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Inhibition of regulatory cells as a possible cure of chronically hepatitis B virus infected patients
G Model
ARTICLE IN PRESS
IMLET-5808; No. of Pages 2
Immunology Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Immunology Letters journal homepage: www.elsevier.com/locate/immlet
Letter to the Editor Inhibition of regulatory cells as a possible cure of chronically hepatitis B virus infected patients Dear Editor, Hepatitis B cells virus (HBV) can persist and causes chronic infection by inducing dysfunction of immune responses. Innate and adaptive immune responses are involved during this infection. Previous finding suggested that interferon (IFN)-␥, which is predominantly secreted by T helper (Th) 1 arises against HBV. In addition to Th1, cytotoxic T lymphocytes (CTLs), and dendritic cells (DC) also play an important role in controlling viral replication. It was shown that Th1/Th2 ratio decreased in CHB patients, which was increased after treatment with antiviral agent [1].The imbalance in Th1:Th2 may be due to promotion of Th2 in addition to decrease in Th1 population [2]. The promotion of Th2 cells follows by increasing of several cytokines, which could inhibit Th1 cells differentiation. Increasing of IL-4 and IL-10, the major productions of Th2 and their association with viral load was also reported [2,3]. In general, multiple studies confirmed the increasing in Th1 population during acute phase, which contribute in recovery from disease and successful control of infection. In contrast, this dominancy shifts toward more Th2 differentiation in chronic phase of HBV infection. Recently, T-cell exhaustion during CHB infection was analyzed [4]. This changing in immune responses may be explained by regulatory cells, which could prevent effector T cells activation. Regulatory T cells (Tregs) and regulatory B cells (Bregs) are responsible for controlling abnormal immune responses. Patients with autoimmune diseases suffer from lack or dysfunction of these cells. However, in patients with CHB infection, elevation regulatory cells, including T and B cells was reported, which are correlated with viral load [2,5]. Interestingly, Tregs in acute hepatitis B cells (AHB) patients was comparable to that in healthy controls [5]. There is some evidence that the function of Tregs in CHB patients may be changed. It was reported that Tregs from CHB patients have reduced levels of SATB1, which is resolved with antiviral therapy [6]. Effect of HBcAg in dysfunction of immune responses via Tregs was demonstrated in another study. Indeed, it was reported that HBcAg-specific Treg clones inhibited the killing capacity of CTLs clones [7]. It was also revealed that Tregs directly suppressed natural killer cell-mediated hepatocytotoxicity [8]. TGF- is one of the most well-known regulatory cytokines and is expressed in natural Tregs (nTregs) at high levels. It also induces differentiation of another type of Tregs (Th3). IL-10 is another regulatory cytokine with a dual role during HBV. It could differentiate naïve CD4+ T cells into type 1 regulatory T cells (Tr1), which suppress effector T cells responses. In a study, increasing of IL-10 in CHB was observed, which could cause the development of impaired anti-HBV immunity via regulatory cells [2]. IL-10 also inhibits Th1 differentiation and lower IFN-␥ could be produced. This cytokine causes promotion of type 1 regulatory B cells (Br1). Indeed, a
negative correlation between Th1 population and the prevalence of Bregs was reported [2]. IL-35 is considered as a new identified regulatory cytokine, which results in differentiation of two specific regulatory cells, including iTr35 cells and IL-35+ Bregs. Recently, it was found that IL-35 could suppress the proliferation of HBV antigen-specific CTLs and IFN-␥ production in vitro [9]. According to several studies that report high level of regulatory cytokines, Tregs and Bregs in CHB patients, it can be suggested that these occurrences is induced by HBV. By suppression of immune responses via regulatory cells, virus could be replicated without any serious barrier. It seems that in HBsAg inactive carriers, there is a balance between Tregs