A COMPARISON OF FETAL AND ADULT PORCINE ISLETS WITH REGARD TO Gal?? (1,3)Gal EXPRESSION AND THE ROLE OF HUMAN IMMUNOGLOBULINS AND COMPLEMENT IN ISLET CELL CYTOTOXICITY1

Bennet, William; Björkland, Anna; Sundberg, Berit; Davies, Hugh; Liu, Jining; Holgersson, Jan; Korsgren, Olle

doi:10.1097/00007890-200004270-00030

Cited by 56 publications

(40 citation statements)

References 19 publications

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“…The rationale for this was that expression of ␣-galactosyl epitopes on neonatal porcine islet cells has previously been shown (23). No staining of any of these islet endocrine cells with BS-1 was detected, which is consistent with the findings that these epitopes are not expressed in adult pig (24) or adult mouse (22) pancreatic tissue.…”

Section: Discussionsupporting

confidence: 81%

Decreased Vascular Density in Mouse Pancreatic Islets After Transplantation

2002

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An adequate revascularization is crucial for islet survival and function after transplantation. Previous studies have suggested that islet revascularization is concluded within 14 days after transplantation. We investigated if the vascular density of transplanted islets and endogenous pancreatic islets differs. Cultured islets were syngeneically transplanted into the kidney, liver, or spleen of C57BL/6 mice. One month later, the graft-bearing organ was removed, and histological specimens were prepared and stained for endothelium with the lectin Bandeiraea simplicifolia. Pancreata from nontransplanted control animals were prepared similarly. Uniform staining of endothelium within the grafts and endogenous islets was obtained. The vascular density was markedly decreased in transplanted islets at all implantation sites, but preferentially in islets implanted into the spleen. The vascular density in the connective tissue surrounding the transplanted islets was very high compared with that of graft intra-islet capillaries. A much lower vascular density was detected in connective tissue surrounding implanted microspheres of a size similar to the islets, which suggests that the islets per se induced blood vessel formation in their vicinity. We conclude that the vascular density in revascularized transplanted islets is markedly decreased compared with endogenous islets. This has potential implications for islet graft metabolism and function. Diabetes 51: [1362][1363][1364][1365][1366] 2002 T he recent application of a new treatment regimen, the so-called Edmonton protocol, has markedly improved the outcome of clinical islet transplantation (1,2). When applying this protocol, however, transplantation of a large number of islets (Ͼ9,000 islet equivalent [IEQ]/kg body wt) has been shown to be necessary to achieve insulin independence. Because of the limited availability of islet tissue, this severely restricts the number of patients who may be treated with islet transplantation. Methods to reduce the number of islets needed to cure a diabetic individual are therefore warranted.Endogenous pancreatic islets have a unique glomerularlike angioarchitecture with a high blood perfusion of 5-7 ml ⅐ min -1 ⅐ g -1 tissue (3,4). This secures an optimal delivery of oxygen and nutrients to islet cells and ensures an adequate dispersal of secreted hormones. When islets are isolated and cultured before transplantation, the islet endothelium dedifferentiates or degenerates (5). A rapid revascularization is therefore crucial for islet function after transplantation, and this has been shown to occur within 7-14 days (6,7). However, the extent of revascularization has not been thoroughly studied, and recent experiments on islets transplanted to the renal, splenic, or hepatic subcapsular space have suggested that this process is insufficient to achieve optimal oxygenation of the transplanted islets (8 -10).The aim of the present study was to compare the vascular density of endogenous pancreatic islets to that of mouse islets syngeneically ...

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Section: Discussionsupporting

confidence: 81%

Decreased Vascular Density in Mouse Pancreatic Islets After Transplantation

2002

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“…Early studies suggested abundant expression of a-Gal on porcine fetal endocrine cells (2); a finding that was debated because of the lack of sensitivity and specificity of the Griffonia simplicifolia IB 4 (4,5), whereas the expression of a-Gal in adult porcine islets is less consistent and appears to be confined to nonendocrine cells (4,5). Still, the role of a-Gal/anti-Gal in pig islet xenograft rejection is controversial, and it has been suggested that although pig islet xenografts are susceptible to antibody-mediated rejection in a1,3-galactosyltransferase (a1,3Gal-T) knockout mice, rejection could not be triggered by anti-Gal and complement (6).…”

Section: Antibodies (Abs) Specific For Carbohydrates Are a Major Concmentioning

confidence: 99%

Anticarbohydrate Antibody Repertoires in Patients Transplanted with Fetal Pig Islets Revealed by Glycan Arrays

