Ex vivodelivery of regulatory T cells for control of alloimmune priming in the donor lung

Abstract

Rationale: Survival after lung transplantation (LTx) is hampered by uncontrolled inflammation and alloimmunity. Regulatory T cells (Tregs) are being studied for post-implantation cell therapy in solid organ transplantation. Whether these systemically administered Tregs can function at the appropriate location and time is an important concern. Objectives: 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. Methods: 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 localization 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. Measurements and Main Results: 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+). Conclusions: 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.

Lymphocytic Airway Inflammation in Lung Allografts

“…Also, an adenosine A2A receptor antagonist is under investigation to reduce invariant NKT cell mediated inflammation in PGD (173). Other strategies to dampen airway inflammation, such as regulatory T cell adoptive therapy and/or pretransplant allograft modification during ex vivo lung perfusion, have shown preclinical promise as adjuncts to traditional immune suppression (174). A fair portion of our understanding of allograft injury comes from in vitro, ex vivo, and animal models which are extremely important in studying the biology that informs our clinical pursuits.…”

Diagnostic and Therapeutic Implications of Ex Vivo Lung Perfusion in Lung Transplantation: Potential Benefits and Inherent Limitations

“…Because of the high immunomodulatory ability of regulatory T cells, Miyamoto E and colleagues reported positive immunomodulatory effects using expanded recipient-derived regulatory T cells in the lungs of rats during EVLP, followed by successful LTx without adverse effects. 84 Depleting passenger leukocyte therapy during EVLP in a porcine lung model also exhibited inhibitory effects on acute rejection by preventing donor leukocytes from migrating to recipient lymph nodes and reducing recipient T cell infiltration into the donor lung. 85 Moreover, in the EVLP porcine model, perfusion with human blood modified by the addition of polymer GAS914, a soluble trisaccharide-polylysine conjugate, showed great potential in binding xenoreactive human antibodies and preserving the function of a porcine lung xenograft, thereby preventing hyperacute rejection in lung xenotransplantation.…”