and effector T cells. However, disruption of this balance toward more Tregs may cause high viral replication in CHB patients. If Tregs be inhibited, the two will likely happen. Firstly, CTLs will be increased can arise against the HBV replication. Secondly, Th1 could be differentiated and it will leads to more production of IFN-␥. Although all of these occurrences seem to result in controlling HBV replication and even HBsAg clearance in CHB patients, activation of effector T cells may lead to breaking the balance between viral replication and immune responses. This possibly leads to the emergence of symptoms similar to acute HBV or even worsens. These symptoms could be mitigated by administration antiviral therapy. Furthermore, initiation of autoimmune diseases may be another possible outcome of regulatory cells depletion. There are various strategies for manipulation of Tregs, including Treg depletion, inhibition of Treg function or blockade of Treg trafficking into lymph nodes or tumors, associated with cancer (review in [10]). These could be used for CHB patients in order to amplifying anti-viral immune responses. As it was demonstrated, depletion of Treg cells in the PBMCs of patients with CHB did not alter the frequency of Breg cells [2]. Thus, targeting of both Tregs and Bregs may be essential. Moreover, targeting the regulatory cytokines, including TGF-, IL-10, and IL-35 may be helpful. As a result of this study, it is suggested that inhibition of both Tregs and Bregs can be a new weapon against HBV in CHB patients. However, this may be along with serious problems, which need for further studies. References [1] Y. Jiang, Z. Ma, G. Xin, H. Yan, W. Li, H. Xu, et al., Th1 and Th2 immune response in chronic hepatitis B patients during a long-term treatment with adefovir dipivoxil, Mediators Inflamm. 2010 (2010). [2] Y. Gong, C. Zhao, P. Zhao, M. Wang, G. Zhou, F. Han, et al., Role of IL-10-producing regulatory B cells in chronic hepatitis B virus infection, Dig. Dis. Sci. 60 (2015) 1308–1314. [3] H.L. Wu, J.H. Kao, T.C. Chen, W.H. Wu, C.H. Liu, T.H. Su, et al., Serum cytokine/chemokine profiles in acute exacerbation of chronic hepatitis B: clinical and mechanistic implications, J. Gastroenterol. Hepatol. 29 (2014) 1629–1636. [4] B. Ye, X. Liu, X. Li, H. Kong, L. Tian, Y. Chen, T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance, Cell Death Dis. 6 (2015) e1694. [5] G. Peng, S. Li, W. Wu, Z. Sun, Y. Chen, Z. Chen, Circulating CD4+ CD25+ regulatory T cells correlate with chronic hepatitis B infection, Immunology 123 (2008) 57–65.
http://dx.doi.org/10.1016/j.imlet.2015.12.007 0165-2478/© 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: S. Tavakolpour, Inhibition of regulatory cells as a possible cure of chronically hepatitis B virus infected patients, Immunol Lett (2015), http://dx.doi.org/10.1016/j.imlet.2015.12.007
G Model IMLET-5808; No. of Pages 2 2
ARTICLE IN PRESS Letter to the Editor / Immunology Letters xxx (2015) xxx–xxx
[6] X.-F. Li, L. Tian, Y.-Y. Wang, H.-S. Kong, Y.-J. Dong, Q.-Y. Zhu, et al., Inhibition of SATB1 expression in regulatory T cells contributes to hepatitis B virus-related chronic liver inflammation, Mol. Med. Rep. 11 (2015) 231–236. [7] L.-B. Koay, I.-C. Feng, M.-J. Sheu, H.-T. Kuo, C.-Y. Lin, J.-J. Chen, et al., Hepatitis B virus (HBV) core antigen-specific regulatory T cells confer sustained remission to anti-HBV therapy in chronic hepatitis B with acute exacerbationtitis B virus (HBV) core antigen-specific regulatory T cells confer sustained remission to anti-HBV therapy in chronic hepatitis B with acute exacerbation, Hum. immunol. 72 (2011) 687–698. [8] Y. Chen, R. Sun, X. Wu, M. Cheng, H. Wei, Tian Z. CD4+ CD25+ regulatory T cells inhibit natural killer Cell hepatocytotoxicity of hepatitis B Virus transgenic mice via membrane-bound TGF- and OX40, J. Innate Immun. (2015). [9] X. Li, L. Tian, Y. Dong, Q. Zhu, Y. Wang, W. Han, et al., IL-35 inhibits HBV antigen-specific IFN-gamma-producing CTLs in vitro, Clin. Sci. (2015). [10] H. Pere, C. Tanchot, J. Bayry, M. Terme, J. Taieb, C. Badoual, et al., Comprehensive analysis of current approaches to inhibit regulatory T cells in cancer, Oncoimmunology 1 (2012) 326–333.
