CD4 T cell knockout does not protect against kidney injury and worsens cancer
2016
Most previous studies of
cisplatin-induced acute kidney injury (AKI) have been in models of acute, high-dose
cisplatinadministration that leads to mortality in non-tumor-bearing mice. The aim of the study was to determine whether CD4 T cell knockout protects against AKI and cancer in a clinically relevant model of low-dose
cisplatin-induced AKI in mice with cancer. Kidney function, serum
neutrophil gelatinase-associated lipocalin(NGAL),
acute tubular necrosis(ATN), and tubular apoptosis score were the same in wild-type and CD4 -/- mice with AKI. The lack of protection against AKI in CD4 -/- mice was associated with an increase in extracellular signal-regulated kinase (ERK), p38,
CXCL1, and TNF-α, mediators of AKI and fibrosis, in both
cisplatin-treated CD4 -/- mice and wild-type mice. The lack of protection was independent of the presence of cancer or not. Tumor size was double, and
cisplatinhad an impaired therapeutic effect on the tumors in CD4 -/- vs. wild-type mice. Mice depleted of CD4 T cells using the GK1.5 antibody were not protected against AKI and had larger tumors and lesser response to
cisplatin. In summary, in a clinically relevant model of
cisplatin-induced AKI in mice with cancer, (1) CD4 -/- mice were not protected against AKI; (2) ERK, p38,
CXCL1, and TNF-α, known mediators of AKI, and interstitial fibrosis were increased in CD4 -/- kidneys; and (3) CD4 -/- mice had faster tumor growth and an impaired therapeutic effect of
cisplatinon the tumors. The data warns against the use of CD4 T cell inhibition to attenuate
cisplatin-induced AKI in patients with cancer.A clinically relevant low-dose
cisplatinmodel of AKI in mice with cancer was used. CD4 -/- mice were not functionally or histologically protected against AKI. CD4 -/- mice had faster tumor growth. CD4 -/- mice had an impaired therapeutic effect of
cisplatinon the tumors. Mice depleted of CD4 T cells were not protected against AKI and had larger tumors.
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