title: Presensitized immune condition of host exaggerates prolonged cold ischemia-mediated injury of cardiac graft involving regulatory T cells.
abstract: BACKGROUND
  The detrimental effect of prolonged cold ischemia time (PCI) on presensitized transplanted graft is conceivable, but the impact of presensitization status of recipient on PCI-mediated graft injury and inflammation is not well defined.
  
  
  METHODS
  Allogeneic skin grafts from BALB/c donors were transplanted into C57BL/6 recipients for presensitization. Syngeneic or allogeneic heterotopic heart transplantations with PCI were performed using C57BL/6 or BALB/c donors for these recipients through different treatments.
  
  
  RESULTS
  We revealed that PCI could not affect isograft survival but significantly shortened allograft survival in the presensitized recipients. Depletion of regulatory T cells (Tregs) starting 1 day before and after heart transplantation with anti-CD25 monoclonal antibody remarkably induced intragraft Foxp3 gene expression, worsened architecture damage and subepicardial and intramuscle inflammatory cellular infiltration, and caused a dramatic fall of intragraft CD4+/CD8+ ratio, whereas adoptive transfer of exogenous wild-type Tregs or endogenous Tregs promoted by rapamycin had a beneficial effect on preventing the infiltration of T lymphocytes and Gr-1+ neutrophils and reversed intragraft CD4+/CD8+ ratio, preserving cardiac graft architecture. However, their distinct protective mechanisms showed that rapamycin treatment mainly diminished CD4+ T-cell infiltration. Nevertheless, CD4+ still outnumbered CD8+ T cells in the graft, whereas adoptive transfer of Tregs expanded both CD4+ and CD8+ T cells, particularly CD8+ T cells.
  
  
  CONCLUSIONS
  Allogeneic immunoresponses synergistically enhanced PCI effect under presensitized condition. PCI could affect subsequent immunoresponses. Tregs were closely involved in this pathophysiologic process. Our data may pave the way to use Tregs as a novel therapeutic approach to prevent PCI-mediated injury in the presensitized transplant recipients.
authors.affiliation: 1 Department of Surgery and Medicine, Transplant International Research Centre (TIRC), Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou City, People's Republic of China. 2 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. 3 Department of Cardiology, Yiwu Central Hospital, Wenzhou Medical College, Yiwu, People's Republic of China. 4 Address correspondence to: Weihua Gong, 88 Jiefang Road, Hangzhou City, Zhejiang Province, 310009, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Gong
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.forename: Fangmin
authors.initials: F
authors.lastname: Ge
authors.forename: Gaojiang
authors.initials: G
authors.lastname: Luo
authors.forename: Shunzong
authors.initials: S
authors.lastname: Yuan
authors.forename: Daming
authors.initials: D
authors.lastname: Gao
authors.forename: Dong
authors.initials: D
authors.lastname: Kong
mesh_terms: D019264:Adoptive Transfer; D064591:Allografts; D000818:Animals; D050377:Cold Ischemia / Q000009:adverse effects*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006085:Graft Survival; D016027:Heart Transplantation / Q000009:adverse effects*; D007114:Immunization / Q000379:methods*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D064596:Isografts; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology; D016038:Skin Transplantation; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D013997:Time Factors; D014185:Transplantation, Isogeneic
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit