Allogeneic T cells cause acute renal injury after hematopoietic cell transplantation.

Acute kidney injury (AKI) is a frequent complication of allogeneic hematopoietic cell transplantation (allo-HCT). There are many causes of AKI after allo-HCT, but it is unknown whether renal acute graft-versus-host disease (aGVHD) caused by direct allogeneic donor T-cell-mediated renal damage contributes. Here, we tested whether allogeneic donor T cells attack kidneys in murine models of aGVHD. To avoid confounding effects of nephrotoxic agents, we did not administer immunosuppressants for GVHD prophylaxis. We found that urinary N-acetyl-ß-D-glucosaminidase, a marker of tubular injury, was elevated in allogeneic recipients on day 14 after allogeneic bone marrow transplantation. Donor major histocompatibility complex-positive cells were present and CD3+ T cells were increased in the glomerulus, peritubular capillaries, interstitium, and perivascular areas in the kidneys of allo-HCT recipient mice. These T cells included both CD4+ and CD8+ cells with elevated activation markers, increased exhaustion markers, and greater secretion of proinflammatory cytokines and cytotoxic proteins. Consistent with allo-T-cell-mediated renal damage, expression of neutrophil gelatinase-binding lipocalin, a marker of AKI, and elafin, a marker of aGVHD, were increased in renal tissue of allogeneic recipients. Because apoptosis of target cells is observed on histopathology of aGVHD target tissues, we confirmed that alloreactive T cells increased apoptosis of renal endothelial and tubular epithelial cells in cytotoxic T-lymphocyte assays. These data suggest that immune responses induced by donor T cells contribute to renal endothelial and tubular epithelial cell injury in allo-HCT recipients and that aGVHD may contribute to AKI after allo-HCT.

[Fecal metabolomic profiles in experimental murine bone marrow transplantation].

Graft-versus-host disease (GVHD) is a life-threating complication of allogeneic hematopoietic cell transplantation (allo-HCT). Prior studies have shown that gastrointestinal (GI) GVHD is associated with a reduction in intestinal microbiota diversity and a change in microbial metabolites. We conducted fecal metabolome analyses using a murine bone marrow transplantation. From this analysis, 290 metabolites were identified; of these, 18 metabolites were significantly or specifically higher and 12 were significantly or specifically lower in the allogeneic group than in the syngeneic one. Particularly, several metabolites in the choline metabolism and tryptophan metabolism were altered in the allogeneic group. Hierarchical clustering analysis demonstrated that the changed metabolites in the allogeneic group had similar profiles. Conclusively, we suggest that alloimmune responses are related to microbial metabolites in recipients receiving allo-HCT. The relationship between metabolites involved in GI GVHD and the intestinal microbiota and its physiological significance warrant further investigations.