Allogenic Donor T Cells Causes Renal Injury in Murine Models of Allogenic Hematopoietic Cell Transplantation

Acute kidney injury (AKI) is a frequent complication of allogeneic hematopoietic cell transplantation (allo-HCT) that has many possible etiologies. One potential etiology is direct allogeneic donor T cell-mediated renal damage. However, the kidney is not considered a main target organ of allogeneic T cell-mediated acute graft-versus-host disease (aGVHD). Here, we tested whether allogeneic donor T cells directly damage renal tissue in murine models of allo-HCT.We tested this in an MHC-mismatched model. BALB/c recipients were lethally irradiated and transplanted with 5 × 106bone marrow (BM) and 0.5 × 106 CD90.2+ splenic T cells from either syngeneic BALB/c or allogeneic MHC-mismatched C57BL/6 (B6) donors. To avoid potential confounding nephrotoxic effects, calcineurin inhibitor aGVHD prophylaxis was not used. Urinary N-acetyl-β-D-glucosaminidase (NAG), a marker of tubular injury, was elevated in allogeneic recipients on day 14 after allo-HCT. Similar results were obtained using an MHC-haploidentical B6 into B6D2F1 model. Renal histopathology demonstrated peritubular vasculitis and infiltration of donor-derived CD3+ T cells in the kidney. To rule out radiation- mediated nephrotoxicity, we performed allo-HCT with a reduced radiation dose (4 Gy). Despite the reduced dose, greater donor T cell infiltration and renal damage on histopathologic analysis persited in allogeneic relative to syngeneic recipients. These data suggested that donor T cells infiltrated renal tissue and potentially aggravated any underlying dose-dependent radiation-mediated nephrotoxicity.Next, we characterized the kidney-infiltrating T cells. Both donor-derived CD4+ and CD8+ T cells were significantly increased in the allogeneic group. These kidney-infiltrating donor T cells were activated and produced inflammatory cytokines and cytotoxic proteins. Neutrophil gelatinase-associated lipocalin (NGAL), a marker of acute kidney injury, and Elafin, a marker of cutaneous GVHD, were increased in renal tissue of allogeneic recipients. Renal damage caused by alloreactive T cells persisted at late time points after allo-HCT. These data suggested that activated, cytotoxic, donor derived allogeneic T cells likely mediated kidney damage throughout the disease course.Apoptotic target cells are frequently observed in aGVHD target tissues. Using in vitro cytotoxic T lymphocyte assays, we confirmed that alloreactive T cells increased apoptosis (TUNEL-positive) of renal endothelial and tubular epithelial cells. Thus, allogeneic T cells were capable of directly damaging renal cells.Collectively, our data suggest that donor T cells contribute to renal injury and that aGVHD may contribute to AKI following allo-HCT. More research is needed to elucidate kidney-intrinsic mechanisms of aGVHD, which may lead to improved strategies for reducing renal dysfunction following allo-HCT.