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.
cisplatin; nephrotoxicity; regulatory T cell
Cisplatin is widely used as a chemotherapeutic agent in various cancers, including ovarian, head and neck, and germ cell tumors. However, nephrotoxicity is commonly reported as an adverse effect of cisplatin.1 Indeed, approximately 25–30% of patients experience renal dysfunction after a single dose of cisplatin.2 Therefore, it is important to understand the pathophysiological mechanism responsible for cisplatin nephrotoxicity for the development of adjunctive therapies to reduce this side effect.
Recent studies in experimental models have confirmed that T cells have a pathophysiological role in cisplatin nephrotoxicity. T cell-deficient nu/nu mice show less kidney injury and tumor necrosis factor (TNF)-α production after cisplatin administration when compared with normal mice. Furthermore, CD4-deficient mice have been found to have a marked degree of protection from renal dysfunction, which indicates that CD4+ T cells are the primary T-cell subsets that mediate cisplatin-induced renal injury.3 However, a study using a chimeric model conducted by Reeves and colleagues4 demonstrated that the production of TNF-α, which is a key cytokine involved in the inflammatory response during cisplatin nephrotoxicity, is more closely related to resident kidney cells than bone marrow-derived immune cells. These two studies demonstrate the complexity of the mechanism that is potentially important in cisplatin-induced acute kidney injury well.5 Therefore, it is necessary to identify a specific target to reduce the toxicity associated with cisplatin, which will require a novel attempt to suppress various immune responses by different cell types.
Recently, CD4+CD25+ regulatory T (CD4+CD25+ Treg) cells have been shown to have a pivotal role in the maintenance of tolerance in the immune system.6, 7, 8 There is a great deal of convincing evidence that CD4+CD25+ Treg cells can suppress the development of autoimmune diseases, such as rheumatoid arthritis,9 multiple sclerosis,10 and lupus.11 Besides having a role in autoimmune diseases, CD4+CD25+ Treg cells have regulatory function in the control of transplantation tolerance,12 tumor immunity,13 allergy,14 and infection.15 These broad suppressive effects in various studies indicate that CD4+CD25+ Treg cells can inhibit the function of many different cell types.
Currently available evidence indicates that CD4+CD25+ Treg cells can suppress CD4+ T cell-mediated pathology in the kidneys. For example, it has been shown that CD4+CD25+ Treg cells inhibit antiglomerular basement membrane glomerulonephritis, which is a complement-dependent Th1-predominant mouse model.16 In addition, the ability of CD4+CD25+ Treg cells to inhibit the innate immune response has been thoroughly investigated.17 It is known that macrophages, which are an important component of innate immunity, are strongly related to the pathogenesis of various renal diseases. By migrating to the kidney, macrophages can contribute to tissue damage and their production of proinflammatory cytokines eventually progresses to renal failure.18 Recent studies have suggested that CD4+CD25+ Treg cells can modulate macrophages by inhibiting their activation, leading to reduced glomerular and interstitial injury in adriamycin nephropathy.19
In this study, we evaluated CD4+CD25+ Treg cells to determine whether they could attenuate cisplatin-induced nephrotoxicity by suppressing their effect on innate immune reaction. To examine the effects of CD4+CD25+ Treg cells, we used the CD4+CD25+ Treg-cell adoptive transfer or depletion methods in T cell-deficient nude mice (nu/nu) and wild-type (WT) Balb/c mice and evaluated survival, kidney function, histology, and cytokine expression after cisplatin administration. In addition, we sought to examine the migration of Foxp3-positive cells into the kidney after cisplatin injection.
|CD4+ CD25+ regulatory T cells attenuate cisplatin-induced nephrotoxicity in mice|
| Kidney International
Volume 78, Issue 11, December 2010, Pages 1100-1109
|10.1038/ki.2010.139 (click 하시면 DOI 검색 결과가 새창으로 나타납니다.)|