Abstract
BackgroundOperational tolerance is an alternative to lifelong immunosuppression after transplantation. One strategy to achieve tolerance is by T regulatory cells. Safety and feasibility of a T regulatory type 1 (Tr1)-cell—based therapy to prevent graft versus host disease in patients with hematological malignancies has been already proven. We are now planning to perform a Tr1-cell—based therapy after kidney transplantation.MethodsUpon tailoring the lab-grade protocol to patients on dialysis, aims of the current work were to develop a clinical-grade compatible protocol to generate a donor-specific Tr1-cell—enriched medicinal product (named T10 cells) and to test the Tr1-cell sensitivity to standard immunosuppression in vivo to define the best timing of cell infusion.ResultsWe developed a medicinal product that was enriched in Tr1 cells, anergic to donor-cell stimulation, able to suppress proliferation upon donor- but not third-party stimulation in vitro, and stable upon cryopreservation. The protocol was reproducible upon up scaling to leukapheresis from patients on dialysis and was effective in yielding the expected number of T10 cells necessary for the planned infusions. The tolerogenic gene signature of circulating Tr1 cells was minimally compromised in kidney transplant recipients under standard immunosuppression and it eventually started to recover 36 weeks post-transplantation, providing rationale for selecting the timings of the cell infusions.ConclusionsThese data provide solid ground for proceeding with the trial and establish robust rationale for defining the correct timing of cell infusion during concomitant immunosuppressive treatment.
Highlights
Operational tolerance is an alternative to lifelong immunosuppression after transplantation
Based on the MLR/dendritic cells (DC)-10 protocol used in the ALT-TEN trial [7], DC-10 were generated from the Peripheral blood mononuclear cells (PBMC) adherent fraction in medium supplemented with fetal bovine serum (FBS) in wells
DC-10 recovery was better when medium supplemented with FBS was used, yet the intraexperiment variability—determined by the coefficients of variation (CV)—was high (Fig. 2)
Summary
Operational tolerance is an alternative to lifelong immunosuppression after transplantation. Safety and feasibility of a T regulatory type 1 (Tr1)-cell—based therapy to prevent graft versus host disease in patients with hematological malignancies has been already proven. Circulating T regulatory type 1 (Tr1) cells with an alloantigen-specific regulatory function have been consistently associated with operational tolerance after transplantation [1]. The ONE Study—a European Commission FP7-funded consortium-aims to test several distinct haematopoietic immunoregulatory cells as therapies after kidney transplantation from living donors by initiating a series. We aimed at: (1) defining a reproducible and clinical-grade compatible protocol for the generation of a Tr1-cell—enriched medicinal product for kidney transplant recipients, (2) characterizing the final cell product, and (3) testing the sensitivity of circulating Tr1 cells to immunosuppressive therapy to determine the ideal timing of the medicinal product infusion
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