SciELO - Scientific Electronic Library Online

vol.101 número5Pseudodestrucción intestinal crónica: un diagnóstico a tener en cuentaMegarrecto y megacolon idiopático índice de autoresíndice de materiabúsqueda de artículos
Home Pagelista alfabética de revistas  

Servicios Personalizados




Links relacionados

  • En proceso de indezaciónCitado por Google
  • No hay articulos similaresSimilares en SciELO
  • En proceso de indezaciónSimilares en Google


Revista Española de Enfermedades Digestivas

versión impresa ISSN 1130-0108

Rev. esp. enferm. dig. vol.101 no.5 Madrid may. 2009




Cytokines - their pathogenic and therapeutic role in chronic viral hepatitis

Citoquinas: papel patogénico y terapéutico de las hepatitis crónicas víricas



J. R. Larrubia, S. Benito-Martínez, J. Miquel-Plaza, E. Sanz-de-Villalobos, F. González-Mateos and T. Parra

Unidad de Hepatología Traslacional. Hospital Universitario de Guadalajara. Universidad de Alcalá, Madrid. Spain

This paper was partly supported by "Fiscam, J.C.C.M" ("Ayuda para proyectos de investigación en salud"; PI-2007/32) and "Fundación de Investigación Médica Mutua Madrileña" ("Beca Ayudas a la Investigación FMMM"; 2548/2008). Benito S was supported by a research grant from "Fiscam" J.C.C.M ("Perfeccionamiento y movilidad de investigadores"; MOV-2007_JI/18).





Cytokines make up a network of molecules involved in the regulation of immune response and organ functional homeostasis. Cytokines coordinate both physiological and pathological processes occurring in the liver during viral infection, including infection control, inflammation, regeneration, and fibrosis. Hepatitis B and hepatitis C viruses interfere with the complex cytokine network brought about by the immune system and liver cells in order to prevent an effective immune response, capable of viral control. This situation leads to intrahepatic sequestration of nonspecific inflammatory infiltrates that release proinflammatory cytokines, which in turn favor chronic inflammation and fibrosis. The therapeutical administration of cytokines such as interferon alpha may result in viral clearance during persistent infection, and revert this process.

Key words: Cytokines. Chronic hepatitis. HBV. HCV. Immunopathogenesis.



Cytokines are small soluble proteins secreted by immune system cells and other body cells, and are part of an intercellular communication system responsible for developmental regulation, tissue repair, and immune response in pluricellular organisms (1). These proteins play their role in an autocrine or paracrine manner by binding specific cell receptors that either induce or inhibit cytokine-regulated genes. Over 100 different cytokines have been reported, which are classified according to their primary role (Table I). These proteins are involved in all immune response aspects, and play a key role in immune response polarization and regulation. The combination of cytokines resulting from a specific antigenic stimulus determines the kind of immune response that will develop.

During viral infection various cytokines play a role both in viral clearance and tissue damage mechanisms. Viruses may interfere with the normal function of this complex cytokine network as an escape route to avoid destruction.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are hepatotropic, non-cytopathic viruses of the hepadnavirus and flavivirus families, respectively, that induce both acute and chronic necro-inflammatory liver disease (2,3). HBV escapes immune control in 10% of adult infections, whereas HCV successfully evades the immune system in 60-80% of cases. Changes in various cytokine activities have been reported for both viral infections, which might favor viral persistence.


The role of cytokines in effective immune response against HBV and HCV

When infecting the liver parenchyma hepatotropic viruses such as HBV or HCV continuously release viral particles into the blood stream. The first line of defense viruses will encounter includes natural killer (NK) cells and natural killer T (NKT) cells, which abound in the liver (4). These cells are activated by type-I interferon (IFN) (α and β) released by infected liver cells. NK and NKT cells both can eliminate infected cells, but also constitute a relevant source of IFN-γ and tumor necrosis factor (TNF) alpha (5). These cytokines inhibit viral replication through non-cytolytic mechanisms, that is, can eliminate viruses without destroying liver cells. NK cells are activated by IL-12 released from dendritic cells (DCs), and thus become empowered to eliminate both infected cells and immature DCs with no Th1 cytokine profile, which would not result in appropriate stimulation of a specific response (6). According to the balance between cytokines released by innate immune system cells resident in or recruited by the liver (IL-4/IFNα/IL-12), NK cells may induce partial or total DC maturation (7).

