Successful Islet Transplantation to Two Recipients From a Single Donor by Targeting Proinflammatory Cytokines in Mice

Satoh, Masayuki; Yasunami, Yohichi; Matsuoka, Naoki; Nakano, Masahiko; Itoh, Takeshi; Nitta, Tomoyuki; Anzai, Keizo; Ono, Junko; Taniguchi, Masaru; Ikeda, Seiyo

doi:10.1097/01.tp.0000260161.81775.58

Cited by 37 publications

(25 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, combined with in vitro findings of elevated concentrations of HMGB1 in the culture medium of isolated islets in the presence of cytotoxic cytokines, the plasma levels of HMGB1 may reflect the degree of islet damage in the liver after transplantation. Furthermore, the treatment with anti-HMGB1 antibody delayed the onset of diabetes in NOD mice, suggesting that HMGB1 plays a significant role in disease progression (23).…”

Section: Discussionmentioning

confidence: 99%

High-mobility group box 1 is involved in the initial events of early loss of transplanted islets in mice

Matsuoka

Itoh²,

Watarai³

et al. 2010

J. Clin. Invest.

Self Cite

132

140

View full text Add to dashboard Cite

Islet transplantation for the treatment of type 1 diabetes mellitus is limited in its clinical application mainly due to early loss of the transplanted islets, resulting in low transplantation efficiency. NKT cell-dependent IFN-γ production by Gr-1 + CD11b + cells is essential for this loss, but the upstream events in the process remain undetermined. Here, we have demonstrated that high-mobility group box 1 (HMGB1) plays a crucial role in the initial events of early loss of transplanted islets in a mouse model of diabetes. Pancreatic islets contained abundant HMGB1, which was released into the circulation soon after islet transplantation into the liver. Treatment with an HMGB1-specific antibody prevented the early islet graft loss and inhibited IFN-γ production by NKT cells and Gr-1 + CD11b + cells. Moreover, mice lacking either of the known HMGB1 receptors TLR2 or receptor for advanced glycation end products (RAGE), but not the known HMGB1 receptor TLR4, failed to exhibit early islet graft loss. Mechanistically, HMGB1 stimulated hepatic mononuclear cells (MNCs) in vivo and in vitro; in particular, it upregulated CD40 expression and enhanced IL-12 production by DCs, leading to NKT cell activation and subsequent NKT cell-dependent augmented IFN-γ production by Gr-1 + CD11b + cells. Thus, treatment with either IL-12-or CD40L-specific antibody prevented the early islet graft loss. These findings indicate that the HMGB1-mediated pathway eliciting early islet loss is a potential target for intervention to improve the efficiency of islet transplantation. IntroductionPancreatic islet transplantation, although an attractive procedure for the treatment of type 1 diabetes mellitus, usually fails to achieve insulin independence of a diabetic recipient from a single donor due to early loss of transplanted islets and therefore requires sequential transplantations of islets with the use of 2-3 donors (1). Thus, the low efficiency of islet transplantation has been a major obstacle facing islet transplantation and hampers its clinical application.We have previously shown in mice that loss of transplanted islets soon after transplantation is caused by NKT cell-dependent IFN-γ production by Gr-1 + CD11b + cells and is successfully prevented by treatment of NKT cells with repeated stimulation with their synthetic ligand, α-galactosylceramide (α-GalCer), to downregulate IFN-γ production of NKT cells, or by depletion of Gr-1 + CD11b + cells with anti-Gr-1 antibody (2). However, precisely how it is involved in the upstream events in the activation of NKT cells and Gr-1 + CD11b + cells in the early loss of transplanted islets remains to be solved.High-mobility group box 1 (HMGB1) protein was initially found to be a DNA-binding protein present in almost all eukaryotic cells, where it stabilizes nucleosome formation and acts as a nuclear factor that enhances transcription (3, 4). Recently,

show abstract

Section: Discussionmentioning

confidence: 99%

High-mobility group box 1 is involved in the initial events of early loss of transplanted islets in mice

Matsuoka

Itoh²,

Watarai³

et al. 2010

J. Clin. Invest.

Self Cite

132

140

View full text Add to dashboard Cite

show abstract

“…Notably, its precursor, biliverdin, exhibited anti-inflammatory properties by inhibiting the activity of NF-κB in a rat model of endotoxin-induced acute lung injury (Sarady-Andrews et al, 2005). IL-1β and TNF-α have been shown to participate in pancreatic islet β-cell death and functional impairment of β-cells causing early loss of islet mass in transplanted islets (Amoli et al, 2006) and IL-1β and TNF-α blockade promoted the survival of islet grafts (Satoh et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Bilirubin protects grafts against nonspecific inflammation-induced injury in syngeneic intraportal islet transplantation

