ALBERT

Description: Chronic graft versus host disease (cGVHD) severely impairs the clinical outcome and quality of life after allogeneic stem cell transplantation (allo-SCT). cGVHD pathophysiology is not fully understood, and treatment often fails. The cytokine macrophage migration inhibitory factor (MIF) is produced by various cell types including T cells, macrophages, epithelial cells and the pituitary gland. It shows a broad range of immunostimulatory and proinflammatory properties. In addition, MIF overrides the inhibitory immunological effects of glucocorticoids, which are an important therapeutic tool both in acute GVHD (aGVHD) and cGVHD. As MIF has been associated with various inflammatory diseases, which pathophysiologically share similarities to cGVHD, we assessed the possible contribution of the −173 G/C polymorphism of the MIF gene in cGVHD development. The presence of the C allele is known to be associated with increased cellular MIF production and elevated serum MIF levels in the context of inflammation, but not in healthy individuals. We genotyped 332 donor-recipient pairs of patients receiving allo-SCT from related (n=115) or unrelated (n=217) donors at two independent SCT centers. Stem cells were derived from bone marrow (n=120) or from peripheral blood stem cells (n=222) and T cell depletion (TCD) was performed in 106 cases. Mean follow up was 654±687 days. The C allele (GC or CC genotype) was present in 27.2% of recipients and 25.7% of donors. Overall, 41.8% of transplanted patients developed cGVHD. The incidence of cGVHD development rose from 39.5% in donor/recipient pairs both carrying the GG genotype to 52.2% in those pairs, in which donors carried the GC or CC genotype (p=0.046). Presence of the C allele in the recipient did not significantly contribute to cGVHD development (p=0.26). As T cells are a major source of MIF and have been associated with cGVHD, we next tested the impact of donor T cells carrying the C allele in the context of TCD. As expected, cGVHD incidence was significantly increased in patients receiving non-TCD allo-SCT from GC or CC donors compared to recipients of GG genotype cells (55.1% versus 38.2%; p=0.045). In contrast, when TCD was performed, transplantation of either cells with the C allele or with GG donor cells did not result in differences in cGVHD (44.4% versus 38.0%; p=0.78). Finally we analyzed, whether this polymorphism has any effects on the development of aGVHD. In total, 52.6% of patients developed aGVHD 〉/= 2, and the incidence of aGVHD was directly associated with the development of cGVHD (p

Description: Genetic polymorphisms of various donor and host genes have been found to be associated risk factors for graft versus host disease and transplant related mortality. Most of these genes are involved in the regulation of immune response and inflammatory reactions towards pathogens. The heme oxygenase (HO) protein is the rate limiting enzyme in heme degradation to biliverdin, free iron and carbon monoxide. Its inducible form I (HO-I) is constitutively expressed in the spleen due to the abundance of its substrate. It is inducible in a wide range of tissues upon exposure to cellular stress factors such as irradiation, bacterial lipopolysaccharide, proinflammatory cytokines and heat shock. Further, HO-I is involved in regulating inflammatory response and has been described as a “protective gene” in solid organ transplantation. In man the promoter region of HO-I displays length polymorphism due to a variable number of gt repeats within a 500bp region upstream of the TATA box. Individuals exhibiting 25 or less gt repeats express HO-I upon cellular stress at a higher level than individuals with more than 30 gt repeats. We retrospectively analysed length polymorphisms of 92 donor and host pairs undergoing allogeneic stem cell transplantation for various malignancies. We show here that donor promoter length polymorphism leading to low expression of HO-1 (〉30 gt repeats) is associated with improved overall survival, relative to donors with ≤ 30 repeats (80.6% versus 54.4%, p=0.023). When subgrouped, having HLA identical siblings as donors had no influence on outcome (see figure below, right panel) whereas having matched unrelated donors strongly influenced overall survival (82.6 vs. 44.2%, p=0.015). Combination of high HO-1 expressing unrelated donors and high expressing hosts displayed a 27.8% survival (left panel, solid line vs.81.3% for individuals with one allele 〉30 repeats dotted line). Polymorphisms of the recipient HO-1 genes did not influence outcome after transplantation. When matched unrelated donors were used, the incidence of grade III gut GvHD was significantly higher when (p=0.032) and overall GvHD (≥ grade III) displayed a trend towards significance (p=0.098). Transplant related mortality was strongly influenced by having a donor who expresses HO-1 at a high level upon cellular stress (p=0.006). In a multivariate Cox regression analysis of pretransplant factors such as age, disease stage, sibling/unrelated donor etc. polymorphism in the donor HO-1 gene had a significant influence on overall survival (p=0.027). These data suggest a role for HO-I in GvHD pathophysiology and a possible role for HO-1 as a non MHC risk factor for unrelated transplantation. Figure Figure