Mechanistic basis for the potential antifibrotic effects of ECP in SOT

The SOT Hub spoke with Andrew Gelman, Washington University School of Medicine, St. Louis, US, about the mechanistic basis for the potential antifibrotic effects of extracorporeal photopheresis (ECP) in solid organ transplantation (SOT). 

Fibrosis is a hallmark of chronic allograft rejection, in which alloimmune responses and autoimmune responses against self-antigens can perpetuate one another, resulting in tissue inflammation and repair processes that contribute to a proinflammatory and profibrotic environment with fibrous tissue deposition.¹ Vascular injury and alloimmune activation may stimulate the release of bioactive mediators, including transforming growth factor-beta (TGF-β), which regulate immune cell and fibroblast responses, and contribute to inflammation and extracellular matrix remodeling. While these mediators can support normal tissue repair, persistent signaling may promote pathological remodeling, fibrosis, and chronic graft dysfunction.² 

In this interview, Gelman discusses potential mechanisms underlying the antifibrotic effects of ECP, highlighting preclinical findings implicating alveolar macrophages (AMs), TGF-β, and decorin. 

Key points 

• ECP is an established leukapheresis-based immunomodulatory therapy that does not cause generalized immunosuppression. However, its mechanism of action, including its potential antifibrotic effects, is not completely understood. ^{3, 4}  
• Macrophages are key regulators of fibrotic processes; during rejection, they can shift to a proinflammatory phenotype and promote fibrosis through the release of profibrotic mediators, including TGF-β. ^{3, 5, 6} 
  • Chronic activation of TGF-β can promote fibrotic remodeling through fibroblast-to-myofibroblast transition and extracellular matrix accumulation.² 
  • Elevated TGF-β levels have been associated with chronic graft complications, such as the development of bronchiolitis obliterans syndrome (BOS) in lung transplant recipients, chronic cholangiopathy in liver transplant, and chronic allograft nephropathy in kidney transplant.² 
• Findings from a murine lung transplant model of BOS suggest a potential mechanism through which ECP may modulate fibrotic processes.⁷ 
  • ECP-treated leukocytes were primarily engulfed by AMs, suggesting that these cells may be important mediators of ECP’s effects.⁷ 
  • TGF-β1 levels in bronchoalveolar lavage (BAL) fluid did not differ between ECP- vs saline-treated recipients; however, TGF-β activity in BAL fluid was lower with ECP, suggesting ECP may alter TGF-β bioavailability.⁷ 
  • ECP-treated AMs showed significant upregulation of TGF-β inhibitors including Dcn, Smad7, and Smurf2, with Dcn the most differentially regulated transcript.⁷ 
  • Secretion of decorin, a TGF-β antagonist, was higher from ECP-treated AMs than saline-treated AMs.⁷ 
  • Supernatants from ECP-treated AMs reduced TGF-β activity in a decorin-dependent manner when compared with ECP-treated decorin-deficient AMs or saline-treated decorin-sufficient AMs.⁷ 
  • In vivo, ECP-treated decorin-sufficient recipients had fewer obliterative lesions and lower BAL fluid TGF-β activity than ECP-treated decorin-deficient recipients.⁷ 
• Collectively, these preclinical findings suggest that ECP may have an antifibrotic effect by inducing AM decorin expression, thereby reducing airway TGF-β bioavailability and inhibiting BOS.⁷ 
• Further research is needed to establish whether this mechanism operates in human lung transplant recipients and whether similar pathways contribute to the potential antifibrotic effects of ECP in other solid organ transplants.⁷ 

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