid IFN-α alone were disappointing with only a small proportion of patients achieving a sustained virological response. The empirical addition of ribavirin to standard interferon significantly improved the long-term virological response. The development of pegylated interferons led to further improvement in the treatment outcome, and currently the combination of pegylated IFN-α plus ribavirin is the standard of care for antiviral therapy in patients with chronic hepatitis C. Both IFN-α and ribavirin possess broad spectrum antiviral and immunomodulatory activities, however the mechanisms of action of these two drugs in hepatitis C treatment, and the hierarchy of their effects in achieving HCV clearance are not fully understood. Immunomodulatory properties of IFN-α IFN-α belongs to the family of type I interferons, which in humans include IFN-α (a mixture of 13 different subtypes - IFN-α1, α2, etc), IFN-β, IFN-ε, IFN-κ and IFN-ω (1). Type I interferons are produced by most cells in response to viral or bacterial infections and have a central role in the innate immune response to pathogens. All type I interferons bind to a common cell surface receptor, which is known as type I IFN-receptor, in contrast to the only type II interferon, IFN-γ, which binds to type II IFN-receptor (Figure 1). IFN-α mediates a wide range of biological effects including direct antiviral, immunomodulatory, antiproliferative, antiangiogenic and antitumour activities (2). The potent direct antiviral effect of IFN-α against HCV was recently demonstrated 1
2 using the new HCV genotype 2a replicon (clone JFH-1)(3). In concentrations comparable to the clinical levels, IFN-α and ribavirin reduced HCV replication down to 0.09% and 54% of baseline levels, respectively, while the combination of the two agents showed about 1.5-fold greater antiviral activity than IFN-α alone (3). In addition to the direct antiviral effect, IFN-α has a broad spectrum of immunomodulatory activities on both innate and adaptive immune responses. These include upregulation of major histocompatibity complex (MHC) class-i and class II, increased natural killer cell activity, enhancement of dendritic cell (DC) activation. In vitro studies with monocyte-derived dendritic cells from healthy donors showed that IFN-α increases DCallostimulatory capacity (4). When DC were stimulated simultaneously with IFN-α and CD40 ligation, the production of both IL-10 and IL-12 was increased; while the stimulation with IFN-α plus lipopolisaccharide (LPS) enhanced mainly IL-10 production (4). In another study, also using DC from healthy donors, IFN-α alone was shown to increase MHC class I, class II and CD86 molecules on immature DC, and it also stimulated IL-12 and TNF-α production (5). In contrast, ribavirin in vitro had no effect on DC maturation, but markedly suppressed the production of TNF-alpha, IL-10 and IL-12. HCV infection has a major and multidirectional impact on dendritic cell function (6) and the relevance of the findings with DC from healthy donors for the treatment outcome in chronic hepatitis C is not established. The multiple immunomodulatory properties of therapeutic IFN-α were recently demonstrated using microarrays detecting directly the gene expression profile in peripheral blood mononuclear cells (PCMC) from patients with HCV infection (7,8). After a single application of IFN-α there was a significant upregulation of 88 genes involved in antigen processing and presentation, T-cell activation, lymphocyte trafficking and effector functions. PBMC after one IFN-α infection, showed a substantial increase in IL-10 production, both in response to antigen-specific and non-specific stimulation, while lymphocyte proliferation was decreased in comparison to PBMC prior to IFN-α injection. Immunomodulatory properties of Ribavirin Ribavirin is a synthetic guanosine analogue with a broad spectrum of antiviral activity, initially approved for treatment of respiratory syncytial virus (RSV) infection. Several mechanisms have been proposed by which ribavirin may be beneficial for the treatment of chronic hepatitis C (reviewed in 9, Figure 2). This summary is focused only on the immunomodulatory properties of Ribavirin. In vitro experiments, using mitogen-stimulated PBMC have shown that ribavirin promotes T helper 1 (Th1) reactivity, while inhibiting Th2 cytokine production (10). Importantly, the immunomodulatory properties of ribavirin appear to vary at different concentrations - at low concentrations ribavirin appears to potentiate Th1-pattern of