Soheil Tavakolpour ∗ Infectious Diseases and Tropical Medicine Research Center, Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran ∗ Corresponding
author at: Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Fax: +98 21 22267157. E-mail address: [email protected] 14 December 2015 21 December 2015 Available online xxx
Please cite this article in press as: S. Tavakolpour, Inhibition of regulatory cells as a possible cure of chronically hepatitis B virus infected patients, Immunol Lett (2015), http://dx.doi.org/10.1016/j.imlet.2015.12.007
ARTICLE IN PRESS
IMLET-5808; No. of Pages 2
Immunology Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Immunology Letters journal homepage: www.elsevier.com/locate/immlet
Letter to the Editor Inhibition of regulatory cells as a possible cure of chronically hepatitis B virus infected patients Dear Editor, Hepatitis B cells virus (HBV) can persist and causes chronic infection by inducing dysfunction of immune responses. Innate and adaptive immune responses are involved during this infection. Previous finding suggested that interferon (IFN)-␥, which is predominantly secreted by T helper (Th) 1 arises against HBV. In addition to Th1, cytotoxic T lymphocytes (CTLs), and dendritic cells (DC) also play an important role in controlling viral replication. It was shown that Th1/Th2 ratio decreased in CHB patients, which was increased after treatment with antiviral agent [1].The imbalance in Th1:Th2 may be due to promotion of Th2 in addition to decrease in Th1 population [2]. The promotion of Th2 cells follows by increasing of several cytokines, which could inhibit Th1 cells differentiation. Increasing of IL-4 and IL-10, the major productions of Th2 and their association with viral load was also reported [2,3]. In general, multiple studies confirmed the increasing in Th1 population during acute phase, which contribute in recovery from disease and successful control of infection. In contrast, this dominancy shifts toward more Th2 differentiation in chronic phase of HBV infection. Recently, T-cell exhaustion during CHB infection was analyzed [4]. This changing in immune responses may be explained by regulatory cells, which could prevent effector T cells activation. Regulatory T cells (Tregs) and regulatory B cells (Bregs) are responsible for controlling abnormal immune responses. Patients with autoimmune diseases suffer from lack or dysfunction of these cells. However, in patients with CHB infection, elevation regulatory cells, including T and B cells was reported, which are correlated with viral load [2,5]. Interestingly, Tregs in acute hepatitis B cells (AHB) patients was comparable to that in healthy controls [5]. There is some evidence that the function of Tregs in CHB patients may be changed. It was reported that Tregs from CHB patients have reduced levels of SATB1, which is resolved with antiviral therapy [6]. Effect of HBcAg in dysfunction of immune responses via Tregs was demonstrated in another study. Indeed, it was reported that HBcAg-specific Treg clones inhibited the killing capacity of CTLs clones [7]. It was also revealed that Tregs directly suppressed natural killer cell-mediated hepatocytotoxicity [8]. TGF- is one of the most well-known regulatory cytokines and is expressed in natural Tregs (nTregs) at high levels. It also induces differentiation of another type of Tregs (Th3). IL-10 is another regulatory cytokine with a dual role during HBV. It could differentiate naïve CD4+ T cells into type 1 regulatory T cells (Tr1), which suppress effector T cells responses. In a study, increasing of IL-10 in CHB was observed, which could cause the development of impaired anti-HBV immunity via regulatory cells [2]. IL-10 also inhibits Th1 differentiation and lower IFN-␥ could be produced. This cytokine causes promotion of type 1 regulatory B cells (Br1). Indeed, a
negative correlation between Th1 population and the prevalence of Bregs was reported [2]. IL-35 is considered as a new identified regulatory cytokine, which results in differentiation of two specific regulatory cells, including iTr35 cells and IL-35+ Bregs. Recently, it was found that IL-35 could suppress the proliferation of HBV antigen-specific CTLs and IFN-␥ production in vitro [9]. According to several studies that report high level of regulatory cytokines, Tregs and Bregs in CHB patients, it can be suggested that these occurrences is induced by HBV. By suppression of immune responses via regulatory cells, virus could be replicated without any serious barrier. It seems that in HBsAg inactive carriers, there is a balance between Tregs and effector T cells. However, disruption of this balance toward more Tregs may