et al. 2010

View full text Add to dashboard Cite

Nonspecific inflammatory response is the major cause for failure of islet grafts at the early phase of intraportal islet transplantation (IPIT). Bilirubin, a natural product of heme catabolism, has displayed anti-oxidative and anti-inflammatory activities. The present study has demonstrated that bilirubin protected islet grafts by inhibiting nonspecific inflammatory response in a syngeneic rat model of IPIT. The inflammation-induced cell injury was mimicked by exposing cultured rat insulinoma INS-1 cells to cytokines (IL-1β, TNF-α and IFN-γ) in in vitro assays. At appropriate lower concentrations, bilirubin significantly attenuated the reduced cell viability and enhanced cell apoptosis induced by cytokines, and protected the insulin secretory function of INS-1 cells. Diabetic inbred male Lewis rats induced by streptozotocin underwent IPIT at different islet equivalents (IEQs) (optimal dose of 1000, and suboptimal doses of 750 or 500), and bilirubin was administered to the recipients every 12 h, starting from one day before transplantation until 5 days after transplantation. Administration of bilirubin improved glucose control and enhanced glucose tolerance in diabetic recipients, and reduced the serum levels of inflammatory mediators including IL-1β, TNF-α, soluble intercellular adhesion molecule 1, monocyte chemoattractant protein-1 and NO, and inhibited the infiltration of Kupffer cells into the islet grafts, and restored insulin-producing ability of transplanted islets.

show abstract

“…The pancreatic islet isolation procedure exerts significant stress on islets by releasing pro-inflammatory cytokines that result in loss of β-cell function and induction of apoptosis [17][18][19]. We initially investigated the tissue protective effects of ARA 290 in an in vitro rat islet-culture model.…”

Section: Ara 290 Protects Isolated Rat Pancreatic Islets From Cytokinmentioning

confidence: 99%

“…In addition, the brain-death status of a donor, which induces a cytokine storm, organ procurement procedures, and prolonged cold ischemia time reduces isolated pancreatic islet yields and functionality after PITx [14][15][16]. Beyond the direct toxic effect on β-cells [17], inflammatory mediators, such as tumor necrosis factor (TNF)-α [18] IL-1β [19] and MCP-1 [20], may damage the transplanted islets by enhancing inflammation and innate immune responses following PITx. These mechanisms play a crucial role in the triggering of graft dysfunction and the eventual loss of islets after PITx.…”

Section: Introductionmentioning

confidence: 99%

An Engineered Innate Repair Receptor Agonist, ARA 290, Protects Rat Islets from Cytokine-induced Apoptosis

Watanabe¹,

Saito²,

Wallmo³

et al. 2016

J Diabetes Metab

View full text Add to dashboard Cite

The efficacy of pancreatic islet transplantation (PITx) is reduced due to severe inflammatory responses triggered by the islet isolation and transplantation procedures. ARA 290, an innate repair receptor agonist, has anti-apoptotic and anti-inflammatory properties and it has been shown to improve clinical symptoms caused by inflammation in sarcoidosis patients and type 2 diabetes. We here investigated whether ARA 290 treatment would improve the efficacy of PITx in a rat pancreatic islet transplantation model. For islets co-cultured with proinflammatory cytokines, addition of ARA290 showed better viability [percent of naïve control in MTT assay: 54.6 ± 5.2 vs. 75.2 ± 6.4], insulin release [stimulation index in static glucose stimulated insulin secretion tests of 1.05 ± 0.63 vs. 2.61 ± 0.89], and reduced apoptosis [caspase3/7 activity182 ± 18 vs. 152 ± 18 luminescence/dsDNA(ng)] (islets with cytokines vs. islets with ARA290+cytokines, respectively, all p<0.05). In order to mimic the clinical situation, islets were isolated after prolonged cold ischemia (18 h). The addition of ARA 290 into preservation solution, however, did not improve islet yields or function. As a marginal syngeneic PITx, 220 syngeneic rat islets were transplanted under the kidney capsule of streptozotocin-induced diabetic rats and the recipients were treated with ARA 290 (120 µg/kg/day) for two weeks after PITx. In this model, no beneficial effect of ARA 290 treatment was observed. Our results indicated that ARA 290 protected rat pancreatic islets from cytokine-induced damage and apoptosis, but did not improve PITx perhaps due to poor penetration of ARA290 into transplant site or low IRR expression. ARA 290 could be useful as an agent to reduce islet injury caused by severe inflammation.

show abstract

Successful Islet Transplantation to Two Recipients From a Single Donor by Targeting Proinflammatory Cytokines in Mice

Cited by 37 publications

References 29 publications

High-mobility group box 1 is involved in the initial events of early loss of transplanted islets in mice

High-mobility group box 1 is involved in the initial events of early loss of transplanted islets in mice

Bilirubin protects grafts against nonspecific inflammation-induced injury in syngeneic intraportal islet transplantation

An Engineered Innate Repair Receptor Agonist, ARA 290, Protects Rat Islets from Cytokine-induced Apoptosis

Contact Info

Product

Resources

About