Prevention of Early Loss of Transplanted Islets in the Liver of Mice by Adenosine

Nitta, Tomoyuki; Itoh, Takeshi; Matsuoka, Naoki; Mera, Toshiyuki; Kojima, Daisuke; Nakano, Masahiko; Yamashita, Yuichi; Yasunami, Yohichi

doi:10.1097/tp.0b013e3181aa6c9b

Cited by 26 publications

(22 citation statements)

References 29 publications

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“…Intraperitoneal glucose tolerance test was performed as described (28). Briefly, mice fasted for 12 h, during which baseline blood glucose levels measured, they were injected intraperitoneally with 10% glucose in PBS (3 g/kg body weight), and blood glucose was determined.…”

Section: Methodsmentioning

confidence: 99%

Long-Term Remission of Diabetes in NOD Mice Is Induced by Nondepleting Anti-CD4 and Anti-CD8 Antibodies

Diz

Martin

et al. 2012

Diabetes

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Residual β-cells found at the time of clinical onset of type 1 diabetes are sufficient to control hyperglycemia if rescued from ongoing autoimmune destruction. The challenge, however, is to develop an immunotherapy that not only selectively suppresses the diabetogenic response and efficiently reverses diabetes, but also establishes long-term β-cell–specific tolerance to maintain remission. In the current study, we show that a short course of nondepleting antibodies (Abs) specific for the CD4 and CD8 coreceptors rapidly reversed clinical disease in recent-onset diabetic NOD mice. Once established, remission was maintained indefinitely and immunity to foreign antigens unimpaired. Induction of remission involved selective T-cell purging of the pancreas and draining pancreatic lymph nodes and upregulation of transforming growth factor (TGF)-β1 by pancreas-resident antigen-presenting cells. Neutralization of TGF-β blocked the induction of remission. In contrast, maintenance of remission was associated with tissue-specific immunoregulatory T cells. These findings demonstrate that the use of nondepleting Ab specific for CD4 and CD8 is a robust approach to establish long-term β-cell–specific T-cell tolerance at the onset of clinical diabetes.

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Section: Methodsmentioning

confidence: 99%

Long-Term Remission of Diabetes in NOD Mice Is Induced by Nondepleting Anti-CD4 and Anti-CD8 Antibodies

Diz

Martin

et al. 2012

Diabetes

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“…In their investigation of the effect of adenosine therapy in islet transplantation, Nitta et al . demonstrated that a single dose of adenosine delivered at the time of islet transplantation suppressed NKT cell-mediated IFN-g production by Gr-1 + CD11b + cells (neutrophils) in the liver of streptozotocin-induced diabetic recipient mice, thus preventing early loss of transplanted syngeneic and allogeneic islets and enabling transplantation using a single donor [141]. This observation combined with the observation of Lappas et al .…”

Section: Strategies To Reverse/prevent Type 1 Diabetes Mellitusmentioning

confidence: 98%

“…However, in contrast, studies by Nitta et al . indicate the involvement of NKT cells in both syngeneic and allogeneic immune rejection of islet allografts in the liver of mice and demonstrate the immunosuppressive role of adenosine in preventing NKT cell-mediated destruction of islet grafts [141]. Recently, a new subset, iNKT17 cells, that produce high levels of the pro-inflammatory cytokine IL-17 implicated in several autoimmune diseases, has been identified [142].…”

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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“…Several studies indicate that inhibition of non specific inflammation improves the function and survival of islet grafts. For instance, Yasunami's group demonstrated that V-alpha14 NKT cell-triggered IFN- γ production by Gr-1+CD11b+ cells mediated early graft loss of syngeneic transplanted islets [94]. Adenosine administration suppressed NKT cell-mediated IFN- γ production of neutrophils in the livers of graft-recipient mice, leading to prevention of early loss of transplanted syngeneic and allogeneic islets.…”

Section: Islet Transplantationmentioning

confidence: 99%

Current Status of Immunomodulatory and Cellular Therapies in Preclinical and Clinical Islet Transplantation

Chhabra

Brayman

2011

Journal of Transplantation

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Clinical islet transplantation is a β-cell replacement strategy that represents a possible definitive intervention for patients with type 1 diabetes, offering substantial benefits in terms of lowering daily insulin requirements and reducing incidences of debilitating hypoglycemic episodes and unawareness. Despite impressive advances in this field, a limiting supply of islets, inadequate means for preventing islet rejection, and the deleterious diabetogenic and nephrotoxic side effects associated with chronic immunosuppressive therapy preclude its wide-spread applicability. Islet transplantation however allows a window of opportunity for attempting various therapeutic manipulations of islets prior to transplantation aimed at achieving superior transplant outcomes. In this paper, we will focus on the current status of various immunosuppressive and cellular therapies that promote graft function and survival in preclinical and clinical islet transplantation with special emphasis on the tolerance-inducing capacity of regulatory T cells as well as the β-cells regenerative capacity of stem cells.

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Prevention of Early Loss of Transplanted Islets in the Liver of Mice by Adenosine

Cited by 26 publications

References 29 publications

Long-Term Remission of Diabetes in NOD Mice Is Induced by Nondepleting Anti-CD4 and Anti-CD8 Antibodies

Long-Term Remission of Diabetes in NOD Mice Is Induced by Nondepleting Anti-CD4 and Anti-CD8 Antibodies

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

Current Status of Immunomodulatory and Cellular Therapies in Preclinical and Clinical Islet Transplantation

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