Mechanisms of Glucocorticoids in the modulation of Graft-versus-Host Disease and the Graft-versus-Leukemia Reaction

Abstract

Acute graft-versus-host disease (aGvHD) is a severe complication that frequently occurs after allogeneic hematopoietic stem cell transplantation and results in a high transplant-related morbidity and mortality. Glucocorticoids (GCs) are widely used to treat aGvHD but some patients are refractory to this therapy. Importantly, the mechanisms of GC-resistance remain partially unclear. In our study, we used an aGvHD mouse model based on the transplantation of allogeneic GC-resistant donor T cells derived from cell type-specific GC receptor (GR) knock-out mice. We found that mice transferred with GC-resistant T cells developed a more severe aGvHD than those receiving GC-responsive T cells. We then analyzed the expression of 54 candidate genes in the first full-blown phase of the disease in the inflamed small intestine, an organ that is strongly affected by aGvHD, by using a high-throughput gene chip technology, and found that the majority of genes were significantly up-regulated in mice transplanted with GC-resistant T cells. In addition, we performed RNA-sequencing to identify further GC target genes in the small intestine, and confirmed differential expression of 26 of them by using high-throughput quantitative RT-PCR. Our findings revealed an altered gene expression profile caused by GC-resistance of transplanted allogeneic T cells in aGvHD, which might be helpful to derive biomarkers or develop new therapeutic concepts. Since GCs not only improve aGvHD but also compromise the beneficial graft-versus-lymphoma (GvL) reaction of the allogenic donor T cells, we also explored whether a specific delivery of GCs may retain the GvL activity but still suppress aGvHD. In our study, we used a nanosized formulation of GCs (BMP-NPs), which are encapsulated in inorganic-organic hybrid nanoparticles that are preferentially taken up by macrophages, to treat mice in a combined aGvHD/GvL mouse model. By detecting the abundance of Bcl1 lymphoma cells in the blood, we found that treatment with BMP-NPs delayed the development of an adoptively transferred lymphoma better than free GCs in our disease model, suggesting that BMP-BPs reduce aGvHD in mice and partially retain the GvL effect. Collectively, this work provides new insights into how treatment of aGvHD, in particular with GCs, could be improved in the future.