Affiliation:
1. Department of Surgery, Division of Transplantation University of Wisconsin School of Medicine and Public Health Madison Wisconsin USA
2. Department of Medicine University of Wisconsin School of Medicine and Public Health Madison Wisconsin USA
3. Pharmaceutical Sciences Division, School of Pharmacy University of Wisconsin‐Madison Madison Wisconsin USA
Abstract
AbstractExtracellular vesicles (EVs) are major contributors to immunological responses following solid organ transplantation. Donor derived EVs are best known for their role in transplant rejection through transferring donor major histocompatibility complex proteins to recipient antigen presenting cells, a phenomenon known as ‛cross‐decoration’. In contrast, donor liver‐derived EVs are associated with organ tolerance in small animal models. Therefore, the cellular source of EVs and their cargo could influence their downstream immunological effects. To investigate the immunological effects of EVs released by the liver in a physiological and transplant‐relevant model, we isolated EVs being produced during normothermic ex vivo liver perfusion (NEVLP), a novel method of liver storage prior to transplantation. We found EVs were produced by the liver during NEVLP, and these EVs contained multiple anti‐inflammatory miRNA species. In terms of function, liver‐derived EVs were able to cross‐decorate allogeneic cells and suppress the immune response in allogeneic mixed lymphocyte reactions in a concentration‐dependent fashion. In terms of cytokine response, the addition of 1 × 109 EVs to the mixed lymphocyte reactions significantly decreased the production of the inflammatory cytokines TNF‐α, IL‐10 and IFN‐γ. In conclusion, we determined physiologically produced liver‐derived EVs are immunologically regulatory, which has implications for their role and potential modification in solid organ transplantation.
Funder
National Institute of Allergy and Infectious Diseases