Blocking Fas Ligand on Leukocytes Attenuates Kidney Ischemia-Reperfusion Injury

Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Journal of the American Society of Nephrology (Impact Factor: 9.34). 03/2011; 22(4):732-42. DOI: 10.1681/ASN.2010010121
Source: PubMed


Inflammation contributes to the pathogenesis of ischemic acute kidney injury (AKI), and T cells mediate the early phase of ischemia-reperfusion injury (IRI). The Fas/Fas ligand (FasL) pathway modulates the balance of T cell subsets in the peripheral circulation as well as multiple inflammatory responses, suggesting that FasL may mediate ischemic AKI. Here, we induced bilateral renal IRI in mice bearing a loss-of-function mutation of FasL (the gld mutation) and in wild-type mice. Compared with wild-type mice, serum creatinine was lower in gld mice (1.4 ± 0.9 mg/dl versus 2.6 ± 0.4) at 24 hours after IRI (P<0.05). In addition, gld mice had fewer TNF-α-producing T lymphocytes in the kidneys and renal lymph nodes. Furthermore, pharmacologic blockade of FasL protected the kidneys of wild-type mice from IRI. Analysis of bone marrow chimeric mice suggested that the pathogenic effect of FasL involves leukocytes; reconstitution of wild-type mice with gld splenocytes attenuated IRI. In contrast, reconstitution of gld mice with wild-type splenocytes enhanced IRI. These data demonstrate that FasL, particularly on leukocytes, mediates ischemic AKI.

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    • "The N2B2 antibody or control IgG (Sigma-Aldrich Japan, Tokyo, Japan) were injected intraperitoneally (500 µg per mouse). Antibodies were given 24 hr before ischemia and a half-dose booster injection was administered into the peritoneal cavity immediately after reperfusion, as described previously [23]. Left kidneys were collected and weighed at the indicated times after reperfusion. "
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    ABSTRACT: Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI). Many investigators have reported that cell death via apoptosis significantly contributed to the pathophysiology of renal IRI. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, and induces apoptosis and inflammation. However, the role of TRAIL in renal IRI is unclear. Here, we investigated whether TRAIL contributes to renal IRI and whether TRAIL blockade could attenuate renal IRI. AKI was induced by unilateral clamping of the renal pedicle for 60 min in male FVB/N mice. We found that the expression of TRAIL and its receptors were highly upregulated in renal tubular cells in renal IRI. Neutralizing anti-TRAIL antibody or its control IgG was given 24 hr before ischemia and a half-dose booster injection was administered into the peritoneal cavity immediately after reperfusion. We found that TRAIL blockade inhibited tubular apoptosis and reduced the accumulation of neutrophils and macrophages. Furthermore, TRAIL blockade attenuated renal fibrosis and atrophy after IRI. In conclusion, our study suggests that TRAIL is a critical pathogenic factor in renal IRI, and that TRAIL could be a new therapeutic target for the prevention of renal IRI.
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    • "As a consequence, the belief that protection from diabetes is an epiphenomenon related to the distortion of the immune system by expansion of DN T cells passed unchallenged and interest in pursuing the Fas pathway as a therapeutic target faded. However, the protective effect of inactivating the Fas pathway has also been seen in other models of organ-specific autoimmune diseases, including multiple sclerosis, and inflammatory conditions (Waldner et al., 1997; Henriques-Pons and de Oliveira, 2009; Ko et al., 2011). "
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    ABSTRACT: The development of type 1 diabetes (T1D) is driven by autoreactive T cells that attack and destroy the insulin-producing β-cells in pancreatic islets, forcing patients to take multiple daily insulin injections. Insulin therapy, however, is not a cure and diabetic patients often develop serious long-term microvascular and cardiovascular complications. Therefore, intensive efforts are being directed toward developing safe immunotherapy for the disease that does not impair host defense and preserves β-cells, leading to better glycemic control than exogenous insulin therapy. Engineering therapies that differentially cripple or tolerate autoreactive diabetogenic T cells while sparing protective T cells necessary for maintaining a competent immune system has proven challenging. Instead, recent efforts have focused on modulating or resetting the immune system through global but transient deletion of T cells or B cells using anti-CD3 or anti-CD20 mAb, respectively. However, phase III clinical trials have shown promising but modest efficacy so far with these approaches. Therefore, there is a need to identify novel biological targets that do not fit the classic properties of being involved in adaptive immune cell activation. In this prospective, we provide preclinical evidence that targeting Fas ligand (FasL) may provide a unique opportunity to prevent or cure T1D and perhaps other organ-specific autoimmune diseases without causing immune suppression. Unlike conventional targets that are involved in T and B lymphocyte activation (such as CD3 and CD20, respectively), FasL is an apoptosis-inducing surface molecule that triggers cell death by binding to Fas (also known as CD95 Apo-1). Therefore, targeting FasL is not expected to cause immune suppression, the Achilles Heel of conventional approaches. We will discuss the hypothesis that targeting FasL has unique benefits that are not offered by current immunomodulatory approaches.
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