Cytokine gene polymorphisms and acute human liver graft rejection

Michiel C. Warlé, Ayar Farhan, Herold J. Metselaar, Wim C.J. Hop, Chris Perrey, Marcel Kap, Sjoerd De Rave, Jaap Kwekkeboom, Pieter E. Zondervan, Jan N.M. Ijzermans, Hugo W. Tilanus, Vera Pravica, Ian V. Hutchinson, Gerda J. Bouma*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Between individuals differences exist in the capacity to produce cytokines. It has been reported that levels of in vitro cytokine production measured after stimulated cell culture are associated with polymorphisms in cytokine genes. Moreover, a correlation between heart, kidney and liver graft rejection with cytokine gene polymorphisms of TNF-alpha and EL-10, and of TGF-beta with lung graft survival has been described. In the present study we analyzed the contribution of the TH1 and the TH2 arms of the immune response, in terms of gene polymorphisms in TH1 and TH2 type and regulatory cytokines on human liver allograft rejection. Patients who received a primary liver graft between 1992 and 1999 and who were seen at the transplant outpatient clinic since then, were included in this study (n=89). Patients and liver donors were HLA-typed routinely. Biopsy- proven rejection within one month after liver transplantation and treated with high dose prednisolone, occurred in 41 of the patients, whereas 48 patients never experienced rejection. After informed consent blood was collected and DNA was obtained. DNA was amplified by specific PCR and the following cytokine gene polymorphisms were determined by sequence-specific oligonucleotide probing: IL-2+166, EL-2-330, IL-15+13689, IL-15-80, TNFA-308, TNFd3, IFNG+874 (TH1 type cytokines), IL-4+33, IL-4-590, IL-6-174, IL-10-819, IL-10-1082, IL-13+2043, IL-13-1055 (TH2 type cytokines) and TGFB10 and TGFB25 (regulatory cytokines). Univariate analysis showed that IL-10-1082, IL-13+2043, TGFB10 and HLA-DR6 were significantly correlated to liver graft rejection. Using multiple logistic regression analysis the variables most predictive for acute rejection were determined. The multivariate analysis revealed that TGFB10 and HLA-DR6 contributed significantly to the occurrence of rejection. These findings suggest a role for TH2 type, as well as regulatory cytokines in human liver graft rejection.

Original languageEnglish
Pages (from-to)204
Number of pages1
JournalEuropean Journal of Immunogenetics
Issue number2
Publication statusPublished - 20 Dec 2001


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