Low Molecular Weight Dextran Sulfate: A Strong Candidate Drug to Block IBMIR in Clinical Islet Transplantation

Johansson, H; Goto, Masafumi; Siegbahn, Agneta; Elgue, Graciela; Korsgren, Olle; Nilsson, Bo

doi:10.1111/j.1600-6143.2005.01186.x

Cited by 121 publications

(96 citation statements)

References 37 publications

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“…Recently, the maximum tolerated doses of DXS were determined in vivo in cynomolgus monkeys and i.v. or intraportal bolus injections of 3-6 mg/kg, followed by continuous infusion of 0.3-1.2 mg/kg/h for 6 h, and appeared to be safe (50). It should also be considered, however, that DXS binds to the surface of activated endothelial cells (3), which may limit the plasma concentration available for its inhibitory effect on DC.…”

Section: Discussionmentioning

confidence: 99%

The Complement Inhibitor Low Molecular Weight Dextran Sulfate Prevents TLR4-Induced Phenotypic and Functional Maturation of Human Dendritic Cells

Spirig¹,

Kooten

Obregon

et al. 2008

The Journal of Immunology

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Low molecular weight dextran sulfate (DXS) has been reported to inhibit the classical, alternative pathway as well as the mannan-binding lectin pathway of the complement system. Furthermore, it acts as an endothelial cell protectant inhibiting complement-mediated endothelial cell damage. Endothelial cells are covered with a layer of heparan sulfate (HS), which is rapidly released under conditions of inflammation and tissue injury. Soluble HS induces maturation of dendritic cells (DC) via TLR4. In this study, we show the inhibitory effect of DXS on human DC maturation. DXS significantly prevents phenotypic maturation of monocyte-derived DC and peripheral myeloid DC by inhibiting the up-regulation of CD40, CD80, CD83, CD86, ICAM-1, and HLA-DR and down-regulates DC-SIGN in response to HS or exogenous TLR ligands. DXS also inhibits the functional maturation of DC as demonstrated by reduced T cell proliferation, and strongly impairs secretion of the proinflammatory mediators IL-1β, IL-6, IL-12p70, and TNF-α. Exposure to DXS leads to a reduced production of the complement component C1q and a decreased phagocytic activity, whereas C3 secretion is increased. Moreover, DXS was found to inhibit phosphorylation of IκB-α and activation of NF-κB. These findings suggest that DXS prevents TLR-induced maturation of human DC and may therefore be a useful reagent to impede the link between innate and adaptive immunity.

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Section: Discussionmentioning

confidence: 99%

The Complement Inhibitor Low Molecular Weight Dextran Sulfate Prevents TLR4-Induced Phenotypic and Functional Maturation of Human Dendritic Cells

Spirig¹,

Kooten

Obregon

et al. 2008

The Journal of Immunology

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“…3,[16][17][18] However, it is difficult to apply these anticoagulants in the clinical environment because systemic administration is associated with an increased risk of severe bleeding. 19 Therefore, there is an urgent need to explore new therapeutic target for treating IBMIR with fewer bleeding complications.…”

Section: Discussionmentioning

confidence: 99%

Thrombin-Activatable Fibrinolysis Inhibitor Is Activated in an Instant Blood-Mediated Inflammatory Reaction After Intraportal Islet Transplant