Blixt

Kumagai‐Braesch

Tibell

et al. 2009

American Journal of Transplantation

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Ten patients with type I diabetes were transplanted with porcine fetal islet-like cell clusters (ICC) between 1990 and 1993. A significant rise in the anti-a -Gal antibody titers was seen posttransplant, but also nona -Gal-specific antibodies were detected in some patients. We have reanalyzed the carbohydrate specificity of antibodies in the sera from seven of these patients taken before transplantation, 1, 6 and 12 months posttransplantation using a glycan array with 200 structurally defined glycans. The main findings were: (i) prepig ICC transplantation patients had antibodies reactive with terminal a -GalNAc (e.g. the Forssman antigen, but not the blood group A determinant in blood group A patients), a -Gal (except blood group B determinants in B individuals), b 3-linked Gal especially Galb 1,3GlcNAc even if terminally sulfated or sialylated, b -GlcNAc except if b 1,3-linked and oligomannosyl compounds; (ii) the titers of all carbohydrate-specific antibodies detected before transplantation rose after transplantation; (iii) the kinetics of the antibody responses differed between patients; (iv) in some patients antibodies reacting with Gala 1,3Lex and several structures terminated with Neu5Gc appeared after transplantation. In conclusion, anti-a -Gal antibodies are the predominant anticarbohydrate antibodies detected after porcine ICC transplantation, with some patients also developing Neu5Gc-specific antibodies. Their clinical significance needs to be established.Key words: Anticarbohydrate antibodies, blood groups, glycan arrays, islet transplantation, xenotransplantation Abbreviations: a 1,3Gal-T, a 1,3-

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“…Each of these sources is associated with distinct advantages and disadvantages in terms of biocompatibility in foreign systems. Sources assert that FP ICCs and NPCCs express the porcine "Gal" epitope, an immunogenic carbohydrate chain incompatible with transplantation in humans, to a greater extent than adult porcine islets [ 43 ]. Should a fragment of a transplanted islet be incompletely encapsulated and protruding into the "extracapsular" environment, preformed human anti-Gal IgM and IgG antibodies immediately recognize this epitope, trigger the complement cascade, and compromise porcine islet survival [ 44 ].…”

Section: +mentioning

confidence: 99%

“…Therefore, they are economically ineffi cient to harvest, isolate and culture compared to FP ICCs and neonatal islets. Like neonatal islets, adult porcine islets express gal alpha [1,3] gal antigens, albeit to a signifi cantly lesser extent [ 43 ]. Consequently, anti-gal antibodies present in human sera are responsible for the lysis of exposed neonatal islet cells, but have a diminished role in the eradication of incompletely encapsulated adult islets [ 74 ].…”

Section: Fetal Porcine Islet-like Cell Clustersmentioning

confidence: 99%

Immunological Challenges Facing Translation of Alginate Encapsulated Porcine Islet Xenotransplantation to Human Clinical Trials

Krishnan

Foster

et al. 2016

Methods in Molecular Biology

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Transplantation of alginate-encapsulated islets has the potential to treat patients suffering from type I diabetes, a condition characterized by an autoimmune attack against insulin-secreting beta cells. However, there are multiple immunological challenges associated with this procedure, all of which must be adequately addressed prior to translation from trials in small animal and nonhuman primate models to human clinical trials. Principal threats to graft viability include immune-mediated destruction triggered by immunogenic alginate impurities, unfavorable polymer composition and surface characteristics, and release of membrane-permeable antigens, as well as damage associated molecular patterns (DAMPs) by the encapsulated islets themselves. The lack of standardization of signifi cant parameters of bioencapsulation device design and manufacture (i.e., purifi cation protocols, surface-modifi cation grafting techniques, alginate composition modifi cations) between labs is yet another obstacle that must be overcome before a clinically effective and applicable protocol for encapsulating islets can be implemented. Nonetheless, substantial progress is being made, as is evident from prolonged graft survival times and improved protection from immune-mediated graft destruction reported by various research groups, but also with regard to discoveries of specifi c pathways involved in explaining observed outcomes. Progress in the latter is essential for a comprehensive understanding of the mechanisms responsible for the varying levels of immunogenicity of certain alginate devices. Successful translation of encapsulated islet transplantation from in vitro and animal model testing to human clinical trials hinges on application of this knowledge of the pathways and interactions which comprise immune-mediated rejection. Thus, this review not only focuses on the different factors contributing to provocation of the immune reaction by encapsulated islets, but also on the defi ning characteristics of the response itself.

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A COMPARISON OF FETAL AND ADULT PORCINE ISLETS WITH REGARD TO Gal?? (1,3)Gal EXPRESSION AND THE ROLE OF HUMAN IMMUNOGLOBULINS AND COMPLEMENT IN ISLET CELL CYTOTOXICITY1

Cited by 56 publications

References 19 publications

Decreased Vascular Density in Mouse Pancreatic Islets After Transplantation

Decreased Vascular Density in Mouse Pancreatic Islets After Transplantation

Anticarbohydrate Antibody Repertoires in Patients Transplanted with Fetal Pig Islets Revealed by Glycan Arrays

Immunological Challenges Facing Translation of Alginate Encapsulated Porcine Islet Xenotransplantation to Human Clinical Trials

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