Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/11823
Title: Cyclosporine and tacrolimus have inhibitory effects on toll-like receptor signaling after liver transplantation.
Authors: Howell, Jessica;Sawhney, Rohit;Testro, Adam G;Skinner, Narelle;Gow, Paul J;Angus, Peter W;Ratnam, Dilip;Visvanathan, Kumar
Affiliation: Liver Transplant Unit, Austin Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.
Issue Date: 1-Oct-2013
Citation: Liver Transplantation : Official Publication of the American Association For the Study of Liver Diseases and the International Liver Transplantation Society; 19(10): 1099-107
Abstract: Toll-like receptors (TLRs) play a key role in transplantation biology. The effect of immunosuppression on TLR function after liver transplantation is unknown. Peripheral blood mononuclear cells (PBMCs) from 113 post-liver transplant patients and 13 healthy controls were stimulated with TLR-specific ligands [lipopolysaccharide (TLR4), pan-3-cys (P3C) (TLR2), Poly (I:C) (PIC) (TLR3), R848 (TLR7/8), and CpG (TLR9)] for 24 hours. PBMCs from 5 healthy controls were also cultured with therapeutic concentrations of cyclosporine A (CYA) and tacrolimus (TAC). Cytokine production was measured with enzyme-linked immunosorbent assays and flow cytometry. PBMCs from patients on calcineurin inhibitors after liver transplantation produced less interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) in response to TLR2 stimulation (IL-6: P=0.02; TNFα: P=0.01), TLR4 stimulation (IL-6: P=0.02; TNFα: P=0.01), and TLR7/8 stimulation (IL-6: P=0.02; TNFα: P=0.02), compared with healthy controls. Both CD56(bright) and CD56(dim) natural killer (NK) cells from patients on calcineurin inhibitors also produced less interferon-γ (IFNγ) with TLR7/8 stimulation compared with healthy controls (CD56(bright) : P=0.002; CD56(dim) : P=0.004). Similar findings were demonstrated in healthy PBMCs cultured with CYA (PBMCs: TLR2, IL-6: P=0.005; TLR4, IL-6: P=0.03, TNFα: P=0.03; TLR7/8, IL-6: P=0.02, TNFα: P=0.01; CD56(dim) NK cells: TLR7/8, IFNγ: P=0.03). TAC impaired TLR4-mediated IL-6 and TNFα production by PBMCs (IL-6; P = 0.02; TNFα P = 0.009). In conclusion, patients on calcineurin inhibitors had impaired inflammatory cytokine production in response to TLR2, TLR4, and TLR7/8 stimulation compared comparison with healthy controls. Importantly, TAC and CYA appear to have different effects on TLR signaling. Impaired TLR function has important repercussions for risk of infection, graft rejection, and disease recurrence after transplantation, and the different immunosuppressive profiles of CYA and TAC may guide the choice of therapy to improve disease outcomes.
Internal ID Number: 23894100
URI: http://ahro.austin.org.au/austinjspui/handle/1/11823
DOI: 10.1002/lt.23712
URL: http://www.ncbi.nlm.nih.gov/pubmed/23894100
Type: Journal Article
Subjects: Adult
Antigens, CD56.metabolism
Calcineurin Inhibitors
Cross-Sectional Studies
Cyclosporine.therapeutic use
Enzyme-Linked Immunosorbent Assay
Female
Flow Cytometry
Humans
Immunosuppression.methods
Immunosuppressive Agents.therapeutic use
Interleukin-6.blood.metabolism
Leukocytes, Mononuclear.cytology
Ligands
Lipopolysaccharides.metabolism
Liver Transplantation.methods
Male
Middle Aged
Signal Transduction
Tacrolimus.therapeutic use
Toll-Like Receptor 2.metabolism
Toll-Like Receptor 4.metabolism
Toll-Like Receptor 7.metabolism
Toll-Like Receptor 8.metabolism
Toll-Like Receptors.metabolism
Tumor Necrosis Factor-alpha.metabolism
Appears in Collections:Journal articles

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