immune responses. In contrast, at higher concentrations (above 5 µg/ml) ribavirin inhibits lymphocyte proliferation and has an immunosuppressive effect. Other studies have also shown that ribavirin can modulate T-cell reactivity and/or cytokine profile, however, the direct effect of ribavirin on HCV-specific T-cell reactivity from patients with hepatitis C has not been defined. As Ribavirin is a purine analogue, it may exert immunomodulatory activities via toll-like receptor (TLR). However, Ribavirin did not stimulate TLR7 or TLR8-mediated signaling in cells transfected with these TLRs (11). A possible mechanism by which ribavirin may exert a a synergistic effect with IFN-α is indicated by the finding that ribavirin upregulates antiviral gene expression via the interferon-stimulated response element in RSV-infected cells (12). 2
3 Immunomodulatory properties of IFN-α and Ribavirin during treatment of hepatitis C The effects of IFN-α and Ribavirin on the immune responses of patients undergoing treatment for hepatitis C are complex and may result from: a) direct immonomodulatory properties of each agent; b) the indirect effect of treatment-induced suppression of HCV replication and decreased viraemia levels on antiviral immune reactivity; c) the interaction between these two agents with their multifunctional effects. In a prospective study we analysed CD4+ T-cell proliferation, together with IFN-gamma and IL-10 production in response to HCV antigens, during treatment with IFN-α alone or in combination with Ribavirin (13). Undetectable HCV viraemia was associated with enhanced CD4+ T-cell reactivity to viral antigens. Importantly, the main difference in the T-cell resposne to HCV antigens of patients treated with the combination of IFN-α plus ribavirin was a significantly lower production of IL-10 in comparison to those treated with IFN-α alone, while there was no significant difference in the IFN-gamma production (Figure 3). These results indicated that the greater efficacy of the combination therapy may be related to its ability to suppress HCV-specific IL-10 production (13). Characterisation of T-cell reactivity during treatment of patients with acute hepatitis C has shown that the outcome of early treatment of acute HCV infection is not associated with enhanced CD4 or CD8+ T-cell reactivity to HCV (14,15). The changes of antiviral T-cell reactivity during treatment of chronic hepatitis C patients with IFN-α plus Ribavirin may be influenced also by patients ethnicity and the HCV genotype (16). Recently, we studied the relationship between early HCV kinetics and antiviral T- cell reactivity in a homogeneous group of patients with HCV genotype 1 chronic hepatitis C (17). Although all patients received the same treatment with pegylated IFN-α2a plus Ribavirin, enhanced frequency of HCV-specific CD4+ and CD8+ T-cells was observed only in fast responders to treatment (Figure 4), thus indicating that the enhanced T-cell reactivity was a consequence of rapid viraemia clearance, rather than a result of direct immunostimulatory effects of IFN-α plus Ribavirin. Collectively, the accumulating evidence suggests that the greater efficacy of IFN-α plus Ribavirin combination therapy is a result of multiple synergistic effects of these agents. These include enhanced antiviral activity (3), ribavirin-induced control of interferon-stimulated IL-10 production (8,13), transient increase of adaptive immunity in fast responders (17), ribavirinupregulated antiviral gene expression via the interferon-stimulated response element (12), and the possibility that ribavirin decreases HCV infectivity during the course of combination therapy (18). References: 1. Platanias LC. Mechanisms of type-i- and type-ii-interferon-mediated signalling. Nat Rev Immunol. 2005;5(5): Theofilopoulos AN, Baccala R, Beutler B, Kono DH. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol. 2005;23: Kato T, Date T, Miyamoto M, Sugiyama M, Tanaka Y, Orito E, Ohno T, Sugihara K, Hasegawa I, Fujiwara K, Ito K, Ozasa A, Mizokami M, Wakita T. Detection of anti-hepatitis C virus effects of interferon and ribavirin by a sensitive replicon system. J Clin Microbiol. 2005; 43(11): Tamir A, Jordan WJ, Ritter M, Habib N, Lechler RI, Foster GR, Lombardi G. Interferonalpha2a is sufficient for promoting dendritic cell immunogenicity. Clin Exp Immunol. 2005; 142(3):
