Stress responses, M2 macrophages, and a distinct microbial signature in fatal intestinal acute graft-versus-host disease

摘要: Steroid-refractory intestinal acute graft-versus-host disease (aGVHD) is a frequently fatal condition with little known about mechanisms driving failed steroid responses in gut mucosa. To uncover novel molecular insights steroid-refractory aGVHD, we compared gene expression profiles of rectosigmoid biopsies from patients at diagnosis clinical stage 3-4 lower aGVHD (N=22), to repeat when the became refractory and normal controls (N=10). We also performed single analyses factors associated tolerance (programmed death ligand-1 [PDL1], indoleamine 2,3 dioxygenase [IDO1], T cell immunoreceptor Ig ITIM domains [TIGIT]) found that significantly higher levels these inhibitory genes (PDL1, IDO1, TIGIT) onset decreased state. examined triggered by microbial ligands stimulate repair, amphiregulin (AREG) aryl hydrocarbon receptor (AhR), both AREG AhR were increased remained elevated aGVHD. identified metallothioneines, metal-binding enzymes induced stress responses, M2 macrophage observed no differences T-cell subsets between Patients rapidly course showed greater DNA damage distinct signature onset, whereas more prolonged survival exhibited profile consistent activation Smoothened. Our results extend paradigm beyond cell-centric therapies for GI highlight new therapeutic exploration.