DCs can process viral antigens and present them to specific immune system cells via class-I and class-II major histocompatibility complex (MHC) molecules. DCs capture viral particles through Toll-like receptors (TLRs). Upon activation these cells secrete several types of cytokines (IL-12, TNF-α, IFN-α, IL-10) that will regulate and polarize the response of adjacent cells (8). Two types of DC have been described; myeloid DCs mainly produce IL-12 or TNF-α, whereas plasmacytoid DCs release IFN-α (9). Mature DCs leave the liver after viral epitope collection and head for lymph nodes, where they will activate T cells in the specific immune system (10).

Cytokines released in the liver parenchyma induce chemokine release by liver cells, including interferon-inducible protein (IP-10/CXCL10), interferon-induced monokine (Mig/CXCL9), macrophage inflammatory protein (MIP/CCL3)-1α, and MIP 1-β/CCL4, which recruit inflammatory infiltration (11) including specific cells capable of infection control.

Both mature DCs and immature T cells, both of which express chemokine receptor CCR7, are recruited towards lymph nodes by secondary lymphoid-tissue cytokine (SLC/CCL21) (10). In the lymph node T cells expressing T-cell receptors (TCRs) appropriate for the recognition of epitopes presented by DCs in their MHC molecules are activated. The interaction between the TCR and MHC-viral epitope complex, together with appropriate co-stimulating molecules and an adequate cytokine environment, results in specific T-cell activation. Certain specific CD8 T cells, cytotoxic T lymphocytes (CTLs), become cytolytic, secrete type-I cytokines (Fig. 1), and express chemokine receptors that will let them travel to the infected liver for infection control (12-14) (Fig. 2). Specific CD4+ T cells will regulate the adaptive response by secreting Th1 cytokines (IL-2, IFN-γ, TNF-α) to facilitate a cytotoxic response, and Th2 cytokines (IL-4, IL-10, IL-13) to regulate humoral response (15).

It is widely accepted that adaptive immune response plays a key role in the control of infection with hepatotropic, non-cytopathic viruses. Infection control correlates to a multispecific polyclonal response capable of secreting type-I cytokines and of expressing Th1/Tc1 response-associated chemokines (16).

However, both HBV and HCV often manage to escape immune response. To this end they interfere with various immune mechanisms including cytokine activity modulation.


The role of cytokines in persistent infection with HBV and HCV

Cell tropism and entry into the host cell

Liver parenchyma is the place for HBV and HCV replication. Receptors for viral entry have not been fully identified, but potential candidates include some cytokine receptors. During infection with HBV IL-6 receptor has been seen to interact with polypeptides included in hepatitis B surface antigen (17), and this may thus be an entry route into the liver cell.

Innate response (Fig. 3)

Production of type-I interferon (IFN): IFN α/β

A primary cell defense mechanism during initial infection is the synthesis of anti-viral cytokines such as type-I interferon (IFN α/β) (18). On binding its receptor this cytokine activates a number of intracellular mechanims that can prevent viral replication and spread to other liver cells. In vitro, HCV can block type-I IFN induction, which is however not the case in vivo. HCV is a good inducer of IFN α/β expression, possibly because this virus replicates via dsRNA intermediaries (4,19,20). These intermediaries rapidly activate the dsRNA-sensitive cell apparatus, and thus stimulate IFN α/β expression induction (21). In HCV chimpanzee models a high expression of type-I IFN-induced genes has been seen early during infection. However, HCV seems to be unresponsive to IFN α/β effects, and effectively replicates in the liver despite such gene induction. This possibly results from the fact that non-structural proteins NS3 and NS5A, and structural protein E2 may both potentially block the expression and transcription of IFN α/β-induced genes. This has been demonstrated in vitro. HCV NS5A protein has also been seen to induce proinflammatory chemokyne IL-8 expression, which is associated with IFN α inhibition both in vitro and in vivo (22). Membrane-sited Toll-like receptors (TLRs) allow cells to detect viral particles. HCV NS3/4A protease blocks TLR-3 signaling, and also blocks a dsRNA binding protein (RIG-1) that activates interferon regulatory factor 3 (IRF-3), a central mediator of IFN-β induction during a response to viral infection (23,24).

In contrast HBV induces no type-I interferon expression during initial infection (25). In HBV infection in chimpanzees, viruses remain hidden from the immune system during the first few weeks, and hence induce no effective innate response. Such relative invisibility results from various viral replication strategy components including transcriptional template retention in the nucleus, sequestration of the replicated genome in the cytoplasm, and similarity between mRNA molecules and normal hepatocyte transcripts (26,27). From all this hepatocytes will not release IFN α/β early during initial infection, hence allowing HBV replication and spread.

These data show two distinct mechanisms used by HCV and HBV to escape IFN α/β anti-viral effects in early infection, and thus propagate before the emergence of any specific response.

Blocked type-II interferon production in natural killer (NK) cells and natural killer T (NKT) cells

NK cells and NKT cells play a central role in innate immune response against several viral infections, as is the case with murine cytomegalovirus infection in mice (28). These cells exert their anti-viral action through direct, non-MHC-restricted cytotoxic mechanisms and IFN-γ production (28). In addition, they play an edition role on dendritic cells, allowing maturation for DCs favoring the development of Th1/Tc1 responses (6). However, they do not seem to play a significant role in infection with HBV or HCV. In chimpazee models with acute HCV or HBV infection no expression of IFN-γ-inducible genes is seen when HBV or HCV is spreading across the liver parenchyma (20,29,30). Therefore, data suggest that these viruses can block NK-cell and NKT-cell functions thus preventing anti-viral cytokines such as IFN-γ from being produced. A potential mechanism for this blockade in HCV infection is via an interaction between HCV E2 protein and NK-cell CD81 molecule (31,32). This interaction would block the activation of NK cells, which subsequently would release no IFN-γ, would develop no cytolytic action, and would not contribute to appropriate dendritic cell maturation.

Changes in cytokines produced by dendritic cells

Cytokine production by DCs is important for T-cell activation and innate immunity. During chronic infection with HCV a decrease in IFNα production by plasmacytoid DCs has been reported after stimulation with TLR-9 ligands (33). A decrease in IL-12 production by myeloid DCs has also been found during chronic infection with HCV in the presence of stimuli such as CD40L or poly-(I:C) (34). This decreased production of type-I IFN and IL-12 may explain the Th1-to-Th2 response shift seen in chronic hepatitis C (15). In vitro studies have shown that HCV structural proteins can interact with TLR2 in monocytes/macrophages, and induce IL-10 production, which eventually inhibits IL-12 production in myeloid cells and IFN-α production in plasmacytoid DCs (35). This decreased production of type-I cytokines contributes to inadequate NK-cell and NKT-cell activation. Furthermore, this dendritic cell-related cytokine profile cannot polarize T-cell responses towards a Th1/Tc1 phenotype (36).

Adaptive response (Fig. 3)

Virus-specific CTLs and helper CD4+ T cells play a key effector and regulatory role in immune responses against HCV and HBV. Specific CD4+ T cells play a key role in adaptive response in that they provide help in activating cytotoxic and humoral responses. They can secrete Th1 cytokines including IFN-γ, which favors neutrophil and macrophage recruitment, and leads to inflammatory response. They also may release Th2 cytokines such as IL-4 and IL-10, which limit Th1 cytokine-mediated response and favor the development of humoral response (37). A multispecific, strong, sustained, CD4+-T-cell-specific Th1 response may be seen in infections with hepatotropic viruses evolving to resolution (38,39,44). However, when infection becomes chronic a weak CD4-T-specific response with few specificities and scarce type-I cytokine production is observed (40,41).

