This is a first-in-human phase I/II safety and preliminary efficacy trial of donor-derived regulatory dendritic cells (DCreg) in living-donor liver transplantation (LTx).
DCreg generated from four separate living-donors’ elutriated monocytes were infused iv (2.5-10x106/kg) 7 days before LTx in 4 separate recipients. A half dose of MPA was given from d-7 to d0 until LTx, followed by standard-of-care immunosuppression (steroid, MPA, tacrolimus) that is gradually withdrawn at 6 months post-LTx. Pre-, post-infusion, and 1, 3, 6, 12 months post-LTx immunological analyses are conducted on recipient blood to track DCreg, donor-specific antibody (DSA), and anti-donor T cell reactivity.
GMP-grade DCreg generated for infusion were HLA-DR+CD1c-CD11c+CD83-IRF4loCD141+ with high PD-L1:CD86 ratio. In addition, DCreg were resistant to maturation (LPS stimulation), produced IL-10hiIL-12lo, induced donor-specific hyporesponsiveness of recipient T cells. No infusion reaction or cytokine release responses were observed. DCreg were detected in whole blood of three recipients immediately after infusion, but no longer after 3 days post-infusion. A small population of DC co-expressing both recipient and donor MHC, ie cross-dressed DC, were detected in the circulation. In one examined patient, a post-infusion signal in the host CD8+ T cells was identified at the time of transplant, indicating a decrease in memory cell subsets, down-regulation of T-bet/Eomes, CTLA-4 and PD-1. No DSA has been detected in the circulation of these 4 patients.
DCreg infusion into LTx recipients appears safe. Cross-dressed DC can be detected in peripheral blood within a few days post-infusion and may have signaled CD8+ T cells, suggesting their possible in vivo regulatory function.