title: Natural killer cells play a critical role in cardiac allograft vasculopathy in an interleukin-6--dependent manner.
abstract: BACKGROUND
  Approximately 50% of cardiac transplants fail in the long term, and currently, there are no specific treatments to prevent chronic rejection. In the clinic, donor cardiac graft ischemia time is limited to within a few hours and correlates with delayed graft function and organ failure. It is still unknown how ischemic injury negatively influences allograft function over the long term despite advances in immunosuppression therapy.
  
  
  METHODS
  Allogeneic cardiac grafts were stored at 4 °C for 4 hr before being transplanted into T/B cell-deficient Rag(-/-) mice or T/B/natural killer (NK) cell-deficient γc(-/-)Rag(-/-) mice. Grafts were harvested 60 days after transplantation and indicators of chronic allograft vasculopathy (CAV) were quantified.
  
  
  RESULTS
  We have found that cold ischemia of cardiac grafts induces CAV after transplantation into Rag1(-/-) mice. Interestingly, cold ischemia-induced CAV posttransplantation was not seen in T/B/NK cell-deficient γc(-/-)Rag(-/-) mice. However, cardiac grafts in γc(-/-)Rag(-/-) mice that received an adoptive transfer of NK cells developed CAV, supporting the role of NK cells in CAV development. Analysis of various cytokines that contribute to NK cell function revealed high interleukin (IL)-6 expression in cardiac grafts with CAV. In addition, IL-6-deficient cardiac grafts did not develop CAV after transplantation into allogeneic Rag(-/-) mice.
  
  
  CONCLUSIONS
  These data demonstrate that cold ischemia and NK cells play critical roles in the development CAV. Natural killer cells and injured grafts may play a reciprocal role for CAV development in an IL-6-independent manner. Specific therapeutic strategies may be required to attenuate NK cell contribution to chronic cardiac rejection.
authors.affiliation: 1 Matthew Mailing Centre for Translational Transplantation Studies, Lawson Health Research Institute, London Health Sciences Centre, London, UK. 2 Departments of Medicine, Surgery and Pathology, University of Western Ontario, London, Ontario, Canada. 3 Address correspondence to: Zhu-Xu Zhang, Ph.D., London Health Sciences Centre,B4-231, 339 Windermere Road, London, Ontario, Canada N6A 5A5.
authors.forename: Zhu-Xu
authors.initials: ZX
authors.lastname: Zhang
authors.forename: Xuyan
authors.initials: X
authors.lastname: Huang
authors.forename: Jifu
authors.initials: J
authors.lastname: Jiang
authors.forename: Dameng
authors.initials: D
authors.lastname: Lian
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Min
authors.forename: Weihua
authors.initials: W
authors.lastname: Liu
authors.forename: Aaron
authors.initials: A
authors.lastname: Haig
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Jevnikar
mesh_terms: D019264:Adoptive Transfer; D064591:Allografts; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002318:Cardiovascular Diseases / Q000209:etiology / Q000276:immunology / Q000473:pathology; D050377:Cold Ischemia / Q000009:adverse effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology / Q000473:pathology; D016027:Heart Transplantation / Q000009:adverse effects*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology; D014019:Tissue Donors
chemical_list: D016207:Cytokines; D018398:Homeodomain Proteins; D015850:Interleukin-6; C064658:RAG-1 protein