CD8+ CTLs can clear viruses using apoptosis-related cytolytic mechanisms, and non-cytolytic mechanisms mediated by type-I cytokines (IFN-γ, TNF-α) (5) (Fig. 1). In chronic infection with HBV or HCV specific CTLs are few and engage few specific targets; they also display anergic characteristics with reduced type-I cytokine secretion (42-44). Changes in CTLs to allow secretion of these cytokines are multifactorial, but a number of cytokines doubtless play a role. The interaction of the HCV core protein with the globular domain of C1q receptor in T cells has been seen to reduce IL-2 production in T cells (45). This change decreases cell spread and maturation, and prevents these cells from reaching their cytotoxic and IFN-γ secreting potential (43,46). On the other hand, intense T-cell receptor stimulation during persistent infection results in an overexpression of PD-1, a negative co-stimulatory molecule, which favors the development of cell anergy with failed type-I cytokine secretion (47-49) (Fig. 5). The presence of inadequate activation mediated by antigen-presenting cells in the setting of Th2/Tc2 cytokine expression is also a factor (36). Another potential mechanism of blocked type-I cytokine production results from regulatory T cell (Treg) activity. These cells can release IL-10 and TGF-β, and inhibit proliferation and cytokine synthesis in T cells, either directly or through other cytokines, in both hepatitis B and C (50,51). The presence of CD8+, CCR7- regulatory T cells has been demonstrated in the liver of patients with chronic hepatitis C; these cells can inhibit HCV-specific CD8+ T cells via IL-10 production (52).

Cytokines produced by T cells play a role in the regulation of humoral responses with both neutralizing and non-neutralizing antibodies (53). Nevertheless, these responses cannot control chronic viral hepatitis, even though they play a role in the pathogenesis of extrahepatic manifestations (15).


Cytokines and liver damage (Fig. 3)

When specific immune response fails to control viral replication nonspecific inflammatory infiltrates are recruited into the liver that are responsible for liver damage (54). The infected liver secretes IFN-γ-induced chemokines such as CXCL9 and CXCL10, which results in the migration of nonspecific mononuclear cells into the liver (11,55). These cells are unable to control infection but result in sustained low-grade liver damage. A positive correlation has been reported between the expression of both these chemokines and their receptors, and histological damage (56-58) (Fig. 4). Inhibiting these chemokines limits nonspecific cell migration, and hence reduces inflammation with no impact on the actions of anti-viral specific CTLs (59). Hepatotropic viruses block the expression of chemokine receptors associated with Tc1/Th1 response in order to hinder the migration of specific and nonspecific responses to the liver, thus favoring viral persistence (60). By binding CD81, HCV E2 protein has been seen to induce RANTES/CCL5 expression in T cells. Overexpressed RANTES/CCL5 binds its CCR5 receptor, which results in receptor internalization. This reduced expression of chemokine receptors associated with Tc1 response in T cells may impair these cells' chemotaxis into the liver (61).

The recruitment of persistent mononuclear infiltrates leads to the development of chronic inflammation, which results in sustained liver damage. Finally, chronic inflammation induces regenerating mechanisms in the liver parenchyma. Several factors influence this process, including cytokines such as IL-6, TNF-α, TGF-β, HGF, and EGF. These and other factors activate transcription factors such as NF-κβ, STAT3, AP-1, and C/EBP, which initiate the gene expression cascade leading to hepatocyte proliferation (62).

Persistent inflammation also activates hepatic stellate cells, myofibroblasts, and fibroblasts, which initiate collagen, laminin, fibronectin, and proteoglycan production and deposition, which favors the development of liver fibrosis. The activation of these cells is regulated by pro-inflammatory cytokines such as TGF-β, IL-6, TNF-α, CCL-21, and PDFG, among other stimuli (63). A dysregulation of liver regeneration processes ultimately occurs, which results in liver cirrhosis.


Therapeutic role of cytokines in chronic viral hepatitis

INFα is the only cytokine currently used in the treatment of chronic viral hepatitis. In chronic hepatitis C pegylated INFα combined with ribavirin leads to sustained viral clearance in 50% of patients (64). In monotherapy it leads to anti-HBe seroconversion in 25% of patients with e+ chronic hepatitis B (65). INFα has direct anti-viral and immunomodulating actions that favor Th1/Tc1 response restoration (66-68). On the other hand ribavirin, a wide-spectrum antiviral agent used in combination therapy for hepatitis C, has immunomodulating effects that induce type-I cytokine production (69). Sustained viral load reduction with antiviral agents has also been seen to facilitate specific T response recovery with type-I cytokine production in both hepatitis B and C (70).

