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

## TL;DR

Extracellular vesicles (EVs) may help detect lung transplant rejection early and could explain how a therapy called ECP works in managing immune responses.

## Contribution

This paper reviews how EVs contribute to lung allograft dysfunction and their potential role in ECP therapy mechanisms.

## Key findings

- EVs from lung allografts express antigens that trigger immune responses in recipients.
- CLAD patients have higher EV levels with unique microRNA signatures, suggesting their use as early biomarkers.
- EVs may modulate immune responses during ECP therapy by altering microRNA expression.

## Abstract

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.

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•EVs express tissue antigens from lung allografts that may trigger immune responses in rejection.•CLAD patients show elevated EV levels with distinct microRNA signatures and self-antigens.•EVs show potential as biomarkers for early CLAD detection up to 12 months before formal diagnosis.•ECP therapy's immunomodulatory effects may involve specific EV microRNA expression changes.•Further studies needed to clarify EV's role in both CLAD pathogenesis and ECP mechanisms.

EVs express tissue antigens from lung allografts that may trigger immune responses in rejection.

CLAD patients show elevated EV levels with distinct microRNA signatures and self-antigens.

EVs show potential as biomarkers for early CLAD detection up to 12 months before formal diagnosis.

ECP therapy's immunomodulatory effects may involve specific EV microRNA expression changes.

Further studies needed to clarify EV's role in both CLAD pathogenesis and ECP mechanisms.