Immunomodulating Effects of the Anti-viral Agent Silibinin in Liver Transplant Patients with HCV Recurrence

Overview

Journal Transplant Res

Publisher Biomed Central

Specialty General Surgery

Date 2016 Jan 23

PMID 26798454

Citations 3

Authors

Antonino Castellaneta

Antonio Massaro

Maria Rendina

Francesca DErrico

Sonia Carparelli

Salvatore Fabio Rizzi

Angus W Thomson

Alfredo Di Leo

Affiliations

Soon will be listed here.

Abstract

Background: Silibinin has been shown to have anti-HCV activity and immune-modulating properties by regulating dendritic cell (DC) function. DCs are antigen-presenting cells that, together with regulatory T cells (Treg), play a pivotal role in controlling alloimmune, as well as anti-HCV immune responses.

Methods: Twelve liver transplant patients with HCV recurrence received iv infusion of Silibinin (iv-SIL) for 14 consecutive days. Using flow cytometry, before and at the end of treatment, we determined the frequencies of circulating myeloid (m) and plasmacytoid (p) DC and Treg and the expression of costimulatory/coregulatory molecules by the DC subsets and Treg. Statistical analysis was performed using the paired Student's t test and Pearson correlation test.

Results: After iv-SIL treatment, we observed an elevated plasmacytoid dendritic cell (pDC)/myeloid dendritic cell (mDC) ratio, while pDC displayed lower HLA-DR and higher immunoglobulin-like transcript 4 (ILT4), CD39, and HLA-G expression compared to the pretreatment baseline. In addition, after iv-SIL, mDC showed increased inducible costimulator ligand (ICOSL) expression. No changes were detected in Treg frequency or programed death (PD)-1 expression by these cells. Moreover, several correlations between DC/Treg markers and clinical parameters were detected.

Conclusions: This descriptive study, in liver transplant patients with HCV recurrence, reveals the impact of iv-SIL on DC and Treg. The changes observed in circulating pDC and mDC that have previously been associated with tolerogenic conditions shed new light on how iv-SIL may regulate anti-viral and alloimmunity. We have also observed multiple clinical correlations that could improve the clinical management of liver transplant patients and that deserve further analysis.

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References

Tokita D, Mazariegos G, Zahorchak A, Chien N, Abe M, Raimondi G . High PD-L1/CD86 ratio on plasmacytoid dendritic cells correlates with elevated T-regulatory cells in liver transplant tolerance. Transplantation. 2008; 85(3):369-77. DOI: 10.1097/TP.0b013e3181612ded. View

Adam R, McMaster P, OGrady J, Castaing D, Klempnauer J, Jamieson N . Evolution of liver transplantation in Europe: report of the European Liver Transplant Registry. Liver Transpl. 2003; 9(12):1231-43. DOI: 10.1016/j.lts.2003.09.018. View

Longman R, Talal A, Jacobson I, Rice C, Albert M . Normal functional capacity in circulating myeloid and plasmacytoid dendritic cells in patients with chronic hepatitis C. J Infect Dis. 2005; 192(3):497-503. DOI: 10.1086/431523. View

Tai X, Cowan M, Feigenbaum L, Singer A . CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol. 2005; 6(2):152-62. DOI: 10.1038/ni1160. View

Longman R, Talal A, Jacobson I, Albert M, Rice C . Presence of functional dendritic cells in patients chronically infected with hepatitis C virus. Blood. 2003; 103(3):1026-9. DOI: 10.1182/blood-2003-04-1339. View

Kushwah R, Hu J . Complexity of dendritic cell subsets and their function in the host immune system. Immunology. 2011; 133(4):409-19. PMC: 3143352. DOI: 10.1111/j.1365-2567.2011.03457.x. View

Gilliet M, Liu Y . Generation of human CD8 T regulatory cells by CD40 ligand-activated plasmacytoid dendritic cells. J Exp Med. 2002; 195(6):695-704. PMC: 2193733. DOI: 10.1084/jem.20011603. View

