CD4+CD25+ regulatory T cells attenuate cisplatin-induced nephrotoxicity in mice.
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.
Lee
Hyojung
H
Department of Physiology, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea.
Nho
Dukhee
D
Chung
Hwan-Suck
HS
Lee
Heekyung
H
Shin
Min-Kyu
MK
Kim
Sung-Hoon
SH
Bae
Hyunsu
H
D019264:Adoptive Transfer; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001806:Blood Urea Nitrogen; D002634:Chemotaxis, Leukocyte; D002945:Cisplatin; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis*; D007668:Kidney / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000637:transplantation*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D015415:Biomarkers; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508017:IL2RA protein, human; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D053645:Interleukin-2 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha; D003404:Creatinine; D002945:Cisplatin