Abstract
Survival after lung transplantation (LTx) is hampered by uncontrolled inflammation and alloimmunity. Regulatory T cells (Tregs) are being studied as a cellular therapy in solid organ transplantation. Whether these systemically administered Tregs can function at the appropriate location and time is an important concern. We hypothesized that in vitro expanded, recipient-derived Tregs can be delivered to donor lungs prior to LTx via ex vivo lung perfusion (EVLP), maintaining their immunomodulatory ability.
In a rat model, Wistar Kyoto (WKy) CD4+CD25high Tregs were expanded in vitro prior to EVLP. Expanded Tregs were administered to Fisher 344 (F344) donor lungs during EVLP; left lungs were transplanted into WKy recipients. Treg localisation and function post-transplant were assessed. In a proof-of-concept experiment, cryopreserved expanded human CD4+CD25+CD127low Tregs were thawed and injected into discarded human lungs during EVLP.
Rat Tregs entered the lung parenchyma and retained suppressive function. Expanded Tregs had no adverse effect on donor lung physiology during EVLP; lung water as measured by wet-to-dry weight ratio was reduced by Treg therapy. The administered cells remained in the graft at 3 days post-transplant where they reduced activation of intragraft effector CD4+ T cells; these effects were diminished by day 7. Human Tregs entered the lung parenchyma during EVLP where they expressed key immunoregulatory molecules (CTLA4+, 4-1BB+, CD39+, and CD15s+).
Pre-transplant Treg administration can inhibit alloimmunity within the lung allograft at early time points post- transplant. Our organ-directed approach has potential for clinical translation.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Miyamoto reports personal fees from The Kyoto University Foundation, Japan, personal fees from The Cell Science Research Foundation, Japan, personal fees from International Society for Heart and Lung Transplantation, during the conduct of the study; .
Conflict of interest: Dr. Takahagi has nothing to disclose.
Conflict of interest: Dr. Ohsumi has nothing to disclose.
Conflict of interest: Dr. Martinu has nothing to disclose.
Conflict of interest: Dr. Hwang has nothing to disclose.
Conflict of interest: Dr. Boonstra has nothing to disclose.
Conflict of interest: Dr. Joe has nothing to disclose.
Conflict of interest: Dr. Umana has nothing to disclose.
Conflict of interest: Dr. Bei has nothing to disclose.
Conflict of interest: Dr. Vosoughi has nothing to disclose.
Conflict of interest: Dr. Liu has nothing to disclose.
Conflict of interest: Dr. Cypel reports other from Perfusix Canada, Traferox Technologies Inc. Toronto, other from Lung Bioengineering, United Therapeutics, during the conduct of the study; .
Conflict of interest: Dr. Keshavjee reports other from Perfusix Canada, Traferox Technologies Inc. Toronto, other from Lung Bioengineering, United Therapeutics, during the conduct of the study; .
Conflict of interest: Dr. Juvet reports grants from Ontario Institute for Regenerative Medicine, grants from The Cystic Fibrosis Canada, during the conduct of the study.
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- Received March 17, 2021.
- Accepted August 17, 2021.
- Copyright ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org
