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

Vos, Paul de; Smedema, I.; Goor, Harry van; Moes, Hendrik; Zanten, Jacoba van; Netters, Sabine J.; Leij, L. F. M. de; Haan, Aalzen de; Haan, Bart J. de

doi:10.1007/s00125-003-1087-7

Cited by 73 publications

(59 citation statements)

References 39 publications

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“…Therefore, any graft rejection might be attributed to immune cells secreting cytokines/chemokines that can enter the capsule through its pores [13]. The cytokines/chemokines may also cause fibrotic overgrowth around the microcapsules to interfere with entry of nutrients, including oxygen [14].…”

Section: Discussionmentioning

confidence: 99%

“…Adult β-cells are particularly sensitive to the adverse effects of proinflammatory cytokines IL-1β, TNF-α, and IFN-γ [15]. Allografted encapsulated islets, but not empty capsules, attract activated macrophages to the surface of the capsules, and such cells release proinflammatory cytokines IL-1β and TNF-α [13]. On the other hand, anti-inflammatory cytokines such as IL-4 and IL-10 protect the pancreatic β-cells against cell death induced by proinflammatory cytokines [16].…”

Section: Discussionmentioning

confidence: 99%

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The Humanized NOD/SCID Mouse as a Preclinical Model to Study the Fate of Encapsulated Human Islets

Vaithilingam¹,

Oberholzer²,

Guillemin³

et al. 2010

Rev Diabet Stud

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■ AbstractDespite encouraging results in animal models, the transplantation of microencapsulated islets into humans has not yet reached the therapeutic level. Recent clinical trials using microencapsulated human islets in barium alginate showed the presence of dense fibrotic overgrowth around the microcapsules with no viable islets. The major reason for this is limited understanding of what occurs when encapsulated human islets are allografted. This warrants the need for a suitable small animal model. In this study, we investigated the usefulness of NOD/SCID mice reconstituted with human PBMCs (called humanized NOD/SCID mice) as a preclinical model. In this model, human T cell engraftment could be achieved, and CD45 + cells were observed in the spleen and peripheral blood. Though the engrafted T cells caused a small fibrotic overgrowth around the microencapsulated human islets, this failed to stop the encapsulated islets from functioning in the diabetic recipient mice. The ability of encapsulated islets to survive in this mouse model might partly be attributed to the presence of Th2 cytokines IL-4 and IL-10, which are known to induce graft tolerance. In conclusion, this study showed that the hu-NOD/SCID mouse is not a suitable preclinical model to study the allograft rejection mechanisms of encapsulated human islets. As another result, the maintained viability of transplanted islets on the NOD/SCID background emphasized a critical role of protective mechanisms in autoimmune diabetes transplanted subjects due to specific immunoregulatory effects provided by IL-4 and IL-10.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Humanized NOD/SCID Mouse as a Preclinical Model to Study the Fate of Encapsulated Human Islets

Vaithilingam¹,

Oberholzer²,

Guillemin³

et al. 2010

Rev Diabet Stud

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“…TACE-inhibition may be relevant for the process of graft rejection, because an inhibitor of TACE decreased injury in a rat model of posttransplant lung injury (42). Although there are no reports that describe prolongation of islet graft survival by TACE inhibition alone, locally secreted TNF␣ was found to be detrimental to islet graft function (43), and islet allograft survival was prolonged after ex vivo transduction with adenovirus-encoded soluble type 1 TNF receptor decoy (44).…”

