A pathophysiologic role for T lymphocytes in murine acute cisplatin nephrotoxicity.
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-alpha, IL-1beta, 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.
Liu
Manchang
M
Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 965, Baltimore, MD 21205, USA.
Chien
Chu-Chun
CC
Burne-Taney
Melissa
M
Molls
Roshni R
RR
Racusen
Lorraine C
LC
Colvin
Robert B
RB
Rabb
Hamid
H
D019264:Adoptive Transfer; D000818:Animals; D001707:Biopsy, Needle; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000378:metabolism; D007677:Kidney Function Tests; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D013045:Species Specificity; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
D015704:CD4 Antigens; D016827:CD8 Antigens; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D002945:Cisplatin