title: Intravenous infusion of donor apoptotic leukocytes before transplantation delays allogeneic islet graft rejection through regulatory T cells.
abstract: OBJECTIVE
  This study describes the ability of intravenous donor apoptotic leukocyte infusion before islet transplantation to delay allogeneic graft rejection and implicates regulatory T cells (T(reg)) in the effect.
  
  
  METHODS
  Allogeneic FVB (Friend virus B-type) islet transplants were placed under the kidney capsule of BALB/c recipient mice rendered diabetic by streptozotocin. Apoptotic donor leukocytes were infused intravenously 7 days before transplantation. Foxp3/DTR/GFP transgenic C57BL/6 mice were used as recipients to show depletion of T(reg) after apoptotic cell infusion. Control mice received islet transplants without apoptotic cells.
  
  
  RESULTS
  The graft median survival time (MST) in recipient mice was 15±1.5 days when apoptotic cells were infused 7 days prior to transplantation of a 1000-islet-containing allograft and 6±0.5 days in the control mice (P<0.01). The same effect was observed using a 500-islet allograft, with an MST of 9±1.1 days vs. 3±0.8 days with and without (controls) apoptotic cells, respectively (P<0.01). This immunomodulatory effect was not observed when apoptotic cell administration was performed on the day of transplantation. Specific T(reg) depletion in Foxp3/DTR/GFP recipient mice inhibited the beneficial effect of apoptotic cell infusion with an MST of 8±1.5 days after apoptotic cell infusion vs. 2±0.2 days when T(reg) were depleted (P<0.01). Furthermore, T(reg) were specifically detected in the islet grafts of mice infused with apoptotic cells prior to islet transplantation.
  
  
  CONCLUSIONS
  Infusion of donor apoptotic cells 7 days before allogeneic transplantation delays islet allograft rejection through a process involving T(reg).
authors.affiliation: Inserm, UMR1098, 25020 Besançon, France. francoismougel@gmail.com
authors.forename: F
authors.initials: F
authors.lastname: Mougel
authors.forename: F
authors.initials: F
authors.lastname: Bonnefoy
authors.forename: S
authors.initials: S
authors.lastname: Kury-Paulin
authors.forename: S
authors.initials: S
authors.lastname: Borot
authors.forename: S
authors.initials: S
authors.lastname: Perruche
authors.forename: B
authors.initials: B
authors.lastname: Kantelip
authors.forename: A
authors.initials: A
authors.lastname: Penfornis
authors.forename: P
authors.initials: P
authors.lastname: Saas
authors.forename: F
authors.initials: F
authors.lastname: Kleinclauss
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D056747:Immunomodulation; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D017708:Leukocyte Transfusion / Q000379:methods*; D007962:Leukocytes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*