CD4+CD25+ regulatory T cells attenuate cisplatin-induced nephrotoxicity in mice

Abstract

Nephrotoxicity limits the use of cisplatin, a widely used chemotherapeutic agent for treatment of various malignancies. Overall, CD4+ T cells mediate cisplatin-induced renal injury; however, the CD4+CD25+ regulatory T-cell subset (CD4+CD25+ Treg) has broad suppressive effects on many different cell types. In this study, we determined whether CD4+CD25+ Treg cells had protective effects against cisplatin-induced acute renal injury in nu/nu mice that lack mature T cells. In these mice, there was marked attenuation of the decreased survival, renal dysfunction and tubular injury, renal tumor necrosis factor-α, and interleukin-1β cytokine levels. Furthermore, renal macrophage accumulation was reduced in CD4+CD25+ Treg cell-adoptive transferred nu/nu mice compared with control mice. Infusion of CD4+CD25+Treg cells into wild-type Balb/c mice reduced serum blood urea nitrogen and creatinine levels equivalent to those in nu/nu mice and extended their survival time after cisplatin injection. In contrast, depletion of CD4+CD25+ Treg cells in wild-type mice exacerbated kidney injury after cisplatin administration. Transcription factor Foxp3-positive cells (Treg cells) were detected in the kidneys of nu/nu mice after cisplatin injection. Our results suggest that CD4+CD25+ Treg cells directly affect cisplatin nephrotoxicity and their modulation represents an additional treatment strategy.

Pathogenic and protective role of macrophages in kidney disease

“…Treatment of peritoneal M⌽ with cisplatin in vitro induced nitric oxide, pro-inflammatory cytokines, and activation of NF-B (9,81). Several recent studies showed a positive correlation between interstitial M⌽ number and degree of kidney injury in cisplatin nephrotoxicity, suggesting a pathogenic role of kidney M⌽ (37,47,49,72). Ramesh found that cisplatin activates p38 MAPK, which leads to increased production of TNF-␣ in M⌽.…”

Endogenous Toll-Like Receptor 9 Regulates AKI by Promoting Regulatory T Cell Recruitment

“…Evidence also indicates that Tregs play protective roles in this model, via inhibitory effects on innate immune cells. 15 Therefore, we examined Treg recruitment in WT and Tlr9 2/2 mice. Twenty-four hours after cisplatin administration, the proportion of renal CD4 + CD25…”

“…Despite the innate nature of this model, Tregs have been found to limit inflammation and injury in cisplatin-induced AKI. 14,15 To investigate the role of TLR9 in AKI, we administered cisplatin to C57BL/6 wild-type (WT) and Tlr9 2/2 mice. After 72 hours, mice developed AKI, with elevated serum urea and acute tubular necrosis.…”

The Role of Dendritic Cells in Renal Inflammation

“…DCs also secrete IL-12 in later stage NTN and lupus nephritis which promotes inflammation [11 •• , 12]. On the other hand, DCs secrete the anti-inflammatory cytokine IL-10 in cisplatin nephrotoxicity (CNT) and early stage NTN [13,14].…”

“…It was found that DCs not only produced IL-10 themselves but also expressed Inducible T cell Co-Stimulator Ligand (ICOS-L) that can interact with Tregs to secrete IL-10 [13]. Endogenous IL-10 reduced inflammation and was protective against CNT [48].…”