McAdam A, Chang T, Lumelsky A, Greenfield E, Boussiotis V, Duke-Cohan J . Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells. J Immunol. 2000; 165(9):5035-40. DOI: 10.4049/jimmunol.165.9.5035. View

Galgani M, Fabozzi I, Perna F, Bruzzese D, Bellofiore B, Calabrese C . Imbalance of circulating dendritic cell subsets in chronic obstructive pulmonary disease. Clin Immunol. 2010; 137(1):102-10. DOI: 10.1016/j.clim.2010.06.010. View

10.

Rendina M, DAmato M, Castellaneta A, Castellaneta N, Brambilla N, Giacovelli G . Antiviral activity and safety profile of silibinin in HCV patients with advanced fibrosis after liver transplantation: a randomized clinical trial. Transpl Int. 2014; 27(7):696-704. DOI: 10.1111/tri.12324. View

11.

Sumpter T, Abe M, Tokita D, Thomson A . Dendritic cells, the liver, and transplantation. Hepatology. 2007; 46(6):2021-31. DOI: 10.1002/hep.21974. View

12.

Yoshida O, Dou L, Kimura S, Yokota S, Isse K, Robson S . CD39 deficiency in murine liver allografts promotes inflammatory injury and immune-mediated rejection. Transpl Immunol. 2015; 32(2):76-83. PMC: 4368493. DOI: 10.1016/j.trim.2015.01.003. View

13.

Shen T, Chen X, Chen Y, Xu Q, Lu F, Liu S . Increased PD-L1 expression and PD-L1/CD86 ratio on dendritic cells were associated with impaired dendritic cells function in HCV infection. J Med Virol. 2010; 82(7):1152-9. DOI: 10.1002/jmv.21809. View

14.

LeMaoult J, Krawice-Radanne I, Dausset J, Carosella E . HLA-G1-expressing antigen-presenting cells induce immunosuppressive CD4+ T cells. Proc Natl Acad Sci U S A. 2004; 101(18):7064-9. PMC: 406466. DOI: 10.1073/pnas.0401922101. View

15.

Tafuri A, Shahinian A, Bladt F, Yoshinaga S, Jordana M, Wakeham A . ICOS is essential for effective T-helper-cell responses. Nature. 2001; 409(6816):105-9. DOI: 10.1038/35051113. View

16.

Rogers N, Isenberg J, Thomson A . Plasmacytoid dendritic cells: no longer an enigma and now key to transplant tolerance?. Am J Transplant. 2013; 13(5):1125-33. PMC: 3977341. DOI: 10.1111/ajt.12229. View

17.

Waldmann H, Chen T, Graca L, Adams E, Daley S, Cobbold S . Regulatory T cells in transplantation. Semin Immunol. 2006; 18(2):111-9. DOI: 10.1016/j.smim.2006.01.010. View

18.

Piccioli D, Tavarini S, Nuti S, Colombatto P, Brunetto M, Bonino F . Comparable functions of plasmacytoid and monocyte-derived dendritic cells in chronic hepatitis C patients and healthy donors. J Hepatol. 2005; 42(1):61-7. DOI: 10.1016/j.jhep.2004.09.014. View

19.

Martinez-Llordella M, Puig-Pey I, Orlando G, Ramoni M, Tisone G, Rimola A . Multiparameter immune profiling of operational tolerance in liver transplantation. Am J Transplant. 2007; 7(2):309-19. DOI: 10.1111/j.1600-6143.2006.01621.x. View

20.

Lee J, Kim S, Kim H, Lee T, Jeong Y, Lee C . Silibinin polarizes Th1/Th2 immune responses through the inhibition of immunostimulatory function of dendritic cells. J Cell Physiol. 2006; 210(2):385-97. DOI: 10.1002/jcp.20852. View