title: Calcineurin inhibitor-free immunosuppressive regimen in type 1 diabetes patients receiving islet transplantation: single-group phase 1/2 trial.
abstract: BACKGROUND
  Our final objective is to develop an adoptive therapy with tolerogenic donor-specific type 1 T regulatory cells for patients with type 1 diabetes undergoing islet transplantation. The achievement of this objective depends on the availability of an immunosuppressive treatment compatible with the survival, function, and expansion of type 1 T regulatory cells.
  
  
  METHODS
  For this purpose, we designed a single-group, phase 1 to 2 trial with an immunosuppression protocol including: (i) rapamycin treatment before the first islet infusion (starting ≥ 30 days before transplantation); (ii) induction therapy with anti-thymocyte globulin (ATG) instead of anti-interleukin-2Ra monoclonal antibody (after the first islet infusion only); (iii) short-term treatment with steroids and interleukin-1Ra (right before and for 2 weeks after each infusion); rapamycin+mycophenolate mofetil treatment as maintenance therapy. The target enrollment was 10 patients.
  
  
  RESULTS
  Ten of 15 patients who started the pretransplant rapamycin treatment completed it. Nine of 10 patients did not complete the induction therapy with ATG, and three of 10 required adaptation of maintenance immunosuppression caused by side effects. Four of 10 patients acquired insulin independence which can be maintained up to year 3 after last infusion. All six other patients have lost their graft, and the early graft loss was associated with lower dose of ATG during induction.
  
  
  CONCLUSIONS
  This protocol resulted feasible, safe but less efficient in maintaining graft survival during the time than other T-cell depletion-based protocols. An adequate induction at the first infusion should be considered to improve the overall clinical outcome.
authors.affiliation: 1 Division of Immunology, Transplantation and Infectious Diseases, Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy. 2 Department of Surgery, Cell Isolation and Transplantation Center, University of Geneva, Genève, Switzerland. 3 Department of Radiology and Center for Experimental Imaging, IRCCS San Raffaele Scientific Institute, Milan, Italy. 4 Vita-Salute San Raffaele University, Milan, Italy. 5 Correspondence to: Prof. Lorenzo Piemonti, MD, Diabetes Research Institute, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Antonio Secchi, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Maffi
authors.forename: Thierry
authors.initials: T
authors.lastname: Berney
authors.forename: Rita
authors.initials: R
authors.lastname: Nano
authors.forename: Nadja
authors.initials: N
authors.lastname: Niclauss
authors.forename: Domenico
authors.initials: D
authors.lastname: Bosco
authors.forename: Raffaella
authors.initials: R
authors.lastname: Melzi
authors.forename: Alessia
authors.initials: A
authors.lastname: Mercalli
authors.forename: Paola
authors.initials: P
authors.lastname: Magistretti
authors.forename: Francesco
authors.initials: F
authors.lastname: De Cobelli
authors.forename: Manuela
authors.initials: M
authors.lastname: Battaglia
authors.forename: Marina
authors.initials: M
authors.lastname: Scavini
authors.forename: Sandrine
authors.initials: S
authors.lastname: Demuylder-Mischler
authors.forename: Antonio
authors.initials: A
authors.lastname: Secchi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
mesh_terms: D000328:Adult; D000961:Antilymphocyte Serum / Q000737:chemistry / Q000627:therapeutic use; D065095:Calcineurin Inhibitors / Q000737:chemistry; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D005260:Female; D005919:Glomerular Filtration Rate; D006085:Graft Survival; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000737:chemistry / Q000627:therapeutic use; D016381:Islets of Langerhans Transplantation; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000737:chemistry / Q000627:therapeutic use; D013256:Steroids / Q000737:chemistry / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D016896:Treatment Outcome
chemical_list: D000961:Antilymphocyte Serum; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D007328:Insulin; D053590:Interleukin 1 Receptor Antagonist Protein; D013256:Steroids; D020123:Sirolimus