An exogenous administration of Th1-inducing cytokines such as IL-12 (71) or anti-inflammatory cytokines such as IL-10 has also been attempted to reduce intrahepatic inflammation severity (72). However, such therapies remain experimental, and their effectiveness is unclear.

From a theoretical standpoint Tc1-associated chemokine receptors may represent an interesting therapeutic target in the development of drugs for patients with chronic hepatitis unresponsive to antiviral agents, their aim being a reduction of liver inflammation and progression to fibrosis by blocking inflammatory cell migration into the liver (55,59).



Cytokines are inter-cell mediators involved in viral control and liver damage as induced by infection with HBV or HCV. The complex cytokine network operating during initial infection allows a coordinated, effective development of both innate and adaptive immune responses. However, both HBV and HCV interfere with cytokines at various levels, and escape immune response by inducing a Th2/Tc2 cytokine profile. Inability to control infection leads to the recruitment of inflammatory infiltrates into the liver parenchyma by pro-inflammatory chemokines, which results in sustained liver damage, and eventually in liver cirrhosis.



1. Steinke JW, Borish L. Cytokines and chemokines. J Allergy Clin Immunol 2006; 117: S441-445.        [ Links ]

2. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001; 345: 41-52.        [ Links ]

3. Ganem D, Prince AM. Hepatitis B virus infection-natural history and clinical consequences. N Eng J Med 2004; 350: 1118-29.        [ Links ]

4. Su AI, Pezacki JP, Wodicka L, Brideau AD, Supekova L, Thimme R, et al. Genomic analysis of the host response to hepatitis C virus infection. Proc Natl Acad Sci U S A 2002 ; 99: 15669-74.        [ Links ]

5. Guidotti LG, Chisari FV. Noncytolitic control of viral infections by the innate and adaptative immune response. Annu Rev Immunol 2001; 19: 65-91.        [ Links ]

6. Moretta A. Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol 2002; 12: 957-64.        [ Links ]

7. Marcenaro E, Della Chiesa M, Bellora F, Parolini S, Millo R, Moretta L, et al. IL-12 or IL-4 prime human NK cells to mediate functionally divergent interactions with dendritic cells or tumors. J Immunol 2005; 174: 3992-8.        [ Links ]

8. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18: 767-811.        [ Links ]

9. Shortman K, Liu YJ. Mouse and human dendritic cell subtypes. Nat Rev Immunol 2002; 2: 151-61.        [ Links ]

10. Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Eng J Med 2006; 354: 610-21.        [ Links ]

11. Shields PL, Morland CM, Salmon M, Qin S, Hubscher SG, Adams DH. Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J Immunol 1999; 163: 6236-43.        [ Links ]

12. Maini MK, Boni C, Ogg GS, King AS, Reignat S, Lee CK, et al. Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection. Gastroenterology 1999; 117: 1386-96.        [ Links ]

13. Lauer GM, Barnes E, Lucas M, Timm J, Ouchi K, Kim AY, et al. High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection. Gastroenterology 2004 ; 127: 924-36.        [ Links ]

14. Larrubia JR, Herberg JA, Reignat S, Webster G, Williams R, Maini M, et al. Chemokine receptor expression and cytokine production of HBV-specific CD8 cells. J Hepatol 2000;32(S2): 90.        [ Links ]

15. Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol Mech Dis 2006; 1: 23-61.        [ Links ]

16. A Bertoletti, MK Maini. Protection or damage: a dual role for the virus-specific cytotoxic T lymphocyte response in hepatitis B and C infection? Curr Opin Immunol 2000; 12: 403-8.        [ Links ]

17. Neurath AR, Strick N, Sproul P. Search for hepatitis B virus cell receptors reveals binding sites for interleukin 6 on virus envelope protein. J Exp Med 1992; 175: 461-9.        [ Links ]