cause high viral replication in CHB patients. If Tregs be inhibited, the two will likely happen. Firstly, CTLs will be increased can arise against the HBV replication. Secondly, Th1 could be differentiated and it will leads to more production of IFN-␥. Although all of these occurrences seem to result in controlling HBV replication and even HBsAg clearance in CHB patients, activation of effector T cells may lead to breaking the balance between viral replication and immune responses. This possibly leads to the emergence of symptoms similar to acute HBV or even worsens. These symptoms could be mitigated by administration antiviral therapy. Furthermore, initiation of autoimmune diseases may be another possible outcome of regulatory cells depletion. There are various strategies for manipulation of Tregs, including Treg depletion, inhibition of Treg function or blockade of Treg trafficking into lymph nodes or tumors, associated with cancer (review in [10]). These could be used for CHB patients in order to amplifying anti-viral immune responses. As it was demonstrated, depletion of Treg cells in the PBMCs of patients with CHB did not alter the frequency of Breg cells [2]. Thus, targeting of both Tregs and Bregs may be essential. Moreover, targeting the regulatory cytokines, including TGF-, IL-10, and IL-35 may be helpful. As a result of this study, it is suggested that inhibition of both Tregs and Bregs can be a new weapon against HBV in CHB patients. However, this may be along with serious problems, which need for further studies. References [1] Y. Jiang, Z. Ma, G. Xin, H. Yan, W. Li, H. Xu, et al., Th1 and Th2 immune response in chronic hepatitis B patients during a long-term treatment with adefovir dipivoxil, Mediators Inflamm. 2010 (2010). [2] Y. Gong, C. Zhao, P. Zhao, M. Wang, G. Zhou, F. Han, et al., Role of IL-10-producing regulatory B cells in chronic hepatitis B virus infection, Dig. Dis. Sci. 60 (2015) 1308–1314. [3] H.L. Wu, J.H. Kao, T.C. Chen, W.H. Wu, C.H. Liu, T.H. Su, et al., Serum cytokine/chemokine profiles in acute exacerbation of chronic hepatitis B: clinical and mechanistic implications, J. Gastroenterol. Hepatol. 29 (2014) 1629–1636. [4] B. Ye, X. Liu, X. Li, H. Kong, L. Tian, Y. Chen, T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance, Cell Death Dis. 6 (2015) e1694. [5] G. Peng, S. Li, W. Wu, Z. Sun, Y. Chen, Z. Chen, Circulating CD4+ CD25+ regulatory T cells correlate with chronic hepatitis B infection, Immunology 123 (2008) 57–65.
http://dx.doi.org/10.1016/j.imlet.2015.12.007 0165-2478/© 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: S. Tavakolpour, Inhibition of regulatory cells as a possible cure of chronically hepatitis B virus infected patients, Immunol Lett (2015), http://dx.doi.org/10.1016/j.imlet.2015.12.007
G Model IMLET-5808; No. of Pages 2 2
ARTICLE IN PRESS Letter to the Editor / Immunology Letters xxx (2015) xxx–xxx
[6] X.-F. Li, L. Tian, Y.-Y. Wang, H.-S. Kong, Y.-J. Dong, Q.-Y. Zhu, et al., Inhibition of SATB1 expression in regulatory T cells contributes to hepatitis B virus-related chronic liver inflammation, Mol. Med. Rep. 11 (2015) 231–236. [7] L.-B. Koay, I.-C. Feng, M.-J. Sheu, H.-T. Kuo, C.-Y. Lin, J.-J. Chen, et al., Hepatitis B virus (HBV) core antigen-specific regulatory T cells confer sustained remission to anti-HBV therapy in chronic hepatitis B with acute exacerbationtitis B virus (HBV) core antigen-specific regulatory T cells confer sustained remission to anti-HBV therapy in chronic hepatitis B with acute exacerbation, Hum. immunol. 72 (2011) 687–698. [8] Y. Chen, R. Sun, X. Wu, M. Cheng, H. Wei, Tian Z. CD4+ CD25+ regulatory T cells inhibit natural killer Cell hepatocytotoxicity of hepatitis B Virus transgenic mice via membrane-bound TGF- and OX40, J. Innate Immun. (2015). [9] X. Li, L. Tian, Y. Dong, Q. Zhu, Y. Wang, W. Han, et al., IL-35 inhibits HBV antigen-specific IFN-gamma-producing CTLs in vitro, Clin. Sci. (2015). [10] H. Pere, C. Tanchot, J. Bayry, M. Terme, J. Taieb, C. Badoual, et al., Comprehensive analysis of current approaches to inhibit regulatory T cells in cancer, Oncoimmunology 1 (2012) 326–333.
Soheil Tavakolpour ∗ Infectious Diseases and Tropical Medicine Research Center, Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran ∗ Corresponding
author at: Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Fax: +98 21 22267157. E-mail address: [email protected] 14 December 2015 21 December 2015 Available online xxx
Please cite this article in press as: S. Tavakolpour, Inhibition of regulatory cells as a possible cure of chronically hepatitis B virus infected patients, Immunol Lett (2015), http://dx.doi.org/10.1016/j.imlet.2015.12.007