4 5. Barnes E, Salio M, Cerundolo V, Medlin J, Murphy S, Dusheiko G, Klenerman P. Impact of alpha interferon and ribavirin on the function of maturing dendritic cells. Antimicrob Agents Chemother. 2004;48(9): Pachiadakis I, Pollara G, Chain BM, Naoumov NV. Is hepatitis C virus infection of dendritic cells a mechanism facilitating viral persistence? Lancet Infect Dis. 2005;5(5): Ji X, Cheung R, Cooper S, Li Q, Greenberg HB, He XS. Interferon alfa regulated gene expression in patients initiating interferon treatment for chronic hepatitis C. Hepatology. 2003; 37(3): Luik A, Knapp S, Thursz M, Thomas HC, Schlaak JF. Autoregulatory role of interleukin-10 in hepatitis C patients treated with IFN-alpha. J Interferon Cytokine Res. 2004;24(10): Lau JY, Tam RC, Liang TJ, Hong Z. Mechanism of action of ribavirin in the combination treatment of chronic HCV infection. Hepatology. 2002;35(5): Tam RC, Pai B, Bard J, Lim C, Averett DR, Phan UT, Milovanovic T. Ribavirin polarizes human T cell responses towards a Type 1 cytokine profile. J Hepatol. 1999;30(3): Vollmer J, Rankin R, Hartmann H, Jurk M, Samulowitz U, Wader T, Janosch A, Schetter C, Krieg AM. Immunopharmacology of CpG oligodeoxynucleotides and ribavirin. Antimicrob Agents Chemother. 2004;48(6): Zhang Y, Jamaluddin M, Wang S, Tian B, Garofalo RP, Casola A, Brasier AR. Ribavirin treatment up-regulates antiviral gene expression via the interferon-stimulated response element in respiratory syncytial virus-infected epithelial cells. J Virol. 2003;77(10): Cramp ME, Rossol S, Chokshi S, Carucci P, Williams R, Naoumov NV. Hepatitis C virusspecific T-cell reactivity during interferon and ribavirin treatment in chronic hepatitis C. Gastroenterology. 2000;118(2): Rahman F, Heller T, Sobao Y, Mizukoshi E, Nascimbeni M, Alter H, Herrine S, Hoofnagle J, Liang TJ, Rehermann B. Effects of antiviral therapy on the cellular immune response in acute hepatitis C. Hepatology. 2004;40(1): Lauer GM, Lucas M, Timm J, Ouchi K, Kim AY, Day CL, et al. Full-breadth analysis of CD8+ T-cell responses in acute hepatitis C virus infection and early therapy. J Virol. 2005; 79(20): Kaplan DE, Sugimoto K, Ikeda F, Stadanlick J, Valiga M, Shetty K, Reddy KR, Chang KM. T-cell response relative to genotype and ethnicity during antiviral therapy for chronic hepatitis C. Hepatology. 2005;41(6): Tang KH, Herrmann E, Cooksley H, Tatman N, Chokshi S, Williams R, Zeuzem S, Naoumov NV. Relationship between early HCV kinetics and T-cell reactivity in chronic hepatitis C genotype 1 during peginterferon and ribavirin therapy. J Hepatol. 2005;43(5): Dixit NM, Layden-Almer JE, Layden TJ, Perelson AS. Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. Nature. 2004;432(7019):
5 Figure 1. Interferon receptors and activation of classical pathways by type I and type II interferons (from reference 1 - reproduced with permission from Nature Reviews Immunology (Vol.5, No.5, pp , 2005), copyright (2005) Macmillan Magazines Ltd.). 5
6 Figure 2. Possible immunomodulatory and direct antiviral activities of ribavirin: (i) drug-induced immune clearance of the virus by facilitating the switch from a Th 2 to a Th 1 phenotype with increased production of antiviral cytokines such as TNF and IFN-gamma; (ii) RMP inhibits the enzymatic activity of IMPDH in the conversion of IMP into GMP; (iii) inhibition of HCV RdRp activity; (iv) Ribavirin, triphosphate (RTP) acts as an RNA mutagen. The combined direct antiviral activities of steps (ii) (iv) result in down-regulation of HCV virion production while HCV particles that are released are defective. CTL, cytotoxic T lymphocytes; HCV, hepatitis C virus; IFN, interferon; IMP, inosine monophosphate; IMPDH, inosine monophosphate dehydrogenase; RDP, ribavirin diphosphate; RdRp, RNA-dependent RNA polymerase; RMP, ribavirin monophosphate; RTP, ribavirin triphosphate; TNF, tumour necrosis factor; RNA, ribonucleic acid (from reference 9 - Hepatology 2002;35(5), pp reproduced with permission of Wiley-Liss, Inc. a subsidiary of John Wiley & Sons, Inc.) 6
7 Figure 3. Changes in HCV-specific IL-10 and IFN-γ production in vitro from patients treated with IFN alone and with IFN plus Ribavirin. The values for IL-10 and IFN-γ represent the difference in the cytokine levels produced from PBMCs cultured in the presence of HCV antigens minus that produced by cells cultured in medium alone. Figure 4. Frequencies of HCV-specific T-cells producing IFN-γ in response to HCV antigens, as determined by ELISpot assay. A) CD4+ T-cells stimulated with HCV Core, NS3 and NS4; B) CD8+ T-cells stimulated with HLA-A2 restricted peptides. TW-treatment week; FR-fastresponders, SR-slow/flat responders. 7
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