XIAP inhibition of β-cell apoptosis reduces the number of islets required to restore euglycemia in a syngeneic islet transplantation model

Plesner, Annette; Soukhatcheva, Galina; Korneluk, Robert G.; Verchere, C. Bruce

doi:10.4161/isl.2.1.9997

Cited by 19 publications

(9 citation statements)

References 32 publications

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“…In fact, Plesner et al . demonstrated that XIAP inhibition of β-cell apoptosis enhanced graft function and reduced the number of islets required to restore euglycemia in a syngeneic islet transplantation model promoting long-term transplant success [147]. …”

Section: Pathogenesis Of Type 1 Diabetes Mellitusmentioning

confidence: 99%

The Immunosuppressive Role of Adenosine A2A Receptors in Ischemia Reperfusion Injury and Islet Transplantation

Chhabra¹,

Linden²,

Lobo³

et al. 2012

CDR

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Activation of adenosine A2A receptors (A2AR) reduces inflammation by generally inhibiting the activation of pro-inflammatory cells, decreasing endothelial adhesion molecule expression and reducing the release of proinflammatory cytokine mediators. Numerous preclinical studies using selective A2AR agonists, antagonists, A2AR knockout as well as chimeric mice have suggested the therapeutic potential of A2AR agonists for the treatment of ischemia reperfusion injury (IRI) and autoimmune diseases. This review summarizes the immunosuppressive actions of A2AR agonists in murine IRI models of liver, kidney, heart, lung and CNS, and gives details on the cellular effects of A2AR activation in neutrophils, macrophages, dendritic cells, natural killer cells, NKT cells, T effector cells and CD4+CD25+FoxP3+ T regulatory cells. This is discussed in the context of cytokine mediators involved in inflammatory cascades. Whilst the role of adenosine receptor agonists in various models of autoimmune disease has been well-documented, very little information is available regarding the role of A2AR activation in type 1 diabetes mellitus (T1DM). An overview of the pathogenesis of T1DM as well as early islet graft rejection in the immediate peri-transplantation period offers insight regarding the use of A2AR agonists as a beneficial intervention in clinical islet transplantation, promoting islet graft survival, minimizing early islet loss and reducing the number of islets required for successful transplantation, thereby increasing the availability of this procedure to a greater number of recipients. In summary, the use of A2AR agonists as a clinical intervention in IRI and as an adjunct to clinical immunesuppressive regimen in islet transplantation is highlighted.

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Section: Pathogenesis Of Type 1 Diabetes Mellitusmentioning

confidence: 99%

The Immunosuppressive Role of Adenosine A2A Receptors in Ischemia Reperfusion Injury and Islet Transplantation

Chhabra¹,

Linden²,

Lobo³

et al. 2012

CDR

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“…X-linked inhibitor of apoptosis protein (XIAP) is the most potent IAP and is a broad-range suppressor of apoptosis that functions by directly inhibiting caspases (Deveraux and Reed, 1999; Deveraux et al, 1999). XIAP is broadly expressed in all human tissues except peripheral blood leukocytes, and XIAP overexpression increases the survival of many cell types upon exposure to a variety of apoptotic triggers (Emamaullee et al, 2005; Zhu et al, 2007; Hu et al, 2010; Plesner et al, 2010; Wang et al, 2010, 2011; Unsain et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

In vivo overexpression of X-linked inhibitor of apoptosis protein protects against neomycin-induced hair cell loss in the apical turn of the cochlea during the ototoxic-sensitive period

Sun

Zhang

et al. 2014

Front. Cell. Neurosci.

