title: Generation of donor-specific Tr1 cells to be used after kidney transplantation and definition of the timing of their in vivo infusion in the presence of immunosuppression.
abstract: Operational 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.
  
  
  
  Upon 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 T10cells) and to test the Tr1-cell sensitivity to standard immunosuppression in vivo to define the best timing of cell infusion.
  
  
  
  We 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 T10cells 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.
  
  
  
  These 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.
authors.affiliation: Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy.
authors.forename: Bechara
authors.identifier: 0000-0002-8361-5240
authors.initials: B
authors.lastname: Mfarrej
authors.affiliation: Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy.|Human T Cell Laboratory, Saint Vincent's Institute of Medical Research, Melbourne, Australia.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Tresoldi
authors.affiliation: Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Stabilini
authors.affiliation: Department of Internal Medicine, Transplantation Medicine, San Raffaele Hospital, Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Paganelli
authors.affiliation: Department of Internal Medicine, Transplantation Medicine, San Raffaele Hospital, Milan, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Caldara
authors.affiliation: Department of Internal Medicine, Transplantation Medicine, San Raffaele Hospital, Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Secchi
authors.affiliation: Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy. battaglia.manuela@hsr.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Battaglia
mesh_terms: D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D016030:Kidney Transplantation; D007937:Leukapheresis; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D015203:Reproducibility of Results; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors; D014019:Tissue Donors; D059467:Transcriptome
chemical_list: D007166:Immunosuppressive Agents; D018950:Lipopolysaccharide Receptors; D016753:Interleukin-10; D007371:Interferon-gamma
keywords: Cell therapy; Clinical-grade compatible protocol; Kidney transplantation; Tolerance induction