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

Chhabra, Preeti; Brayman, Kenneth L.

doi:10.1155/2011/637692

Cited by 32 publications

(35 citation statements)

References 250 publications

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“…Of significance, the loss of HS following islet isolation and in engrafted islets early after transplantation are properties that are likely to contribute to early beta cell death in islet transplants (62,63). Our findings suggest that HS recovery by de novo synthesis of HS in isolated islets is limited.…”

Section: Discussionmentioning

confidence: 74%

Islet Heparan Sulfate but Not Heparan Sulfate Proteoglycan Core Protein Is Lost During Islet Isolation and Undergoes Recovery Post-Islet Transplantation

Choong

Freeman

Parish

et al. 2015

American Journal of Transplantation

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Islet beta cells in situ express intracellular heparan sulfate (HS), a property previously shown in vitro to be important for their survival. We report that HS levels inside islet beta cells correlate with the novel intracel-lular localization of the HSPG core proteins for collagen type XVIII (Col18), a conventional extracellular matrix component. Syndecan-1 (Sdc1) and CD44 core proteins were similarly localized inside beta cells. During isolation, mouse islets selectively lose HS to 11-27% of normal levels but retain their HSPG core proteins. Intra-islet HS failed to recover substantially during culture for 4 days and was not reconstituted in vitro using HS mimetics. In contrast, significant recovery of intra-islet HS to $40-50% of normal levels occurred by 5-10 days after isotransplantation. Loss of islet HS during the isolation procedure is independent of heparanase (a HS-degrading endoglycosidase) and due, in part, to oxidative damage. Treatment with antioxidants reduced islet cell death by $60% and increased the HS content of isolated islets by $twofold compared to untreated islets, preserving intra-islet HS to $60% of the normal HS content of islets in situ. These findings suggest that the preservation of islet HS during the islet isolation process may optimize islet survival posttransplant. Abbreviations: AEC, 3-amino-9-ethylcarbazole; A.U., arbitrary units; B6.Hpse-KO, heparanase knockout C57BL/6; BHA, butylated hydroxyanisole; BM, basement membrane; Col18, collagen type XVIII; DMTU, dimethylthiourea; ECM, extracellular matrix; EXT1-2, exostosin 1-2; EXTL1-3, exostosin-like 1-3; FITC, fluo-rescein isothiocyanate; GMFR, geometric mean fluo-rescence ratio; Gpc2, glypican-2; H&E, haematoxylin and eosin; HS, heparan sulfate; HSPG, heparan sulfate proteoglycan; MFI, mean fluorescence intensity; MNCs, mononuclear cells; Ndst2, N-deacetylase/N-sulfotransferase 2; NOD/Lt, nonobese diabetic; PSN, penicillin-streptomycin-neomycin; qRT-PCR, quantitative reverse transcription polymerase chain reaction; ROS, reactive oxygen species; Sdc1, syndecan-1; SEM, standard error of the mean

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Section: Discussionmentioning

confidence: 74%

Islet Heparan Sulfate but Not Heparan Sulfate Proteoglycan Core Protein Is Lost During Islet Isolation and Undergoes Recovery Post-Islet Transplantation

Choong

Freeman

Parish

et al. 2015

American Journal of Transplantation

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“…A recent review has summarized progress related to this approach [14]. In the era of 1999 to 2002, TNF- α inhibitors were utilized in a small proportion (11.8%) of islet transplants, while in the 2007 to 2010 period, they were used in 33.8% of transplants [129].…”

Section: Anti-inflammatory Strategies To Improve Islet Transplantamentioning

confidence: 99%

Inflammatory Response in Islet Transplantation

Kanak

Takita²,

Kunnathodi³

et al. 2014

International Journal of Endocrinology

111

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Islet cell transplantation is a promising beta cell replacement therapy for patients with brittle type 1 diabetes as well as refractory chronic pancreatitis. Despite the vast advancements made in this field, challenges still remain in achieving high frequency and long-term successful transplant outcomes. Here we review recent advances in understanding the role of inflammation in islet transplantation and development of strategies to prevent damage to islets from inflammation. The inflammatory response associated with islets has been recognized as the primary cause of early damage to islets and graft loss after transplantation. Details on cell signaling pathways in islets triggered by cytokines and harmful inflammatory events during pancreas procurement, pancreas preservation, islet isolation, and islet infusion are presented. Robust control of pre- and peritransplant islet inflammation could improve posttransplant islet survival and in turn enhance the benefits of islet cell transplantation for patients who are insulin dependent. We discuss several potent anti-inflammatory strategies that show promise for improving islet engraftment. Further understanding of molecular mechanisms involved in the inflammatory response will provide the basis for developing potent therapeutic strategies for enhancing the quality and success of islet transplantation.

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“…While exogenous insulin therapy remains the most common and effective standard for day-to-day control of Type 1 Diabetes (T1D), recurring incidences of hypoglycemic episodes and long-term complications such as retinopathy, neuropathy, nephropathy, and cerebrovascular/cardiovascular diseases necessitate transplantation of either whole pancreas or pancreatic islets as a more effective treatment in a high percentage of patients [1][2][3][4][5][6]. Of the two, clinical islet transplantation is less invasive, being associated with a 20% lower morbidity risk compared to whole pancreas transplantation.…”

Section: Editorialmentioning

confidence: 99%

Anti-inflammatory Interventional Strategies to Promote Islet Transplantation Outcomes

Chhabra¹,

Bowers

Langman³

et al. 2014

Surgery Curr Res

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

Cited by 32 publications

References 250 publications

Islet Heparan Sulfate but Not Heparan Sulfate Proteoglycan Core Protein Is Lost During Islet Isolation and Undergoes Recovery Post-Islet Transplantation

Islet Heparan Sulfate but Not Heparan Sulfate Proteoglycan Core Protein Is Lost During Islet Isolation and Undergoes Recovery Post-Islet Transplantation

Inflammatory Response in Islet Transplantation

Anti-inflammatory Interventional Strategies to Promote Islet Transplantation Outcomes

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