Section: Discussionmentioning

confidence: 99%

α1-Antitrypsin monotherapy prolongs islet allograft survival in mice

Lewis

Shapiro

Bowers

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

166

203

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Islet transplantation for type 1 diabetic patients shows promising results with the use of nondiabetogenic immunosuppressive therapy. However, in addition to compromising the immune system of transplant recipients, long-term studies demonstrate that islet viability is impaired. Here, we demonstrate that, in the absence of immunosuppressive agents, monotherapy with clinical-grade human ␣1-antitrypsin (hAAT), the major serum serine-protease inhibitor, prolongs islet graft survival and normoglycemia in transplanted allogeneic diabetic mice, lasting until the development of anti-hAAT antibodies. Compared to untreated or albumin-controltreated graft recipients, which rejected islets at day 10, AATtreated mice displayed diminished cellular infiltrates and intact intragraft insulin production throughout treatment. Using peritoneal infiltration models, we demonstrate that AAT decreases allogeneic fibroblast-elicited natural-killer-cell influx by 89%, CD3-positive cell influx by 44%, and thioglycolate-elicited neutrophil emigration by 66%. ATT also extended islet viability in mice after streptozotocin-induced beta cell toxicity. In vitro, several islet responses to IL-1␤͞IFN␥ stimulation were examined. In the presence of AAT, islets displayed enhanced viability and inducible insulin secretion. Islets also released 36% less nitric oxide and 82% less macrophage inflammatory protein 1 ␣ and expressed 63% fewer surface MHC class II molecules. TNF␣ release from IL-1␤͞ IFN␥-stimulated islet cells was reduced by 99%, accompanied by an 8-fold increase in the accumulation of membrane TNF␣ on CD45-positive islet cells. In light of the established safety record and the nondiabetogenic potential of AAT, these data suggest that AAT may be beneficial as adjunctive therapy in patients undergoing islet transplantation.interleukin 1 ͉ nitric oxide ͉ TNF␣ I slet damage and an increased incidence of diabetes are associated with the use of immunosuppressive drugs in organ transplantation and present a major obstacle for clinically applicable human islet transplantation (1). Therefore, the advent of nondiabetogenic steroid-free, immunosuppressive treatment protocols, such as rapamycin-based protocols, have greatly facilitated human islet transplantation (reviewed in ref.2). However, although clinically effective, rapamycin-based protocols have been associated with an increased risk of hyperlipidemia and hypertension, limiting the applicability of islet transplantation to severe cases of diabetes type 1. Long-term follow-up studies reveal that the viability of engrafted islets is also compromised (3, 4).␣1-Antitrypsin (AAT), the major serum serine-protease inhibitor, inhibits the enzymatic activity of neutrophil elastase, cathepsin G, proteinase 3, thrombin, trypsin, and chymotrypsin (reviewed in ref. 5). AAT may facilitate the survival of islet transplants in engrafted patients, because the inhibitor prevents inflammatory cytokine production, blocks immune cell infiltration and function, inhibits complement activation, and delays the develop...

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“…However, the long-term survival and function of encapsulated islets is significantly compromised by a number of factors (including the porosity, size, and biocompatibility of the capsule) as well as by insufficient oxygen and nutrient supplies to encapsulated islets caused by the lack of microvascular perfusion (46). Although shielded from cell-mediated immune attack, en- capsulated islets are still subject to oxidative stress and damage caused by free radicals that are generated from activated immune cells such as macrophages, contributing to islet cell apoptosis and early graft failure (47,48). In addition, intraperitoneally transplanted microencapsulated islets are associated with significantly delayed and diminished responsiveness in releasing insulin after an oral or intravenous glucose challenge (46).…”

Section: Discussionmentioning

confidence: 99%

Elevated Vascular Endothelial Growth Factor Production in Islets Improves Islet Graft Vascularization

et al. 2004

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Successful islet transplantation depends on the infusion of sufficiently large quantities of islets, of which only ϳ30% become stably engrafted. Rapid and adequate revascularization of transplanted islets is important for islet survival and function. Delayed and insufficient revascularization can deprive islets of oxygen and nutrients, resulting in islet cell death and early graft failure. To improve islet revascularization, we delivered human vascular endothelial growth factor (VEGF) cDNA to murine islets, followed by transplantation under the renal capsule in diabetic mice. Diabetic animals receiving a marginal mass of 300 islets that were pretransduced with a VEGF vector exhibited near normoglycemia. In contrast, diabetic mice receiving an equivalent number of islets that were transduced with a control vector remained hyperglycemic. Immunohistochemistry with anti-insulin and anti-CD31 antibodies revealed a relatively higher insulin content and greater degree of microvasculature in the VEGF vector-transduced islet grafts, which correlated with significantly improved blood glucose profiles and enhanced insulin secretion in response to glucose challenge in this group of diabetic recipient mice. These results demonstrate that VEGF production in islets stimulates graft angiogenesis and enhances islet revascularization. This mechanism might be explored as a novel strategy to accelerate islet revascularization and improve longterm survival of functional islet mass posttransplantation. Diabetes 53: [963][964][965][966][967][968][969][970] 2004

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

Cited by 73 publications

References 39 publications

The Humanized NOD/SCID Mouse as a Preclinical Model to Study the Fate of Encapsulated Human Islets

The Humanized NOD/SCID Mouse as a Preclinical Model to Study the Fate of Encapsulated Human Islets

α1-Antitrypsin monotherapy prolongs islet allograft survival in mice

Elevated Vascular Endothelial Growth Factor Production in Islets Improves Islet Graft Vascularization

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