Wang

Zhang²,

Cong³

et al. 2014

Exp Clin Transplant

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Objectives: Activated thrombin-activatable fibrinolysis inhibitor is a coagulation factor in some thrombotic diseases. However, available data on whether thrombin-activatable fibrinolysis inhibitor is activated in islet transplant are limited. In this study, changes of plasma-activated thrombinactivatable fibrinolysis inhibitor levels in instant blood-mediated inflammatory reaction after islet transplant were assessed. Materials and Methods: Plasma concentrations of thrombin-antithrombin complex, D-dimer, C-peptide, and activated thrombin-activatable fibrinolysis inhibitor were assessed at 0 minutes, 30 minutes, 1 hour, 6 hours, 12 hours, and 24 hours after an intraportal islet transplant using rats via an enzymelinked immunosorbent assay, or solid-phase, 2-site chemiluminescent immunometric assay. We recovered the liver at 1 hour after the transplant for histologic examination. Results: Thrombin-antithrombin complex, C-peptide, and activated thrombin-activatable fibrinolysis inhibitor levels increased immediately after we stopped islet infusion, and their peak levels occurred at 1 hour after islet infusion. D-dimer levels increased continually after islet infusion was stopped, and peaked 24 hours after infusion. Histologic examination of the liver 1 hour after islet infusion revealed frequent portal venous thrombi, with entrapped islets. The entrapped islets showed a disrupted morphology. Conclusions:Activated thrombin-activatable fibrinolysis inhibitor was generated and peaked 1 hour after islet transplant according with activating coagulation, indicating that thrombin-activatable fibrinolysis inhibitor is activated and accumulated at levels in instant blood-mediated inflammatory reaction was sufficient to affect fibrinolysis.

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“…Ikada et al [47] developed a bio-artificial pancreas (encapsulated islets) using LMW-DS and succeeded in preventing complement attack. The Korsgren group revealed that LMW-DS is useful in preventing instant blood-mediated inflammatory reaction (IBMIR: a rapid thrombotic reaction, in which binding of platelets to the islet surface, activation of the coagulation and complement systems, and leukocyte infiltration of the islets when the islets are exposed to blood occur) [48][49][50] . Various materials have been studied and shown to have positive results, but encapsulated islets that can be utilized permanently have not been developed yet.…”

Section: Resultsmentioning

confidence: 99%

“…However, several recent studies have clearly shown that most of the islets (approximately 60% islets) transplanted intraportally are immediately destroyed, mainly due to the IBMIR [49,70] . Moreover, the infusion of islets with some other pancreatic tissues 23 February 15, 2012|Volume 3|Issue 1| WJGP|www.wjgnet.com (acinar cells, ductal cells or connective tissues) in the portal vein always has a risk of causing portal hypertension and portal vein embolization [71] .…”

Section: Ideal Transplantation Site For Encapsulated Isletsmentioning

confidence: 99%

Encapsulated islets transplantation: Past, present and future

Sakata

Sumi²,

Yoshimatsu³

et al. 2012

WJGP

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Islet transplantation could become an ideal treatment for severe diabetes to prevent hypoglycemia shock and irreversible diabetic complications, once some of the major and unresolved obstacles are overcome, including limited donor supplies and side effects caused by permanent immunosuppressant use. Approximately 30 years ago, some groups succeeded in improving the blood glucose of diabetic animals by transplanting encapsulated islets with semi-permeable membranes consisting of polymer. A semi-permeable membrane protects both the inner islets from mechanical stress and the recipient's immune system (both cellular and humoral immunities), while allowing bidirectional diffusion of nutrients, oxygen, glucose, hormones and wastes, i.e., immune-isolation. This device, which enables immune-isolation, is called encapsulated islets or bio-artificial pancreas. Encapsulation with a semipermeable membrane can provide some advantages: (1) this device protects transplanted cells from the recipient's immunity even if the xenogeneic islets (from large animals such as pig) or insulin-producing cells are derived from cells that have the potential for differentiation (some kinds of stem cells). In other words, the encapsulation technique can resolve the problem of limited donor supplies; and (2) encapsulation can reduce or prevent chronic administration of immunosuppressants and, therefore, important side effects otherwise induced by immunosuppressants. And now, many novel encapsulated islet systems have been developed and are being prepared for testing in a clinical setting.

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Low Molecular Weight Dextran Sulfate: A Strong Candidate Drug to Block IBMIR in Clinical Islet Transplantation

Cited by 121 publications

References 37 publications

The Complement Inhibitor Low Molecular Weight Dextran Sulfate Prevents TLR4-Induced Phenotypic and Functional Maturation of Human Dendritic Cells

The Complement Inhibitor Low Molecular Weight Dextran Sulfate Prevents TLR4-Induced Phenotypic and Functional Maturation of Human Dendritic Cells

Thrombin-Activatable Fibrinolysis Inhibitor Is Activated in an Instant Blood-Mediated Inflammatory Reaction After Intraportal Islet Transplant

Encapsulated islets transplantation: Past, present and future

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