Die Rolle von Zytokin- und Zytokinrezeptorgenvariationen für die Ausprägung von GvHD und GvL nach allogener Blutstammzelltransplantation bei Patienten mit hämatologischer Neoplasie

Abstract

Many publications show the influence of cytokine-gene-variations on the development of Graft versus Host disease. I studied the influence of cytokine-gene- and cytokine-receptor-gene-variations of the IL 10 gene on the occurrence of Graft versus Host disease (GvHD) and the overall survival after allogeneic stem cell transplantation in patients with hemic diseases. GvHD is still a feared complication after stem cell transplantation. It can occur within 100 days (acute GvHD) or later on (chronic GvHD). It is not well understood why some patients develop a severe GvHD and possibly die from it while others only develop a mild GvHD that even helps to fight the cancer cells through the Graft versus leukemia effect. Interleukin 10 plays an important role in the pathophysiology of GvHD because of its anti-inflammatory function. For this analysis we included the GvHD-relevant clinical data of 360 Patients that received allogeneic stem cell transplantation in Göttingen between the years of 2001 and 2011. Genotyping of different single nucleotide polymorphisms of the IL 10 gene was done through SNaPshot analysis and TaqMan Genotyping Assays. The Analysis of the clinical, together with the SNP-data was done through univariate followed by multivariate regression analysis. One of the already known SNPs of the IL 10 gene that decreases the risk for a severe acute GvHD is SNP IL10-597 allele A in the patient even more so in combination with the receptor beta K47E allele G in the donor. We couldn’t show this protective effect within our collective. But contrary to the studies of Hansen at al that used only data from MRD transplanted patients, we based our analysis on mixed data from matched related and matched unrelated transplantations. The homozygote genotype GG of SNP IL 10-1087 showed an increased risk for the development of an extensive chronic disease in our data. This genotype is associated with high levels of IL 10. One SNP that was never studied before is the IL 10 receptor alpha G351R. We showed an increased risk for a severe GvHD for patients with a homozygote donor for G351R AA . This risk was increased even further for patients who received ATG before the transplantation. This receptor has not been studied before so it is not known how this receptor works. It is important to study the receptor alpha G351R further in independent bigger collectives. Also it is important to study other cytokines and their influence on the occurrence of a severe GvHD so that it may be possible to some day judge the patients risk for allogeneic stem cell transplantation by their genetic profile.