title: Transforming growth factor-β released by apoptotic white blood cells during red blood cell storage promotes transfusion-induced alloimmunomodulation.
abstract: BACKGROUND
  Red blood cell (RBC) alloimmunization is a major immunologic risk of transfusion. However, RBC storage facilitates white blood cell (WBC) apoptosis and apoptotic cells have immunomodulatory properties. We investigated the behavior of WBCs, and apoptosis in particular, in RBC units during storage and then studied the impact of WBC apoptosis on the modulation of posttransfusion alloimmunization in RBC products stored short term.
  
  
  METHODS
  We used a mouse model of alloimmunization to transfused HEL-ovalbumin-Duffy (HOD) surface antigen expressed specifically on RBCs. The presence of circulating anti-HOD immunoglobulin G detected by flow cytometry confirmed immunization to HOD+ RBCs. WBC apoptosis and factors released by apoptotic WBCs during storage were determined and in particular the role of transforming growth factor (TGF)-β was assessed on RBC alloimmunization.
  
  
  RESULTS
  In blood stored 72 hours, 30% of WBCs were apoptotic, and transfusion of short-term-stored blood resulted in lesser immunization than did fresh blood or stored leukoreduced (LR) RBCs. WBCs undergoing apoptosis released during short-term storage factors modulating RBC alloimmunization. Indeed apoptotic cell-released factors modulate alloimmunization whereas exogenous apoptotic cells directly transfused with LR RBCs did not. While microparticles released during RBC storage had no immunomodulatory role, TGF-β found in the supernatant of stored blood demonstrated the capacity to favor Treg polarization of naïve CD4+CD25- T cells in vitro and limited RBC alloimmunization in vivo. Indeed, addition of recombinant TGF-β to stored LR RBC transfusion strongly limited posttransfusion RBC alloimmunization.
  
  
  CONCLUSIONS
  Our findings show that short-term storage of non-LR blood facilitates WBC apoptosis therefore releasing TGF-β that modulates posttransfusion RBC alloimmunization.
authors: INSERM, UMR1098.|Université de Bourgogne Franche-Comté, UMR1098.|EFS Bourgogne Franche-Comté, UMR1098.|LabEx LipSTIC, ANR-11-LABX-0021, FHU INCREASE, Besançon, France.
authors: Romain
authors: R
authors: Vallion
authors: INSERM, UMR1098.|Université de Bourgogne Franche-Comté, UMR1098.|EFS Bourgogne Franche-Comté, UMR1098.|LabEx LipSTIC, ANR-11-LABX-0021, FHU INCREASE, Besançon, France.
authors: Francis
authors: F
authors: Bonnefoy
authors: INSERM, UMR1098.|Université de Bourgogne Franche-Comté, UMR1098.|EFS Bourgogne Franche-Comté, UMR1098.|LabEx LipSTIC, ANR-11-LABX-0021, FHU INCREASE, Besançon, France.
authors: Anna
authors: A
authors: Daoui
authors: INSERM, UMR1098.|Université de Bourgogne Franche-Comté, UMR1098.|EFS Bourgogne Franche-Comté, UMR1098.|LabEx LipSTIC, ANR-11-LABX-0021, FHU INCREASE, Besançon, France.
authors: Loredane
authors: L
authors: Vieille
authors: INSERM, UMR1098.|Université de Bourgogne Franche-Comté, UMR1098.|EFS Bourgogne Franche-Comté, UMR1098.|LabEx LipSTIC, ANR-11-LABX-0021, FHU INCREASE, Besançon, France.
authors: Pierre
authors: P
authors: Tiberghien
authors: INSERM, UMR1098.|Université de Bourgogne Franche-Comté, UMR1098.|EFS Bourgogne Franche-Comté, UMR1098.|LabEx LipSTIC, ANR-11-LABX-0021, FHU INCREASE, Besançon, France.
authors: Philippe
authors: P
authors: Saas
authors: INSERM, UMR1098.|Université de Bourgogne Franche-Comté, UMR1098.|EFS Bourgogne Franche-Comté, UMR1098.|LabEx LipSTIC, ANR-11-LABX-0021, FHU INCREASE, Besançon, France.
authors: Sylvain
authors: S
authors: Perruche
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001793:Blood Preservation; D017707:Erythrocyte Transfusion; D004912:Erythrocytes / Q000276:immunology* / Q000378:metabolism; D056747:Immunomodulation; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016212:Transforming Growth Factor beta / Q000097:blood / Q000276:immunology*
chemical_list: D016212:Transforming Growth Factor beta