The role of extracellular vesicles in chronic lung allograft dysfunction and response to extracorporeal photopheresis

Current research highlights the growing role of extracellular vesicles (EV) in mechanisms of lung allograft dysfunction. In particular, EVs are involved in antigen presentation, where they are released from lung allografts and express tissue associated antigens which are recognized by recipient immune cells, thereby triggering an immune response against the transplanted lung. In the context of chronic rejection, patients with chronic lung allograft dysfunction (CLAD) demonstrate elevated levels of EVs, which contain diverse molecular cargo that can influence the alloimmune response. This highlights the potential of EVs as translatable biomarkers for the early detection, prediction, or diagnosis of lung allograft dysfunction. The mechanisms by which EVs contribute to this process may include immune cell activation, epithelial-to-mesenchymal transition, and disruption of angiogenesis. Furthermore, their immunomodulatory potential is evident by their emerging involvement in regulating the immune response during extracorporeal photopheresis (ECP) therapy following lung transplantation, where they contribute to the balance of immunoregulatory and autoimmune responses within a highly interwoven network. While ECP shows promise for broader or earlier use in solid organ transplantation, its application is limited by a lack of mechanistic understanding. This review summarizes the role of EVs in development of lung allograft dysfunction, their involvement in immunomodulation, and the current literature exploring their potential role in the mechanisms of ECP therapy.