title: Intragraft IL-4 mRNA expression is associated with down-regulation of liver graft rejection.
abstract: The mechanism underlying spontaneously resolving allograft rejection following clinical liver transplantation is unidentified. In this process, immunoregulatory T helper (Th)-2 cytokines like IL-4, often identified with down-regulation of the Th1-dependent (IL-2) cell-mediated response, might play a significant but unknown role. For this reason, we analyzed mRNA expression by reverse transcriptase-polymerase chain reaction (RT-PCR) in 57 biopsies derived from 19 recipients. Specimens included biopsies without evidence of rejection (n = 36), biopsies with histological evidence of rejection (n = 10) not followed by clinical signs of graft rejection, and biopsies with histological rejection that were 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 resolving rejections. In 70% (7/10) of these biopsies, IL-4 mRNA was detectable, 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 biopsies concurrent with graft dysfunction expressed the IL-4 gene (p = 0.03). In contrast, IL-2 mRNA expression was not detectable in biopsies derived from the spontaneously resolving rejections. None (0/10) of these samples expressed the IL-2 gene, which was not significantly different from the proportion of biopsies transcribing the IL-2 gene in the absence of rejection (11%, 4/36). IL-2 mRNA expression was found more often in biopsies associated with graft dysfunction (36%, 4/11). These results show that IL-4, in contrast to IL-2 mRNA expression, is associated with spontaneously resolving liver rejection. This suggests that Th2 cells down-regulate the Th1-dependent cell-mediated immune response after clinical liver transplantation.
authors.affiliation: Department of Internal Medicine, University Hospital Rotterdam-Dijkzigt, The Netherlands.
authors.forename: C C
authors.initials: CC
authors.lastname: Baan
authors.forename: H J
authors.initials: HJ
authors.lastname: Metselaar
authors.forename: W M
authors.initials: WM
authors.lastname: Mol
authors.forename: H W
authors.initials: HW
authors.lastname: Tilanus
authors.forename: J M
authors.initials: JM
authors.lastname: IJermans
authors.forename: P E
authors.initials: PE
authors.lastname: Zondervan
authors.forename: S W
authors.initials: SW
authors.lastname: Schalm
authors.forename: H G
authors.initials: HG
authors.lastname: Niesters
authors.forename: W
authors.initials: W
authors.lastname: Weimar
mesh_terms: D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D001706:Biopsy; D015139:Blotting, Southern; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000097:blood / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics* / Q000276:immunology; D016031:Liver Transplantation / Q000276:immunology* / Q000473:pathology; D008297:Male; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics* / Q000276:immunology; D012075:Remission, Spontaneous; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014158:Transcription, Genetic; D014184:Transplantation, Homologous
chemical_list: D007376:Interleukin-2; D012333:RNA, Messenger; D015847:Interleukin-4; D001219:Aspartate Aminotransferases; D001663:Bilirubin