title: The nature of acute rejection is associated with development of graft vascular disease after clinical heart transplantation.
abstract: BACKGROUND
  To determine mechanisms that trigger graft vascular disease (GVD) after heart transplantation, we studied parameters that reflect both early and late intragraft allogeneic reactions.
  
  
  METHODS
  With reverse transcriptase-polymerase chain reaction analysis, mRNA expression of interleukin-2 (IL-2), interleukin-4, interleukin-6, interleukin-10, interferon-gamma, platelet-derived growth factor-alpha, and transforming growth factor-beta was measured in endomyocardial biopsy (EMB) specimens obtained from 34 recipients during the first acute rejection episode (n = 29) or at a comparable time after transplantation for patients without rejection (n = 5) and at time of assessment of GVD by coronary angiography at 1 year (n = 34).
  
  
  RESULTS
  At the time of assessment of GVD, mRNA expression of IL-2, interleukin-4, and interleukin-6 were barely detectable, whereas messenger coding for interferon-gamma, interleukin-10, transforming growth factor-beta, and platelet-derived growth factor-alpha genes were constitutively expressed. Moreover, intragraft mRNA patterns of cytokines and growth factors between patients with GVD (n = 17) or without GVD (n = 17) were comparable. In contrast, during the first acute rejection episode a completely different pattern was found. Development of GVD was associated with IL-2 mRNA expression and not with the other cytokines analyzed. IL-2 mRNA was present in 77% of rejection EMB specimens obtained from patients with GVD versus 33% of the EMB specimens obtained from patients without GVD (p = 0.03) and not detectable in EMB specimens obtained from patients with no rejection. Also nonimmunologic risk factors such as longer ischemia time (median 193 vs 141 minutes; p = 0.002) and higher donor age (median 32 vs 23 years; p = 0.02) were associated with GVD. But no relation was found between these nonimmunologic risk factors and IL-2-positive acute rejections.
  
  
  CONCLUSIONS
  Nonspecific risk factors and IL-2-positive rejections may independently trigger GVD after clinical heart transplantation.
authors.affiliation: Department of Internal Medicine 1, University Hospital Rotterdam-Dijkzigt, Rotterdam, The Netherlands. baan@inw1.azr.nl
authors.forename: C C
authors.initials: CC
authors.lastname: Baan
authors.forename: C T
authors.initials: CT
authors.lastname: Holweg
authors.forename: H G
authors.initials: HG
authors.lastname: Niesters
authors.forename: T
authors.initials: T
authors.lastname: van Gelder
authors.forename: W M
authors.initials: WM
authors.lastname: Mol
authors.forename: P E
authors.initials: PE
authors.lastname: Zondervan
authors.forename: B
authors.initials: B
authors.lastname: Mochtar
authors.forename: A H
authors.initials: AH
authors.lastname: Balk
authors.forename: W
authors.initials: W
authors.lastname: Weimar
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D001706:Biopsy; D016022:Case-Control Studies; D017023:Coronary Angiography; D003327:Coronary Disease / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D005260:Female; D006084:Graft Rejection / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D016027:Heart Transplantation / Q000009:adverse effects* / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis / Q000235:genetics; D016753:Interleukin-10 / Q000032:analysis / Q000235:genetics; D007376:Interleukin-2 / Q000032:analysis / Q000235:genetics; D015847:Interleukin-4 / Q000032:analysis / Q000235:genetics; D015850:Interleukin-6 / Q000032:analysis / Q000235:genetics; D007511:Ischemia / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010982:Platelet-Derived Growth Factor / Q000032:analysis / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D012307:Risk Factors; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics; D014184:Transplantation, Homologous
chemical_list: D007376:Interleukin-2; D015850:Interleukin-6; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma