THE NATURE OF ACUTE REJECTION IS ASSOCIATED WITH DEVELOPMENT OF GRAFTVASCULAR-DISEASE AFTER CLINICAL HEART-TRANSPLANTATION

Background: To determine mechanisms that trigger graft vascular diseas e (GVD) after heart transplantation, we studied parameters that reflec t both early and late intragraft allogeneic reactions. Method: With re verse transcriptase-polymerase chain reaction analysis, mRNA expressio n of interleukin-2 (IL-2), interleukin-4, interleukin-6, interleukin-1 0, interferon-gamma, platelet-derived growth factor-alpha, and transfo rming growth factor-beta was measured in endomyocardial biopsy (EMB) s pecimens obtained from 34 recipients during the first acute rejection episode (n = 29) or at a comparable time after transplantation for pat ients without rejection (n = 5) and at time of assessment of GVD by co ronary angiography at 1 year (n = 34). Results: At the time of assessm ent 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, in tragraft mRNA patterns of cytokines and growth factors between patient s with GVD (n = 17) or without GVD (n = 17) were comparable. In contra st, during the first acute rejection episode a completely different pa ttern was found. Development of GVD was associated with IL-2 mRNA expr ession and not with the other cytokines analyzed. IL-2 mRNA was presen t in 77% of rejection EMB specimens obtained from patients with GVD ve rsus 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 (med ian 32 vs 23 years; p = 0.02) were associated with GVD. But no relatio n was found between these nonimmunologic risk factors and IL-2-positiv e acute rejections.Conclusions: Nonspecific risk factors and IL-2-posi tive rejections may independently trigger GVD after clinical heart tra nsplantation.