The cyclophilin-inhibitor alisporivir stimulates antigen presentation thereby promoting antigen-specific CD8+ T cell activation
Background & Aims - Cyclophilin-inhibitors have potent antiviral activity against Hepatitis C virus (HCV) and are promising candidates for broad-spectrum antiviral therapy. Cyclosporine A (CsA) acts immunosuppressive by blocking T cell activation and antigen presentation. Alisporivir, a non-immu...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
26 February 2016
|
| In: |
Journal of hepatology
Year: 2016, Volume: 64, Issue: 6, Pages: 1305-1314 |
| ISSN: | 1600-0641 |
| DOI: | 10.1016/j.jhep.2016.02.027 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.jhep.2016.02.027 Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S0168827816001616 
|
| Author Notes: | Katharina Esser-Nobis, Julia Schmidt, Katja Nitschke, Christoph Neumann-Haefelin, Robert Thimme, Volker Lohmann |
| Summary: | Background & Aims - Cyclophilin-inhibitors have potent antiviral activity against Hepatitis C virus (HCV) and are promising candidates for broad-spectrum antiviral therapy. Cyclosporine A (CsA) acts immunosuppressive by blocking T cell activation and antigen presentation. Alisporivir, a non-immunosuppressive CsA analog in clinical development, does not inhibit T cell activation. In this study we explored the impact of alisporivir on antigen presentation. - Methods - Hepatoma cells endogenously expressing the epitope-restricting major histocompatibility complex-class I (MHC-I) allele HLA-A2 and constitutively expressing a viral antigen were established to study the impact of cyclophilin-inhibitors on antigen presentation. Antigen-specific CD8+ T cell activation and MHC-I surface expression were measured to quantify antigen presentation. - Results - Our work establishes a novel cell culture model to study antigen presentation in liver-derived cells. Authentic regulation of antigen presentation was ensured by the action of pro- and anti-inflammatory cytokines. Alisporivir pretreatment stimulated antigen presentation by hepatoma target cells, leading to enhancement of antigen-specific CD8+ T cell activation by 40%. Alisporivir, as well as a panel of other cyclophilin-inhibitors, induced an increase of MHC-I and beta-2 microglobulin on the surface of several cell lines. The drug neither enhanced MHC-I transcript or protein levels nor affected surface expression of other proteins or protein trafficking in general. Proteasome-inhibitors completely blocked the alisporivir-directed enhancement of surface MHC-I, suggesting an influence of the drug on peptide-availability. - Conclusions - Alisporivir stimulates antigen presentation by inducing enhanced MHC-I surface expression, thereby promoting antigen-specific CD8+ T cell activation. This immunostimulatory function might further contribute to the antiviral activity of non-immunosuppressive cyclophilin-inhibitors. |
|---|---|
| Item Description: | Im Titel ist "+" hochgestellt Gesehen am 11.05.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1600-0641 |
| DOI: | 10.1016/j.jhep.2016.02.027 |