Allogeneic T cells cause acute renal injury after hematopoietic cell transplantation

• Published in: Blood advances Vol. 7; no. 22; pp. 6936 - 6948
• Main Authors: Miyata, Masahiro, Matsuki, Eri, Ichikawa, Kazunobu, Takehara, Tomohiro, Hosokawa, Yuka, Sekiguchi, Erika, Peltier, Daniel, Reddy, Pavan, Ishizawa, Kenichi, Watanabe, Masafumi, Toubai, Tomomi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.11.2023
• Subjects: acute graft-versus-host disease; acute kidney injury; Acute Kidney Injury - etiology; allogeneic hematopoietic cell transplantation; Animals; Bone Marrow Transplantation - adverse effects; donor-derived T cells; Graft vs Host Disease - prevention & control; Hematopoietic Stem Cell Transplantation - adverse effects; Mice; Transplantation, Homologous - adverse effects; acute graft-versus-host disease; acute kidney injury; donor-derived T cells; allogeneic hematopoietic cell transplantation
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2023009721

•Donor-derived T cells are increased and activated in the kidney after allogeneic hematopoietic cell transplantation (allo-HCT).•Allogeneic immune responses induced by donor T cells contribute to renal endothelial and tubular epithelial cell damage following allo-HCT. 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-β-D-glucosaminidase (NAG), a marker of tubular injury, was elevated in allogeneic recipients on day 14 after allo-BMT. Donor MHC-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 (NGAL), a marker of acute kidney injury, 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 (CTL) 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 following allo-HCT.