18. Samuel CE. Antiviral actions of interferons. Clin Microbiol Rev 2001; 14: 778-809.        [ Links ]

19. Bigger CB, Brasky KM, Landford RE. DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection. J Virol 2001; 75: 7059-66.        [ Links ]

20. Bigger CB, Guerra B, Brasky KM, Hubbard G, Beard MR, Luxon BA, et al. Intrahepatic gene expression during chronic hepatitis C virus infection in chimpanzees. J Virol 2004; 78: 13779-92.        [ Links ]

21. Moradpour D, Brass V, Bieck E, Friebe P, Gosert R, Blum HE, et al. Membrane association of the RNA-dependent RNA polymerase is essential for hepatitis C virus RNA replication. J Virol 2004; 78: 13278-84.        [ Links ]

22. Polyak SJ, Khabar KS, Paschal DM, Ezelle HJ, Duverlie G, Barber GN, et al. Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. J Virol 2001; 75: 6095-106.        [ Links ]

23. Li K, Foy E, Ferreon JC, Nakamura M, Ferreon AC, Ikeda M, et al. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc Natl Acad Sci U S A 2005; 102: 2992-7.        [ Links ]

24. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 2004; 5: 730-7.        [ Links ]

25. Wieland S, Thimme R, Purcell RH, Chisari FV. Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A 2004; 101: 6669-74.        [ Links ]

26. Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev 2000; 64: 51-68.        [ Links ]

27. Summers J. The replication cycle of hepatitis B viruses. Cancer 1988; 61: 1957-1962.        [ Links ]

28. Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 1999; 17: 189-220.        [ Links ]

29. Guidotti LG, Rochford R, Chung J, Shapiro M, Purcell R, Chisari FV. Viral clearance without destruction of infected cells during acute HBV infection. Science 1999; 284: 825-9.        [ Links ]

30. Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, Purcell RH, et al. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol 2003; 77: 68-76.        [ Links ]

31. Crotta S, Stilla A, Wack A, D'Andrea A, Nuti S, D'Oro U, et al. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J Exp Med 2002; 195: 35-41.        [ Links ]

32. Tseng CT, Klimpel GR. Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions. J Exp Med 2002; 195: 43-9.        [ Links ]

33. Ulsenheimer A, Gerlach JT, Jung MC, Gruener N, Wachtler M, Backmund M, et al. Plasmacytoid dendritic cells in acute and chronic hepatitis C virus infection. Hepatology 2005;41: 643-51.        [ Links ]

34. Anthony DD, Yonkers NL, Post AB, Asaad R, Heinzel FP, Lederman MM, et al. Selective impairments in dendritic cell-associated function distinguish hepatitis C virus and HIV infection. J Immunol 2004; 172: 4907-16.        [ Links ]

35. Szabo G, Dolganiuc A. Subversion of plasmacytoid and myeloid dendritic cell functions in chronic HCV infection. Immunobiology 2005; 210: 237-47.        [ Links ]

36. Kanto T, Inoue M, Miyazaki M, Itose I, Miyatake H, Sakakibara M, et al. Impaired function of dendritic cells circulating in patients infected with hepatitis C virus who have persistently normal alanine aminotransferase levels. Intervirology 2006; 49: 58-63.        [ Links ]

37. Moser M, Murphy KM. Dendritic cell regulation of Th1-Th2 development. Nat Immunol 2001; 1: 199-03.        [ Links ]

38. Day CL, Lauer GM, Robbins GK, McGovern B, Wurcel AG, Gandhi RT, et al. Broad specificity of virus-specific CD4+ T-helper-cell responses in resolved hepatitis C virus infection. J Virol 2002; 76:12584-95.        [ Links ]

39. Webster GJ, Reignat S, Maini MK, Whalley SA, Ogg GS, King A, et al. Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms. Hepatology 2000; 32: 1117-24.        [ Links ]

40. Gerlach JT, Diepolder HM, Jung MC, Gruener NH, Schraut WW, Zachoval R, et al. Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C. Gastroenterology 1999; 117: 933-41.        [ Links ]

