title: Heat shock protein-27 delays acute rejection after cardiac transplantation: an experimental model.
abstract: BACKGROUND
  Rejection is the major obstacle to survival after cardiac transplantation. We investigated whether overexpression of heat shock protein (Hsp)-27 in mouse hearts protects against acute rejection and the mechanisms of such protection.
  
  
  METHODS
  Hearts from B10.A mice overexpressing human Hsp-27 (Hsp-27tg), or Hsp-27-negative hearts from littermate controls (LCs) were transplanted into allogeneic C57BL/6 mice. The immune response to B10.A hearts was investigated using quantitative polymerase chain reaction for CD3+, CD4+, CD8+ T cells, and CD14+ monocytes and cytokines (interferon-γ, interleukin [IL]-2, tumor necrosis factor-α, IL-1β, IL-4, IL-5, IL-10, transforming growth factor-β) in allografts at days 2, 5, and 12 after transplantation. The effect of Hsp-27 on ischemia-induced caspase activation and immune activation was investigated.
  
  
  RESULTS
  Survival of Hsp-27tg hearts (35±10.37 days, n=10) was significantly prolonged compared with LCs (13.6±3.06 days, n=10, P=0.0004). Hsp-27tg hearts expressed significantly more messenger RNA (mRNA) markers of CD14+ monocytes at day 2 and less mRNA markers of CD3+ and CD8+T cells at day 5 compared with LCs. There was more IL-4 mRNA in Hsp-27tg hearts at day 2 and less interferon-γ mRNA at day 5 compared with LCs. Heat shock protein-27tg hearts subjected to ischemia or to 24 hr ischemia-reperfusion injury demonstrated significantly less apoptosis and activation of caspases 3, 9, and 1 than LCs. T cells removed from C57BL/6 recipients of Hsp-27tg hearts produced a vigorous memory response to B10.A antigens, suggesting immune activation was not inhibited by Hsp-27.
  
  
  CONCLUSIONS
  Heat shock protein-27 delays allograft rejection, by inhibiting tissue damage, through probably an antiapoptotic pathway. It may also promote an anti-inflammatory subset of monocytes.
authors.affiliation: 1 Transplant Immunology Group, National Heart and Lung Institute, Imperial College, Harefield Heart Science Centre, Harefield, United Kingdom. 2 Molecular Biology Group, National Heart and Lung Institute, Imperial College, Harefield Heart Science Centre, Harefield, United Kingdom. 3 Address correspondence to: Marlene Rose, Ph.D., National Heart and Lung Institute, Imperial College, Heart Science Centre, Harefield Hospital, Harefield, Middlesex, UB9 6JH, UK.
authors.forename: Borggia
authors.initials: B
authors.lastname: Seemampillai
authors.forename: Renee
authors.initials: R
authors.lastname: Germack
authors.forename: Leanne E
authors.initials: LE
authors.lastname: Felkin
authors.forename: Ann
authors.initials: A
authors.lastname: McCormack
authors.forename: Marlene L
authors.initials: ML
authors.lastname: Rose
mesh_terms: D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D016027:Heart Transplantation / Q000009:adverse effects*; D006360:Heat-Shock Proteins; D006801:Humans; D007156:Immunologic Memory; D018836:Inflammation Mediators / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D013997:Time Factors
chemical_list: D016207:Cytokines; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018836:Inflammation Mediators; D018832:Molecular Chaperones; D012333:RNA, Messenger; D020169:Caspases