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.
Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 965, Baltimore, MD 21205, USA.
Manchang
M
Liu
Chu-Chun
CC
Chien
Melissa
M
Burne-Taney
Roshni R
RR
Molls
Lorraine C
LC
Racusen
Robert B
RB
Colvin
Hamid
H
Rabb
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