41. Rosen HR, Miner C, Sasaki AW, Lewinsohn DM, Conrad AJ, Bakke A, et al. Frequencies of HCV-specific effector CD4+ T cells by flow cytometry: correlation with clinical disease stages. Hepatology 2002; 35: 190-8.        [ Links ]

42. Gruener NH, Lechner F, Jung MC, Diepolder H, Gerlach T, Lauer G, et al. Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus. J Virol 2001; 75: 5550-8.        [ Links ]

43. Wedemeyer H, He XS, Nascimbeni M, Davis AR, Greenberg HB, Hoofnagle JH, et al. Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection. J Immunol 2002; 169: 3447-58.        [ Links ]

44. Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 2001; 194: 1395-406.        [ Links ]

45. Kittlesen DJ, Chianese-Bullock KA, Yao ZQ, Braciale TJ, Hahn YS. Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation. J Clin Invest 2000; 106: 1239-49.        [ Links ]

46. Accapezzato D, Francavilla V, Rawson P, Cerino A, Cividini A, Mondelli MU, et al. Subversion of effector CD8+ T cell differentiation in acute hepatitis C virus infection: the role of the virus. Eur J Immunol 2004; 34: 438-46.        [ Links ]

47. Golden-Mason L, Palmer B, Klarquist J, Mengshol JA, Castelblanco N, Rosen HR. Upregulation of PD-1 expression on circulating and intrahepatic hepatitis C virus-specific CD8+ T cells associated with reversible immune dysfunction. J Virol 2007; 81: 9249-58.        [ Links ]

48. Benito S, Larrubia JR, Sanz de Villalobos E, Calvino M, García-Buey ML, González-Mateos F, et al. Association between HCV infection control and development of an specific cytotoxic cellular reservoir PD1 negative. J Hepatol 2008; 48(S2): S224.        [ Links ]

49. Zhang Z, Zhang JY, Wherry EJ, Jin B, Xu B, Zou ZS, et al. Dynamic programmed death 1 expression by virus-specific CD8 T cells correlates with the outcome of acute hepatitis B. Gastroenterology 2008; 134: 1938-49.        [ Links ]

50. Cabrera R, Tu Z, Xu Y, Firpi RJ, Rosen HR, Liu C, et al. An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection. Hepatology 2004; 40: 1062-71.        [ Links ]

51. Franzese O, Kennedy PT, Gehring AJ, Gotto J, Williams R, Maini MK, et al. Modulation of the CD8+-T-cell response by CD4+ CD25+ regulatory T cells in patients with hepatitis B virus infection. J Virol 2005; 79: 3322-8.        [ Links ]

52. Accapezzato D, Francavilla V, Paroli M, Casciaro M, Chircu LV, Cividini A, et al. Hepatic expansion of a virus-specific regulatory CD8(+) T cell population in chronic hepatitis C virus infection. J Clin Invest 2004; 113: 963-72.        [ Links ]

53. Burton DR, Williamson RA, Parren PW. Antibody and virus: binding and neutralization. Virology 2000; 270:1-3.        [ Links ]

54. Maini MK, Boni C, Lee CK, Larrubia JR, Reignat S, Ogg GS, et al. The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med 2000; 191: 1269-80.        [ Links ]

55. Larrubia JR, Benito-Martínez S, Calvino M, Sanz de Villalobos E, Parra-Cid T. Role of chemokines and their receptors in viral persistence and liver damage during chronic hepatitis C virus infection. World J Gastroenterol 2008; 14(47): 7149-59.        [ Links ]

56. Apolinario A, Majano PL, Alvarez-Perez E, Saez A, Lozano C, Vargas J, et al. Increased expression of T cell chemokines and their receptors in chronic hepatitis C: relationship with the histological activity of liver disease. Am J Gastroenterol 2002; 97: 2861-70.        [ Links ]

57. Calvino M, Larrubia JR, Sanz E, Perna C, Pérez J, Benito S, et al. Chemokine receptor expression on T cells according to inflammatory activity and liver fibrosis in chronic hepatitis C virus infection. J Hepatol 2006; 44(S2):161.        [ Links ]

