Donor extracellular vesicle trafficking via the pleural space represents a novel pathway for allorecognition after lung transplantation

Andreas Habertheuer, Shampa Chatterjee, Alberto Sada Japp, Chirag Ram, Laxminarayana Korutla, Takahiro Ochiya, Wenjun Li, Yuriko Terada, Tsuyoshi Takahashi, Ruben G. Nava, Varun Puri, Daniel Kreisel, Prashanth Vallabhajosyula

Research output: Contribution to journalArticlepeer-review


Restoration of lymphatic drainage across the bronchial anastomosis after lung transplantation requires several weeks. As donor antigen and antigen presenting cell trafficking via lymphatics into graft-draining lymph nodes is an important component of the alloresponse, alternative pathways must exist that account for rapid rejection after pulmonary transplantation. Here, we describe a novel allorecognition pathway mediated through donor extracellular vesicle (EV) trafficking to mediastinal lymph nodes via the pleural space. Pleural fluid collected early after lung transplantation in rats and humans contains donor-specific EVs. In a fully MHC mismatched rat model of lung transplantation, we demonstrate EVs carrying donor antigen preferentially accumulate in mediastinal lymph nodes and colocalize with MHC II expressing cells within 4 h of engraftment. Injection of allogeneic EVs into pleural space of syngeneic lung transplant recipients confirmed their selective trafficking to mediastinal lymph nodes and resulted in activation of T cells in mediastinal, but not peripheral lymph nodes. Thus, we have uncovered an alternative pathway of donor antigen trafficking where pulmonary EVs released into the pleural space traffic to locoregional lymph nodes via pleural lymphatics. This pathway obviates the need for restoration of lymphatics across the bronchial anastomosis for trafficking of donor antigen to draining lymph nodes. (Figure presented.).

Original languageEnglish
Pages (from-to)1909-1918
Number of pages10
JournalAmerican Journal of Transplantation
Issue number7
StatePublished - Jul 2022


  • basic (laboratory) research/science
  • immunobiology
  • lung (allograft) function/dysfunction
  • lung transplantation/pulmonology
  • lymph node
  • lymphocyte biology: activation
  • lymphocyte biology: proliferation
  • major histocompatibility complex (MHC)
  • translational research/science


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