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Aminoglycoside-induced cochlear ototoxicity causes hair cell (HC) loss and results in hearing impairment in patients. Previous studies have developed the concept of an ototoxicity-sensitive period during which the cochleae of young mice are more vulnerable to auditory trauma than adults. Here, we compared neomycin-induced ototoxicity at the following four developmental ages in mice: postnatal day (P)1–P7, P8–P14, P15–P21, and P60–P66. We found that when neomycin was administered between P8 and P14, the auditory brainstem response threshold increase was significantly higher at low frequencies and HC loss was significantly greater in the apical turn of the cochlea compared to neomycin administration during the other age ranges. Quantitative real-time PCR (qPCR) data revealed that the expression of apoptotic markers, including Casp3 and Casp9, was significantly higher when neomycin was injected from P8 to P14, while the expression of the X-linked inhibitor of apoptosis protein (XIAP) gene was significantly higher when neomycin was injected from P60 to P66. Because XIAP expression was low during the neomycin-sensitive period, we overexpressed XIAP in mice and found that it could protect against neomycin-induced hearing loss at low frequencies and HC loss in the apical turn of the cochlea. Altogether, our findings demonstrate a protective role for XIAP against neomycin-induced hearing loss and HC loss in the apical turn of the cochlea during the ototoxic-sensitive period, and suggest that apoptotic factors mediate the effect of neomycin during the ototoxic-sensitive period.

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“…A variety of approaches have been explored to prevent the apoptotic destruction of islets in the experimental setting and, while promising data has been generated in vitro , demonstration of an in vivo benefit to islet graft survival has been more elusive (reviewed in [2], [4]). Such attempts have included genetic manipulation of the donor islets with anti-inflammatory and antiapoptotic genes such as Bcl-2 [5], [6], X-linked inhibitor of apoptosis protein (XIAP) [6]-[9] and the suppressor of cytokine signalling 1 (SOCS1) [10], as well as the overexpression of the antiapoptotic A20, which preserved functional islet β-cell mass [11]. Pre-treatment of islets with the caspase inhibitors zDEVD-FMK [12], EP1013 [13] or V5 [14] also improved islet survival.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Nuclear Factor-κB Activation in Pancreatic β-Cells Has a Protective Effect on Allogeneic Pancreatic Islet Graft Survival

et al. 2013

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Pancreatic islet transplantation, a treatment for type 1 diabetes, has met significant challenges, as a substantial fraction of the islet mass fails to engraft, partly due to death by apoptosis in the peri- and post-transplantation periods. Previous evidence has suggested that NF-κB activation is involved in cytokine-mediated β-cell apoptosis and regulates the expression of pro-inflammatory and chemokine genes. We therefore sought to explore the effects of β-cell-specific inhibition of NF-κB activation as a means of cytoprotection in an allogeneic model of islet transplantation. To this end, we used islets isolated from the ToI-β transgenic mouse, where NF-κB signalling can specifically and conditionally be inhibited in β-cells by expressing an inducible and non-degradable form of IκBα regulated by the tet-on system. Our results show that β-cell-specific blockade of NF-κB led to a prolonged islet graft survival, with a relative higher preservation of the engrafted endocrine tissue and reduced inflammation. Importantly, a longer delay in allograft rejection was achieved when mice were systemically treated with the proteasome inhibitor, Bortezomib. Our findings emphasize the contribution of NF-κB activation in the allograft rejection process, and suggest an involvement of the CXCL10/IP-10 chemokine. Furthermore, we suggest a potential, readily available therapeutic agent that may temper this process.

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XIAP inhibition of β-cell apoptosis reduces the number of islets required to restore euglycemia in a syngeneic islet transplantation model

Abstract: Verchere (2010) XIAP inhibition of β-cell apoptosis reduces the number of islets required to restore euglycemia in a syngeneic islet transplantation model, Islets, 2:1, 18-23,

Cited by 19 publications

References 32 publications

The Immunosuppressive Role of Adenosine A2A Receptors in Ischemia Reperfusion Injury and Islet Transplantation

The Immunosuppressive Role of Adenosine A2A Receptors in Ischemia Reperfusion Injury and Islet Transplantation

In vivo overexpression of X-linked inhibitor of apoptosis protein protects against neomycin-induced hair cell loss in the apical turn of the cochlea during the ototoxic-sensitive period

Inhibition of Nuclear Factor-κB Activation in Pancreatic β-Cells Has a Protective Effect on Allogeneic Pancreatic Islet Graft Survival

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