Purpose: We have embarked on 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).

Methods: In the study protocol, DCreg are generated from monocytes isolated from the leukapheresed donor, 14-28 days (d) before transplant. The donor-derived DCreg are infused iv (target range 2.5-10.10⁶/kg) 7 d before transplant (d -7), while a half dose of MPA is given from d -7 to d 0. Standard-of-care immunosuppression (steroid, MPA, tacrolimus) is given post-LTx, and in those patients that meet eligibility criteria, immunosuppressive therapy is gradually withdrawn, starting with MPA reduction 6 m post-LTx. Immunological analyses are conducted to track the infused DCreg, evaluate anti-donor reactivity and examine potential mechanisms of immune hyporesponsiveness. In the first LTx recipient (HLA-B12⁺) to receive donor-derived (HLA-A3⁺) DCreg, blood was obtained before and after cell infusion; native liver tissue was obtained at graft implantation.

Results: DCreg generated for infusion were HLA-DR⁺, CD1c^–, CD11c⁺, CD83^–, IRF4^lo with a high programed death ligand-1 (PD-L1):CD86 ratio. In small scale functional tests, they failed to respond to LPS and induced donor-specific hyporesponsiveness of recipient CD4 and CD8 T cells. Donor-derived DCreg (HLA-A3⁺) with a similar phenotype to that exhibited pre-infusion, were detected in blood immediately after the infusion that comprised 5.10⁶ DCreg/kg (450.10⁶ total DCreg). No infusion reaction or cytokine release response was observed. Three days post-infusion (d -4), HLA-A3⁺ donor-derived DC could no longer be detected in blood, although a small population of DC co-expressing both recipient (HLA-B12) and donor MHC (HLA-A3), ie cross-dressed DC, were evident in the circulation. At the time of transplant, before graft implantation, cross-dressed (HLA-A3⁺B12⁺) DC could also be detected in native liver and were PD-L1^hi, IRF4^lo and Foxp3^hi.

Conclusions: After infusion of donor-derived DCreg into a prospective LTx recipient, cross-dressed DC were evident in blood within a few days and in native liver at the time of graft implantation. These cross-dressed DC, that appear to have acquired donor MHC from the infused DCreg, exhibit low levels of the DC transcription/maturation factor IRF4 and high levels of PD-L1 and Foxp3, suggesting possible in vivo regulatory function.

CITATION INFORMATION: Thomson A., Humar A., Lakkis F., Styn S., Zahorchak A., Macedo C., Metes D. Regulatory Dendritic Cell (DCreg) Cell Infusion in Living Donor Liver Transplantation Am J Transplant. 2017;17 (suppl 3).

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