title: CD4 T cell knockout does not protect against kidney injury and worsens cancer.
abstract: Most previous studies of cisplatin-induced acute kidney injury (AKI) have been in models of acute, high-dose cisplatin administration 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 cisplatin had 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 cisplatin on the tumors. The data warns against the use of CD4 T cell inhibition to attenuate cisplatin-induced AKI in patients with cancer.
  
  
  CONCLUSIONS
  A clinically relevant low-dose cisplatin model 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 cisplatin on the tumors. Mice depleted of CD4 T cells were not protected against AKI and had larger tumors.
authors.affiliation: Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Box C281, 12700 East, 19 th Ave, Aurora, CO, 80045, USA.
authors.forename: Kameswaran
authors.initials: K
authors.lastname: Ravichandran
authors.affiliation: Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Box C281, 12700 East, 19 th Ave, Aurora, CO, 80045, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Box C281, 12700 East, 19 th Ave, Aurora, CO, 80045, USA.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Ozkok
authors.affiliation: Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Box C281, 12700 East, 19 th Ave, Aurora, CO, 80045, USA.
authors.forename: Alkesh
authors.initials: A
authors.lastname: Jani
authors.affiliation: Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Box C281, 12700 East, 19 th Ave, Aurora, CO, 80045, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Box C281, 12700 East, 19 th Ave, Aurora, CO, 80045, USA.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: He
authors.affiliation: University Hospital Dubrava, Zagreb, Croatia.
authors.forename: Danica
authors.initials: D
authors.lastname: Ljubanovic
authors.affiliation: Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Box C281, 12700 East, 19 th Ave, Aurora, CO, 80045, USA.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Weiser-Evans
authors.affiliation: Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Box C281, 12700 East, 19 th Ave, Aurora, CO, 80045, USA.
authors.forename: Raphael A
authors.initials: RA
authors.lastname: Nemenoff
authors.affiliation: Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Box C281, 12700 East, 19 th Ave, Aurora, CO, 80045, USA. Charles.edelstein@ucdenver.edu.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Edelstein
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002945:Cisplatin / Q000009:adverse effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055786:Gene Knockout Techniques; D006720:Homozygote; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007677:Kidney Function Tests; D008212:Lymphocyte Depletion / Q000379:methods; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D047368:Tumor Burden; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016207:Cytokines; D009195:Peroxidase; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D002945:Cisplatin
keywords: CD4 T cell; Cancer; Kidney