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Success of antiviral therapy in chronic hepatitis C infection relates to functional status of myeloid dendritic cells.

Rana D, Chawla Y, Arora SK - Indian J. Med. Res. (2013)

Bottom Line: Various immunological factors, both innate and adaptive, play role in the pathogenesis of the disease and become dysfunctional in active disease.Recent reports suggest the major impact of functional and numerical status of dendritic cells in deciding the fate of antiviral therapy.In this review we take a look at the involvement of dendritic cells in playing an important role in the response to therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunopathology, Postgraduate Institute of Medical Education & Research, Chandigarh, India.

ABSTRACT
Chronic hepatitis C infection poses a major global health predicament and appears to be potent threat to mankind. The treatment in wide use is interferon/ribavirin combination therapy which is generally effective in about 60-70 per cent of patients carrying genotype 3 and causes significant morbidity. The response to therapy is largely guided by limited number of factors such as genotype of virus, rapid virological response, ethnicity, pre-therapy viral load, etc. While involvement of host genetic factors has been a major focus of research in playing an important role in the outcome of disease, the role of immune system cannot be marginalized. Poor cellular trafficking and suboptimal T cell responses in liver, the hall marks of chronic hepatitis C virus infection, might be attributed to defective antigen presentation. Various immunological factors, both innate and adaptive, play role in the pathogenesis of the disease and become dysfunctional in active disease. Recent reports suggest the major impact of functional and numerical status of dendritic cells in deciding the fate of antiviral therapy. In this review we take a look at the involvement of dendritic cells in playing an important role in the response to therapy.

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Cytokine profile of monocyte-derived dendritic (mo-DCs) cells pre- and post-lipopolysaccharide (LPS) stimulation. Secretion of IL1β, IL12 and TNF-α increased significantly in LPS stimulated mo-DCs after therapy in SVR+ patients, although those from SVR-patients secreted high IL10 before and after therapy. HC, healthy controls; SVRO+, treatment naïve sustained virological responders; SVR6+, responders post 6 months treatment; SVR6-, non-responders post 6 months treatment.(Reproduced with permission from John Wiley and Sons Ltd., Philadelphia, USA [Liver Int 2012; 32 : 1128-37]68.
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Figure 4: Cytokine profile of monocyte-derived dendritic (mo-DCs) cells pre- and post-lipopolysaccharide (LPS) stimulation. Secretion of IL1β, IL12 and TNF-α increased significantly in LPS stimulated mo-DCs after therapy in SVR+ patients, although those from SVR-patients secreted high IL10 before and after therapy. HC, healthy controls; SVRO+, treatment naïve sustained virological responders; SVR6+, responders post 6 months treatment; SVR6-, non-responders post 6 months treatment.(Reproduced with permission from John Wiley and Sons Ltd., Philadelphia, USA [Liver Int 2012; 32 : 1128-37]68.

Mentions: Besides the expression of co-stimulatory and MHC class II molecules on their surface, DCs also secret many cytokines, as a direct evidence of their maturation and activation. A few reports have demonstrated that purified DCs or mo-DCs from CHC patients showed lower IL-12 and higher IL-10 production in response to poly-IC or TNFα stimulation ex vivo7980. However, no difference in cytokine profile from CHC and HC was found in another report55. IL-10 has been shown to be an important player in the pathogenesis of HCV infection, being induced by various HCV antigens81. We also reported recently that the mo-DCs from non-responders to antiviral therapy were not able to secrete proinflammatory cytokines such as IL-1β and IL-12 in response to LPS stimulation but showed an increased IL-10 and TNFα production68 (Fig. 4). This aberrant cytokine profile also conforms to immature phenotype of mo-DCs in these patients. Consequently, the patients who did not achieve SVR also had high IL-10 secreting mo-DCs, even prior to the start of antiviral treatment and continued to have that trend even after completion of therapy. This finding implies the possibility of the tolerogenic signals by immature DCs under the influence of IL-10 in these individuals which might be responsible for their inability to ultimately clear the virus. The persistence of high vireamia in CHC patients who failed to achieve SVR might be a possible reason behind the abnormal cytokine secretion. On the other hand, the viral clearance in SVR+ patients alleviated the ‘stress’ causing the DCs to secrete pro-inflammatory cytokines. However, the immunomodulatory role of IFNα/ribavirin therapy cannot be ignored. A previous in vitro study had revealed that IFNα and ribavirin act synergistically to normalize the functions of defective dendritic cells, while the IFNα enhances the production of IL-12 and TNFα, the ribavirin at the same time suppresses the production of IL-10, thereby tilting the balance towards Th1 response55.


