A Pathophysiologic Role for T Lymphocytes in Murine Acute Cisplatin Nephrotoxicity

Abstract

Recent evidence supports a role for an inflammatory pathogenesis of cisplatin nephrotoxicity, but immune cell-mediated mechanisms in this disease are still largely unknown. The role for T lymphocytes on cisplatin-induced acute kidney injury was examined with C57BL/6 T cell-deficient (nu/nu) mice and CD4-or CD8-deficient mice and their wild-type (WT) littermates. All mice received a single dose of cisplatin at 40 mg/kg (intraperitoneally) and were followed up for 72 h. At 72 h after cisplatin administration, T cell-deficient mice had a marked attenuation in renal dysfunction (serum creatinine 3.2 ؎ 0.5 versus 0.8 ؎ 0.1 mg/dl; P ‫؍‬ 0.007), kidney tubular injury (scores 1.44 ؎ 0.15 versus 0.22 ؎ 0.08; P < 0.0001), and survival. Adoptive transfer of T cells into nu/nu mice followed by cisplatin enhanced renal dysfunction and tubular injury. The increase in renal myeloperoxidase activity after cisplatin administration was blunted in nu/nu mice. Renal TNF-␣, IL-1␤, and keratinocyte-derived chemokine protein expression was increased in WT mice but not in nu/nu mice after cisplatin administration. T cell levels significantly increased in kidneys of WT mice after cisplatin administration as early as at 1 h, peaked at 12 h, and declined by 24 h. CD4-and, to a lesser degree, CD8-deficient mice were relatively protected from cisplatin-induced mortality and renal dysfunction compared with WT mice. These data demonstrate that T lymphocytes are direct mediators of experimental cisplatin nephrotoxicity. Targeting T lymphocytes could lead to improved ways to administer cisplatin safely to cancer patients.

Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI

“…After intraperitoneal (ip) cisplatin injection, we noted infiltrating eGFP + T cells scattered throughout the renal parenchyma (Figure 1B) peaking at 12 hours, consistent with previous findings by Liu et al 11 We then tested whether abrogating AT 1 receptor signals selectively within T lymphocytes influences the development of cisplatin-induced AKI. Wildtype (WT) mice and mice genetically deficient of the dominant murine AT 1 receptor isoform (AT 1A ) solely within T cells (TKO; Supplemental Figure 1) had similar levels of BUN and serum creatinine (sCr) after saline treatment, indicating that the T cell AT 1 receptor does not affect baseline renal function ( Figure 1, C and D).…”

“…Although our findings confirm the importance of CD4 + T lymphocytes in mediating cisplatin-induced AKI, 11 these experiments are the first, to our knowledge, to document a protective effect of the T cell AT 1 receptor in the setting of AKI and highlight a potential danger of treating patients who require cisplatin chemotherapy with an ARB. Although we cannot exclude a TNFindependent contribution to the exaggerated renal injury in the TKOs, the actions of AT 1 receptors on T cells to limit TNF production are consistent with our previous findings in the setting of hypertensive kidney damage and can accrue from both an effect on T-betmediated T cell differentiation and a reduction in T cell-renal tubular cell interactions caused by effects of the T cell AT 1 receptor on chemokine generation.…”

Renal Dendritic Cells Ameliorate Nephrotoxic Acute Kidney Injury

“…Compelling evidence suggests that renal dysfunction in different forms of AKI is the outcome of secretion of immune mediators [5][6][7][8][9] and the activation of renal resident and recruited leukocytes 2,3,10,11 ; however, recent studies also suggested that certain cytokines 40 -43 and immune cells 23,44,45 may limit kidney injury by reducing the immune-mediated inflammatory response. 46 During renal injury, DCs are thought to contribute to renal inflammation and exacerbate kidney injury.…”

“…[1][2][3][4] The elaborated chemokines and cytokines, including TNF-␣, IL-18, keratinocyte-derived chemokine, and monocyte chemoattractant protein 1, subsequently recruit additional immune cells to the kidney, such as neutrophils, T cells, monocytes, and inflammatory dendritic cells (DCs), which may cause further injury through pathways that are not fully defined. 2,[5][6][7][8][9][10][11][12] DCs are sentinels of the immune system and under steady-state conditions induce tolerance by various mechanisms, including production of TGF-␤, IL-10, or indoleamine 2,3-dioxygenase [13][14][15][16] ; expression of PDL-1, PDL-2, or Fc␥R2B 17,18 ; clonal deletion of autoreactive T cells 19 ; and induction of T regulatory cells via the inducible co-stimulator (ICOS) pathway. 20 -23 In response to pathogens or products of tissue injury, DCs mature and initiate immunity or inflammatory diseases.…”

The pathological role of IL-18Rα in renal ischemia/reperfusion injury

“…Splenocytes that were collected from WT mice were minced on a nylon mesh as described. 23 Approximately 5 Â 10 6 spleen cells were injected intraperitoneally into each IL-18Ra-deficient mouse 3 weeks before the IRI. IL-18Ra-deficient mice (n ¼ 5), WT mice (n ¼ 6), and IL-18Ra-deficient mice that received a transfer of splenocytes (n ¼ 8) were culled on day 1.…”