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Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine, which inhibits both development of Th1 and Th2 subsets and the Th1 proinflammatory response. TGF-beta1 production is influenced through several single nucleotide polymorphisms (SNP) in the structural gene and promoter region. Acute rejection of transplants depends on the Th1/Th2 balance within the graft, high levels of TGF-beta1 shift this balance towards Th2. We investigated whether genotypes of 4 SNP (-800 and -509 in the promoter region, codon 10 and codon 25 in the first exon) were correlated with cardiac disease or with incidence of rejection after heart transplantation (HTX). Genotypes were determined for 70 HTX patients and 61 donors by sequencing or oligonucleotide ligation assay. No association between SNP genotypes and heart disease or acute transplant rejection was observed. We conclude that genetic variation in the TGF-beta1 gene neither influences the existence of cardiomyopathy nor the incidence of rejection upon HTX.

Interleukin-4 (IL-4) is a cytokine of the Th2 subtype. It is suggested that Th2 cytokines are involved in induction of tolerance towards the graft after organ transplantation. Therefore, we studied the association between the frequencies of IL-4 producing helper T lymphocytes (IL-4 HTL) and acute rejection in a panel of 31 cardiac transplant patients. It was also investigated whether these frequencies were influenced by: (1) a single nucleotide polymorphism (SNP) at position -590 in the promoter region of the IL-4 gene, which influences the production level of IL-4; and (2) the expression of an IL-4 splice variant (IL-4delta2), which inhibits the IL-4 receptor. Frequencies of IL-4 HTL were determined by limiting dilution analysis. Genotyping for the SNP was carried out by sequencing. The ratio of wild type versus IL-4delta2 mRNA was determined by quantitative RT-PCR of mRNA isolated from stimulated MNC of cardiac transplant patients. Frequencies of IL-4 HTL were significantly higher in patients who did not suffer from acute cardiac transplant rejection, than in patients that suffered from at least one rejection episode requiring treatment in the first year after heart transplantation. The genotype of the promoter SNP and the ratio between wild type/splice variant IL-4 mRNA did not influence the measured frequencies of IL-4 HTL or the presence of transplant rejection itself.

Background: The cytokine interleukin-4 (IL-4) is secreted mainly by activated T lymphocytes and characterizes the T-helper 2 (Th2) sub-type. In transplantation Th2 cells are believed to induce graft tolerance. Previous studies revealed that patients with a relatively high frequency of IL-4 producing helper T lymphocytes (HTL) before heart transplantation (HTX) had no or less rejection episodes compared with patients with a low frequency of IL-4 producing HTL. Three single nucleotide polymorphisms (SNPs) have been identified in the promoter region of the IL-4 gene, which influence promoter strength. We investigated whether there was a correlation between SNP genotypes in the IL-4 promoter and heart failure, and rejection after HTX., Methods: Seventy HTX patients, 61 donors, and 36 controls were genotyped for the 3 SNPs by sequencing., Results: Of the SNPs at -285 and -81, only the C and A alleles, respectively, were found in this study. Both alleles were found for the -590 SNP. No relation between patient genotype of the SNP at -590 and heart failure and rejection was found. However, incidence of rejection was significantly lower in patients that received a donor heart with the T-positive genotype compared with patients that received a heart from a T-negative donor. Patients who had the T-negative genotype and received a heart from a T-positive donor, suffered significantly less from rejection than T-negative patients that received a T-negative donor heart. This was not significant in the T-positive patient group., Conclusions: This indicates that IL-4 production within the donor heart and by cells from the donor is important for reducing incidence of episodes of rejection.

Expression of interleukin (IL)-10 influences the frequency of rejection events after organ transplantation. Therefore, 70 heart transplant patients were genotyped for three single nucleotide polymorphisms and a microsatellite polymorphism in the promotor region of the IL-10 gene. The promoter region was amplified by polymerase chain reaction and genotyped by a colorometric oligo ligation assay and gene scan analysis, respectively. Patient groups consisted of patients suffering from dilated cardiomyopathy or ischaemic heart disease. Cardiac donors served as control group. No correlation was found between genotypes and heart failure or rejection after heart transplantation. This may indicate that in heart transplantation, the total balance of cytokine production is more important for post-transplant rejection activities than the levels of IL-10 as such.