58. Larrubia JR, Calvino M, Benito S, Sanz-de-Villalobos E, Perna C, Pérez-Hornedo J, et al. The role of CCR5/CXCR3 expressing CD8+ cells in liver damage and viral control during persistent hepatitis C virus infection. J Hepatol 2007; 47: 632-41.        [ Links ]

59. Kakimi K, Lane TE, Wieland S, Asensio VC, Campbell IL, Chisari FV, et al. Blocking chemokine responsive to gamma-2/interferon (IFN)-gamma inducible protein and monokine induced by IFN-gamma activity in vivo reduces the pathogenetic but not the antiviral potential of hepatitis B virus-specific cytotoxic T lymphocytes. J Exp Med 2001; 194: 1755-66.        [ Links ]

60. Calvino M, Larrubia JR, Parra T, Sanz de Villalobos E, González F, Perna C, et al. Analysis of CCR5 receptor expression on CD8 T cells during chronic hepatitis C virus infection. Role of pegylated-interferon a2b plus ribavirine treatment. J Hepatol 2005; 42(S2): 155.        [ Links ]

61. Nattermann J, Nischalke HD, Feldmann G, Ahlenstiel G, Sauerbruch T, Spengler U. Binding of HCV E2 to CD81 induces RANTES secretion and internalization of CC chemokine receptor 5. J Viral Hepat 2004; 11: 519-26.        [ Links ]

62. Taub R, Greenbaum LE, Peng Y. Transcriptional regulatory signals define cytokine-dependent and -independent pathways in liver regeneration. Semin Liver Dis 1999; 19: 117-27.        [ Links ]

63. Ramadori G, Saile B. Inflammation, damage repair, immune cells, and liver fibrosis: specific or nonspecific, this is the question. Gastroenterology 2004; 127: 997-1000.        [ Links ]

64. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 958-65.        [ Links ]

65. Cooksley WG, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, et al. Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat 2003; 10: 298-305.        [ Links ]

66. Cacciarelli TV, Martinez OM, Gish RG, Villanueva JC, Krams SM. Immunoregulatory cytokines in chronic hepatitis C virus infection: pre- and posttreatment with interferon alfa. Hepatology 1996; 24: 6-9.        [ Links ]

67. Kamal SM, Fehr J, Roesler B, Peters T, Rasenack JW. Peginterferon alone or with ribavirin enhances HCV-specific CD4 T-helper 1 responses in patients with chronic hepatitis C. Gastroenterology 2002; 123: 1070-83.        [ Links ]

68. Yang YF, Tomura M, Iwasaki M, Ono S, Zou JP, Uno K, et al. IFN-alpha acts on T-cell receptor-triggered human peripheral leukocytes to up-regulate CCR5 expression on CD4+ and CD8+ T cells. J Clin Immunol 2001; 21: 402-9.        [ Links ]

69. Ning Q, Brown D, Parodo J, Cattral M, Gorczynski R, Cole E, et al. Ribavirin inhibits viral-induced macrophage production of TNF, IL-1, the procoagulant fgl2 prothrombinase and preserves Th1 cytokine production but inhibits Th2 cytokine response. J Immunol 1998; 160: 3487-93.        [ Links ]

70. Boni C, Penna A, Ogg GS, Bertoletti A, Pilli M, Cavallo C, et al. Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy. Hepatology 2001; 33: 963-71.        [ Links ]

71. Rigopoulou EI, Suri D, Chokshi S, Mullerova I, Rice S, Tedder RS, et al. Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: antiviral and immunological activity. Hepatology 2005; 42: 1028-36.        [ Links ]

72. Nelson DR, Lauwers GY, Lau JY, Davis GL. Interleukin 10 treatment reduces fibrosis in patients with chronic hepatitis C: a pilot trial of interferon nonresponders. Gastroenterology 2000; 118: 655-60.        [ Links ]



J.R. Larrubia.
Sección de Aparato Digestivo. Hospital Universitario de Guadalajara.
C/ Donante de Sangre, s/n. 19002 Guadalajara, Spain.

Received: 09-02-09.
Accepted: 08-03-09.

Creative Commons License Todo el contenido de esta revista, excepto dónde está identificado, está bajo una Licencia Creative Commons