Successful Reversal of Spontaneous Diabetes in Dogs by Intraperitoneal Microencapsulated Islets

Soon‐Shiong, Patrick; Feldman, Edward C; Nelson, Richard W.; Komtebedde, Jan; Smidsrød, Olav; Skjåk‐Bræk, Gudmund; Espevik, Terje; Heintz, R; Lee, Martin

doi:10.1097/00007890-199211000-00001

Cited by 203 publications

(110 citation statements)

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“…Consistent with this notion, immune-isolated, microencapsulated islets injected in the dog peritoneal cavity fail within 6 mo (48), and islets placed into vascularized, biohybrid pancreas fail at 1 y (49). Histological evaluation reveals a major loss of islet mass in these devices (48,49), demonstrating the destruction of islets in the absence of cellular immune responses. Therefore, NIRILOD is likely one of the major factors contributing to low islet transplantation efficiency.…”

Section: Discussionmentioning

confidence: 99%

TGF-βi Promotes Islet β-Cell Function and Regeneration

Han

et al. 2011

The Journal of Immunology

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TGF-βi is a secreted protein and is capable of binding to both extracellular matrix (ECM) and cells. It thus acts as a bifunctional molecule enhancing ECM and cell interactions, a lack of which results in dysfunction of many cell types. In this study, we investigated the role of TGF-βi in the function and survival of islets. Based on DNA microarray followed by quantitative PCR confirmation, TGFβi gene showed drastic increase in expression in islets after culture. We demonstrated that recombinant TGF-βi could preserve the integrity and enhance the function of cultured islets. Such a beneficial effect was mediated via signaling through FAK. Exogenous TGF-βi was capable of sustaining high-level FAK phosphorylation in isolated islets, and FAK knockdown by small interfering RNA in islets resulted in compromised islet function. TGF-βi transgenic (Tg) islets showed better integrity and insulin release after in vitro culture. In vivo, β-cell proliferation was detectable in Tg but not wild-type pancreata. At age above 12 mo, Tg pancreata contained giant islets. Tg mice displayed better glucose tolerance than that of the controls. Tg islets were more potent in lowering blood glucose when transplanted into syngeneic mice with streptozotocin-induced diabetes, and these transplanted islets also underwent regeneration. Our results indicate that TGF-βi is a vital trophic factor promoting islet survival, function, and regeneration. At least some of its beneficial effect was mediated by signaling through FAK.

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Section: Discussionmentioning

confidence: 99%

TGF-βi Promotes Islet β-Cell Function and Regeneration

Han

et al. 2011

The Journal of Immunology

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“…During recent years, important advances have been made with this technology. Human trials have been started and showed temporary but pertinent survival of human microencapsulated tissue after allotransplantation of encapsulated parathyroid cells [3] and islets [4]. Also, microencapsulation has been shown to allow for prolonged survival of xenotransplanted islet grafts in both chemically induced and autoimmune diabetic rodents [5], dogs [4], and monkeys [6].…”

Section: Introductionmentioning

confidence: 99%

“…Human trials have been started and showed temporary but pertinent survival of human microencapsulated tissue after allotransplantation of encapsulated parathyroid cells [3] and islets [4]. Also, microencapsulation has been shown to allow for prolonged survival of xenotransplanted islet grafts in both chemically induced and autoimmune diabetic rodents [5], dogs [4], and monkeys [6]. Although this illustrates the principle applicability of the alginateencapsulation technique, a fundamental barrier has to be overcome since graft survival varies considerably from several days to months [7].…”

Section: Introductionmentioning

confidence: 99%

Long-term biocompatibility, chemistry, and function of microencapsulated pancreatic islets

et al. 2003

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“…It is generally assumed that the loss of islets associated with this small portion of overgrown capsules has no consequences for the function of the remaining 90 to 98% of the graft. Unfortunately, the reduction in tissue reactions did not bring about the expected permanent survival of the microencapsulated islet grafts since survival of the grafts is still limited to periods of 4 to 9 months [13,14,15].…”

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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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Successful Reversal of Spontaneous Diabetes in Dogs by Intraperitoneal Microencapsulated Islets

Cited by 203 publications

References 0 publications

TGF-βi Promotes Islet β-Cell Function and Regeneration

TGF-βi Promotes Islet β-Cell Function and Regeneration

Long-term biocompatibility, chemistry, and function of microencapsulated pancreatic islets

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

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