Session Time: 2:30pm-4:00pm
Presentation Time: 3:30pm-3:42pm
Location: Room 208
*Purpose: 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) in conjunction with withdrawal of immunosuppression (ClinicalTrials.gov Identifier: NCT03164265)
*Methods: DCreg generated from four separate living donors’ elutriated monocytes were infused iv (2.5-10×106/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). For those patients that meet eligibility criteria for weaning, immunosuppressive therapy is gradually withdrawn, starting with MPA reduction at 6 months post-LTx. Sequential (pre-, post-infusion, and 1, 3, 6, 12 months post-LTx) immunological analyses are conducted on recipient blood to track donor-derived DCreg (by flow cytometry and image stream), detect donor-specific antibody (DSA), and evaluate anti-donor T cell phenotype and reactivity.
*Results: GMP-grade DCreg generated for infusion were HLA-DR+, CD1c–, CD11c+, CD83–, IRF4lo with high PD-L1:CD86 ratio. In addition, DCreg were resistant to maturation (LPS stimulation), produced IL-10 but minimal IL-12, induced donor-specific hyporesponsiveness of recipient CD4 and CD8 T cells. DCreg exhibited gene expression profiles that reflect their tolerogenic properties (significant fold change decrease in LAMP3, IRF4 and CD1c), as compared to donor derived immature DC. 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. However, a small population of DC co-expressing both recipient and donor MHC, ie cross-dressed DC, were detected in the circulation. At the time of transplant, just before graft implantation, we identified in one patient examined to date a post-infusion signal in the host CD8+ T cell population, indicating a decrease in effector memory and central memory cell subsets, down-regulation of T-bet and Eomes, as well as of CTLA-4 and PD-1. Importantly no DSA has been detected in the circulation of these 4 patients.
*Conclusions: DCreg infusion into LTx recipients appears to be safe and is not associated with generation of DSA. Cross-dressed DC can be detected in peripheral blood within a few days post-infusion and appear to have signaled CD8+ T cells, suggesting their possible in vivo regulatory function.
To cite this abstract in AMA style:Thomson A, Macedo C, Zahorchak A, Dai H, Humar A, Lakkis FG, Styn M, Metes D. Preliminary Mechanistic Studies of Regulatory Dendritic Cell (DCreg) Cell Infusion in Living Donor Liver Transplant Recipients [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/preliminary-mechanistic-studies-of-regulatory-dendritic-cell-dcreg-cell-infusion-in-living-donor-liver-transplant-recipients/. Accessed September 29, 2020.
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