Long-term reversal of diabetes by the injection of immunoprotected islets.

Soon‐Shiong, Patrick; Feldman, Edward C; Nelson, Richard W.; Heintz, R; Yao, Qiang; Yao, Zhiwen; Zheng, Tianli; Merideth, N.; Skjåk‐Bræk, Gudmund; Espevik, Terje

doi:10.1073/pnas.90.12.5843

Cited by 228 publications

(93 citation statements)

References 12 publications

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“…The immunomodulating properties of alginate are of commercial importance as alginate is used in several biomedical applications (43), and alginate capsules are currently being evaluated for use as implantation material for hormone-producing cells (44,45). Moreover, carbohydrates have interesting potentials for treatment of various infections and cancers (46).…”

Section: Tlr2 and Tlr4 Mediate Activation By Mannuronic Acid Polymersmentioning

confidence: 99%

Involvement of Toll-like Receptor (TLR) 2 and TLR4 in Cell Activation by Mannuronic Acid Polymers

Flo

Ryan

Latz

et al. 2002

Journal of Biological Chemistry

178

106

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The alginate capsule produced by the human pathogen Pseudomonas aeruginosa is composed mainly of mannuronic acid polymers (poly-M) that have immunostimulating properties. Poly-M shares with lipopolysaccharide the ability to stimulate cytokine production from human monocytes in a CD14-dependent manner. In the present study we examined the role of Toll-like receptor (TLR) 2 and TLR4 in responses to poly-M. Blocking antibodies to TLR2 and TLR4 partly inhibited tumor necrosis factor production induced by poly-M in human monocytes, and further inhibition was obtained by combining the antibodies. By transiently transfecting HEK293 cells, we found that membrane CD14 together with either TLR2 or TLR4/MD-2 could mediate activation by poly-M. Transfection of HEK293 cells with TLR2 and fluorescently labeled TLR4 followed by co-patching of TLR2 with an antibody revealed no association of these molecules on the plasma membrane. However, macrophages from the Tlr4 mutant C3H/HeJ mice and TLR4 knockout mice were completely non-responsive to poly-M, whereas the tumor necrosis factor release from TLR2 knockout macrophages was half of that seen with wild type cells. Taken together the results suggest that both TLR2 and TLR4 are involved in cell activation by poly-M and that TLR4 may be required in primary murine macrophages.

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Section: Tlr2 and Tlr4 Mediate Activation By Mannuronic Acid Polymersmentioning

confidence: 99%

Involvement of Toll-like Receptor (TLR) 2 and TLR4 in Cell Activation by Mannuronic Acid Polymers

Flo

Ryan

Latz

et al. 2002

Journal of Biological Chemistry

178

106

View full text Add to dashboard Cite

show abstract

“…The first allotransplantations in humans with encapsulated parathyroid cells and pancreatic islets have been successfully carried out [2,3]. Also, it has been shown to allow for successful xenotransplantation of islet grafts in both chemically induced and autoimmune diabetic rodents [4], dogs [5], and monkeys [6]. Although this illustrated the principle applicability of the alginate-encapsulation technique, a fundamental barrier has to be overcome since graft survival varies considerably from several days to months [4].…”

mentioning

confidence: 99%

Association between macrophage activation and function of micro-encapsulated rat islets

et al. 2003

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Aims/hypothesis. Survival of microencapsulated islet grafts is limited, even when inflammatory reactions against the capsules are restricted to a small portion of less than 10%. Methods. This study investigates both in vivo in rat recipients and in vitro whether cellular overgrowth on this minority of the capsules contributes to limitations in the functional survival of the 90% of the encapsulated islets which remain free of any cellular overgrowth. Results. In successful rat recipients of an allogenic microencapsulated islet graft we found that the vast majority of cells in the capsular overgrowth were activated ED-1 and ED-2 positive macrophages which were found in numbers of approximately 1500 per capsule. Co-culture of encapsulated islets with 1500 (nr8383) rat-macrophages per capsule showed that the activation of macrophages was caused by islet-derived bioactive factors since TNF-α and IL-1β secretion by macrophages was induced by islet-containing capsules and not by empty capsules. This activation of macrophages was associated with a decrease in function of the encapsulated islets as evidenced by a quantitatively reduced (35%) insulin response in static incubation and a slower response in perifusion. Conclusion/interpretation. Present research aims to design strategies for the temporary inhibition of macrophage activation since macrophages are predominantly present in the first two months after implantation. These strategies will serve as a pertinent basis for future clinical application of microencapsulated islets. [Diabetologia (2003) 46:666-673]

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“…Diabetic canine recipients, receiving 15,000-20,000 IEq islets/kg in alginate microcapsule into the intraperitoneal cavity, were able to maintain normoglycemia without insulin injection for up to 110 days, with c-peptide detectable in the blood for more than 1 year [16]. In 2010, allogeneic transplant in nonhuman primate was tested using subcutaneous and kidney capsule transplants of alginate micro and macroencapsulated islets, at a dose of 30,000 IEQ/kg.…”

Section: History Of Animal and Human Trials Of Islet Encapsulationmentioning

confidence: 99%

Avoiding Immunosuppression for Islet Transplantation: Use of Protective Biomaterials

Alexander¹,

Nguyen²,

Flores³

et al. 2017

Challenges in Pancreatic Pathology

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Islet transplantation, with the advent of the Edmonton protocol in 2000, has offered a significant alternative for long-lasting treatment of type 1 diabetes. However, the immunosuppression required for transplantation has the cytotoxic effect on pancreatic islets, and thus limiting the long-term efficacy of the transplant. Immediate loss of islets after transplant was also observed because of immediate blood-mediated inflammatory response (IBMIR), which kills islets transplanted in the liver through portal vein. There is also commonly a lack of microvascular blood supply to the transplanted islets. In this chapter, we will review the variety of technologies used to protect transplanted islets against toxicity of immunosuppression, immune rejection, and inflammatory response. We will evaluate the mechanisms of these technologies and their progress in solving the challenges to islet transplantation. The technologies include encapsulation of transplanted islets in various polymers, transplants in sites other than the liver, and creation of new prevascularized transplant site. These technologies offer several mechanisms to prevent immune rejection or immediate contact with cytotoxic inflammatory response, in addition to maintaining islet integrity. New transplant sites are also being developed to support the islets, by allowing establishment of microvasculature and innervation, prior to addition of the islets.

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Long-term reversal of diabetes by the injection of immunoprotected islets.

Abstract: The intraperitoneal injection of insulinproducing islets immunoprotected by an alginate-poly(amino acid) membrane is a potential method of reversing diabetes without the need for lifelong immunosuppression

Cited by 228 publications

References 12 publications

Involvement of Toll-like Receptor (TLR) 2 and TLR4 in Cell Activation by Mannuronic Acid Polymers

Involvement of Toll-like Receptor (TLR) 2 and TLR4 in Cell Activation by Mannuronic Acid Polymers

Association between macrophage activation and function of micro-encapsulated rat islets

Avoiding Immunosuppression for Islet Transplantation: Use of Protective Biomaterials

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