The nature of acute rejection is associated with development of graft vascular disease after clinical heart transplantation.
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.
Baan
C C
CC
Department of Internal Medicine 1, University Hospital Rotterdam-Dijkzigt, Rotterdam, The Netherlands. baan@inw1.azr.nl
Holweg
C T
CT
Niesters
H G
HG
van Gelder
T
T
Mol
W M
WM
Zondervan
P E
PE
Mochtar
B
B
Balk
A H
AH
Weimar
W
W
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
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