IL-4 promotor gene polymorphism in heart transplantation

Abstract

IL-4 is a cytokine of the Th2 subtype, secreted mainly by activated T- lymphocytes. IL-4 acts by down regulation of Th1 responses of macrophage and Th1 cells. On the other hand, IL-4 stimulates growth and differentiation of Th2 lymphocytes and mast cells. In transplantation Th2 cells are believed to be involved in induction of graft tolerance. Previous studies revealed that patients with a high frequency of IL-4 producing precursor T- helper cells (pHTL) before heart transplantation (HTX) had no or less rejection episodes compared to patients with low frequency of IL-4 producing pHTL (van Hoffen et al., Transpl Int. 13,S216,2000). Recently, single nucleotide polymorphisms (SNP) in the promoter regions of various cytokine genes have been identified. These SNP influence promoter strength and hence production of the cytokine. The promoter region of the IL-4 gene contains three SNP at positions -590 (C>T), -285 (C>T) and -81 (A>G) from the transcriptional start site. Three polymorphic alleles (resp T, T and G) increase promoter strength. We hypothesize that presence of these polymorphic alleles decreases rejection by increasing IL-4 production. Seventy HTX patients and 61 donors were genotyped for all three SNP by sequencing. SNP at -285 and -81 were not polymorphic in this study. We found 66 % CC, 30% CT and 4% TT at position -590 in patients and 80% CC, 18% CT, 2%TT in donors. Our results show that the incidence of rejection is significantly lower in patients receiving the T-allele from their donor compared to patients who did not ( x2 = 4.52, p= 0.034, relative risk = 3.31), regardless of the patients own haplotype. This indicates that IL-4 production within the donor heart and by cells from that donor is important. Potential candidates for this IL-4 production are various stromal elements, but also interstitial mast cells may be responsible.