INTRAGRAFT IL-4 MESSENGER-RNA EXPRESSION IS ASSOCIATED WITH DOWN-REGULATION OF LIVER GRAFT-REJECTION

The mechanism underlying spontaneously resolving allograft rejection f ollowing clinical liver transplantation is unidentified. In this proce ss, immunoregulatory T helper (Th)-2 cytokines like IL-4, often identi fied with down-regulation of the Th1-dependent (IL-2) cell-mediated re sponse, might play a significant but unknown role. For this reason, we analyzed mRNA expression by reverse transcriptase-polymerase chain re action (RT-PCR) in 57 biopsies derived from 19 recipients. Specimens i ncluded biopsies without evidence of rejection (n=36), biopsies with h istological evidence of rejection (n=10) not followed by clinical sign s of graft rejection, and biopsies with histological rejection that we re accompanied with clinical rejection (n=11), defined by rising serum bilirubin and aspartate amino transaminase (ASAT) levels. Intragraft IL-4 mRNA expression significantly correlated with spontaneously resol ving rejections. In 70% (7/10) of these biopsies, IL-4 mRNA was detect able, while only 19% (7/36) of the biopsies without signs of rejection (p<0.01; Fisher's exact test) and 18% (2/11) of the rejection biopsie s concurrent with graft dysfunction expressed the IL-4 gene (p=0.03). In contrast, IL-2 mRNA expression was not detectable in biopsies deriv ed from the spontaneously resolving rejections. None (0/10) of these s amples expressed the IL-2 gene, which was not significantly different from the proportion of biopsies transcribing the IL-2 gene in the abse nce of rejection (11%, 4/36). IL-2 mRNA expression was found more ofte n in biopsies associated with graft dysfunction (36%, 4/11). These res ults show that IL-4, in contrast to IL-2 mRNA expression, is associate d with spontaneously resolving liver rejection. This suggests that Th2 cells down-regulate the Th1-dependent cell-mediated immune response a fter clinical liver transplantation.