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Inhibitory effects of pirfenidone on dendritic cells and lung allograft rejection
Peyman Bizargity1, Kaifeng Liu, Liqing Wang
1Division of Respiratory Medicine, Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
Background:
Pirfenidone (PFD) is an antifibrotic agent with beneficial effects on proinflammatory disorders. In this study, we further investigated PFD and long-acting form, "deuterated PFD," immune-modulating properties by evaluating their effects on mouse dendritic cells (DCs).
Methods:
The effects of PFD on DCs were examined in vivo using an orthotopic mouse lung transplant model and in vitro using isolated bone marrow-derived DCs in response to lipopolysaccharide and allogeneic stimulation.
Results:
In mouse lung transplants, PFD and deuterated PFD treatment improved allograft lung function based on peak airway pressure, less infiltrates/consolidation on micro-computed tomography scan imaging, and reduced lung rejection/injury. DC activation from lung allografts was suppressed with PFD, and there seemed to be a greater effect of PFD on CD11c(+)CD11b(-)CD103(+) lung DCs. In addition, PFD reduced the expression of several proinflammatory cytokines/chemokines from lung allografts. In vitro, DCs treated with PFD showed decreased expression of major histocompatibility complex class II and costimulatory molecules and the capacity of these DCs to stimulate T-cell activation was impaired, although antigen uptake was preserved. PFD directly inhibited the release of inflammatory cytokines from isolated DCs, was associated with a reduction of stress protein kinases, and attenuated lipopolysaccharide-dependent mitogen-activated protein kinase p38 phosphorylation.
Conclusions:
PFD has lung allograft protective properties, and in addition to its known effects on T-cell biology, PFD immune-modulating activities encompass inhibitory effects on DC activation and function.
Insights
Pirfenidone (PFD) protects lung allografts by suppressing dendritic cell (DC) activation and function. This antifibrotic agent reduces inflammation and improves transplant outcomes, offering new therapeutic avenues.
Area of Science:
- Immunology
- Transplantation Biology
- Pharmacology
Background:
- Pirfenidone (PFD) is an established antifibrotic agent with known anti-inflammatory effects.
- Its long-acting form, deuterated PFD, was also investigated for immune-modulating properties.
- Dendritic cells (DCs) play a crucial role in immune responses, including transplant rejection.
Purpose of the Study:
- To investigate the immune-modulating effects of Pirfenidone (PFD) and deuterated PFD on mouse dendritic cells (DCs).
- To evaluate the impact of PFD on DC activation and function in the context of lung allografts.
Main Methods:
- In vivo studies utilized an orthotopic mouse lung transplant model.
- In vitro studies employed isolated bone marrow-derived DCs stimulated with lipopolysaccharide and allogeneic stimuli.
- Effects on DC activation markers, cytokine/chemokine production, antigen uptake, and T-cell stimulation capacity were assessed.
Main Results:
- PFD and deuterated PFD treatment improved lung allograft function, reducing inflammation and injury.
- PFD suppressed DC activation in lung allografts, particularly affecting CD11c(+)CD11b(-)CD103(+) DCs.
- In vitro, PFD impaired DC ability to stimulate T-cells by reducing MHC class II and costimulatory molecule expression, while inhibiting inflammatory cytokine release and p38 MAPK phosphorylation.
Conclusions:
- Pirfenidone (PFD) demonstrates protective properties in lung allografts.
- PFD's immune-modulating activities include the inhibition of dendritic cell (DC) activation and function.
- These findings expand the understanding of PFD's therapeutic mechanisms beyond its antifibrotic effects.
