Donor -173 G/C Polymorphism of Macrophage Migration Inhibitory Factor Gene Is Associated with the Development of Chronic Graft Versus Host Disease.
Authors: Chang Yayi , Holler Ernst , Bremm Heike , Greinix Hildegard T. , Andreesen Reinhard , Hildebrandt Gerhard 
Published: October 2019

Abstract
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<0.001). However no association between the onset of aGVHD and the G/C polymorphism of either the donor or the recipient was seen. Collectively, our data show, that the risk of developing cGVHD is increased after allo-SCT, when the donor but not the recipient has a G to C transition at position −173 of the MIF gene. Most likely, donor T cells are critical, as this observation vanishes when TCD is performed. Interestingly, carrying the C allele is not a risk factor for aGVHD development, therefore demonstrating a heretofore unknown distinct and independent property of donor T cells in the pathophysiology of cGVHD. Animal studies targeting MIF signaling are ongoing, and in future this may prove as a beneficial and promising approach to decrease the incidence and severity of this serious complication after allo-SCT.