Success of antiviral therapy in chronic hepatitis C infection relates to functional status of myeloid dendritic cells.

Rana D, Chawla Y, Arora SK - Indian J. Med. Res. (2013)

Cytokine profile of monocyte-derived dendritic (mo-DCs) cells pre- and post-lipopolysaccharide (LPS) stimulation. Secretion of IL1β, IL12 and TNF-α increased significantly in LPS stimulated mo-DCs after therapy in SVR+ patients, although those from SVR-patients secreted high IL10 before and after therapy. HC, healthy controls; SVRO+, treatment naïve sustained virological responders; SVR6+, responders post 6 months treatment; SVR6-, non-responders post 6 months treatment.(Reproduced with permission from John Wiley and Sons Ltd., Philadelphia, USA [Liver Int 2012; 32 : 1128-37]68.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928708&req=5

Figure 4: Cytokine profile of monocyte-derived dendritic (mo-DCs) cells pre- and post-lipopolysaccharide (LPS) stimulation. Secretion of IL1β, IL12 and TNF-α increased significantly in LPS stimulated mo-DCs after therapy in SVR+ patients, although those from SVR-patients secreted high IL10 before and after therapy. HC, healthy controls; SVRO+, treatment naïve sustained virological responders; SVR6+, responders post 6 months treatment; SVR6-, non-responders post 6 months treatment.(Reproduced with permission from John Wiley and Sons Ltd., Philadelphia, USA [Liver Int 2012; 32 : 1128-37]68.
Mentions: Besides the expression of co-stimulatory and MHC class II molecules on their surface, DCs also secret many cytokines, as a direct evidence of their maturation and activation. A few reports have demonstrated that purified DCs or mo-DCs from CHC patients showed lower IL-12 and higher IL-10 production in response to poly-IC or TNFα stimulation ex vivo7980. However, no difference in cytokine profile from CHC and HC was found in another report55. IL-10 has been shown to be an important player in the pathogenesis of HCV infection, being induced by various HCV antigens81. We also reported recently that the mo-DCs from non-responders to antiviral therapy were not able to secrete proinflammatory cytokines such as IL-1β and IL-12 in response to LPS stimulation but showed an increased IL-10 and TNFα production68 (Fig. 4). This aberrant cytokine profile also conforms to immature phenotype of mo-DCs in these patients. Consequently, the patients who did not achieve SVR also had high IL-10 secreting mo-DCs, even prior to the start of antiviral treatment and continued to have that trend even after completion of therapy. This finding implies the possibility of the tolerogenic signals by immature DCs under the influence of IL-10 in these individuals which might be responsible for their inability to ultimately clear the virus. The persistence of high vireamia in CHC patients who failed to achieve SVR might be a possible reason behind the abnormal cytokine secretion. On the other hand, the viral clearance in SVR+ patients alleviated the ‘stress’ causing the DCs to secrete pro-inflammatory cytokines. However, the immunomodulatory role of IFNα/ribavirin therapy cannot be ignored. A previous in vitro study had revealed that IFNα and ribavirin act synergistically to normalize the functions of defective dendritic cells, while the IFNα enhances the production of IL-12 and TNFα, the ribavirin at the same time suppresses the production of IL-10, thereby tilting the balance towards Th1 response55.

Bottom Line: Various immunological factors, both innate and adaptive, play role in the pathogenesis of the disease and become dysfunctional in active disease.Recent reports suggest the major impact of functional and numerical status of dendritic cells in deciding the fate of antiviral therapy.In this review we take a look at the involvement of dendritic cells in playing an important role in the response to therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunopathology, Postgraduate Institute of Medical Education & Research, Chandigarh, India.

ABSTRACT
Chronic hepatitis C infection poses a major global health predicament and appears to be potent threat to mankind. The treatment in wide use is interferon/ribavirin combination therapy which is generally effective in about 60-70 per cent of patients carrying genotype 3 and causes significant morbidity. The response to therapy is largely guided by limited number of factors such as genotype of virus, rapid virological response, ethnicity, pre-therapy viral load, etc. While involvement of host genetic factors has been a major focus of research in playing an important role in the outcome of disease, the role of immune system cannot be marginalized. Poor cellular trafficking and suboptimal T cell responses in liver, the hall marks of chronic hepatitis C virus infection, might be attributed to defective antigen presentation. Various immunological factors, both innate and adaptive, play role in the pathogenesis of the disease and become dysfunctional in active disease. Recent reports suggest the major impact of functional and numerical status of dendritic cells in deciding the fate of antiviral therapy. In this review we take a look at the involvement of dendritic cells in playing an important role in the response to therapy.

Show MeSH
Related in: MedlinePlus