Transplantation of organ cultured fetal pig pancreas in non‐obese diabetic (NOD) mice and primates (<i>Macaca fascicularis</i>)

Mandel, T. E.; Koulmanda, Maria; Kovařík, Jiří; Georgiou, Harry M.; Francis, D. M. A.; Dawson, Peter; Stainsby, G. V.

doi:10.1111/j.1399-3089.1995.tb00079.x

Cited by 19 publications

(11 citation statements)

References 13 publications

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“…This is one of the few studies of adult porcine islet transplantation into non‐human primates [9–11], and the first in which a `standard' triple drug immunosuppressive regimen has been compared with a more suppressive non‐myeloablative regimen combined with CD154 blockade. There were, however, several other differences between the two groups that might have contributed to the varying survival of the islets.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, high titers of anti‐Gal Ab have been shown to accelerate rejection of Gal‐positive islets in α1,3galactosyltransferase (Gal)‐knockout mice, indicating that humoral responses participate in the rejection process [8]. Most studies of islet xenograft transplantation have been performed in rodents, and experiments in the pig‐to‐non‐human primate model have been uncommon [9–11].…”

Section: Introductionmentioning

confidence: 99%

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Adult porcine islet transplantation in baboons treated with conventional immunosuppression or a non‐myeloablative regimen and CD154 blockade

Bühler

Deng

O’Neil

et al. 2002

Xenotransplantation

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The aim of the present study was to assess the survival of adult porcine islets transplanted into baboons receiving either (I) conventional triple drug immunosuppressive therapy or (2) a non-myeloablative regimen and an anti-CD154 monoclonal antibody (mAb) aimed at tolerance-induction. Group 1 baboons (n = 3) were pancreatectomized prior to intraportal injection of 10,000 porcine islet equivalents (IE)/kg and immunosuppressed with anti-thymocyte globulin (ATG), cyclosporine and azathioprine. In Group 2 (n = 2), non-pancreatectomized baboons underwent induction therapy with whole body and thymic irradiation, and ATG. Extracorporeal immunoadsorption (EIA) of anti-Galalpha1,3Gal (Gal) antibody was carried out. Maintenance therapy was with cobra venom factor, cyclosporine. mycophenolate mofetil, methylprednisolone and anti-CD154 mAb. Porcine islets were injected intraportally (14,000 and 32,000 IE/kg, respectively) and high-dose pig mobilized peripheral blood progenitor cells (3 x 10(10) cells/kg) were infused into a systemic vein. Porcine islets were also implanted in the sternomastoid muscle to facilitate subsequent biopsies. In both groups. porcine C-peptide was measured, and histological examination of liver or sternomastoid muscle biopsies was performed at regular intervals. In Group 1, total pancreatectomy reduccd human C-peptide to < 0.1 ng/ml and induced insulin-requiring diabetes. The transplantation of porcine islets was followed by normalization of glycemia for 15-24 h. Porcine C-peptide was detected only transiently immediately after porcine islet injection (maximum 0.12 ng/ml). Histological examination of liver biopsies taken between days 2 and 19 did not reveal viable islets, but necrotic cell structures with mononuclear cell infiltrates were identified in portal venules. In Group 2, injection of porcine islets into non-pancreatectomized recipients induced a transient hypoglycemia (2-4 h) requiring concentrated intravenous dextrose administration. Porcine C-peptide was detectable for 5 and 3 days (maximum 2.8 and 1.0 ng/ml), respectively. Baboon #4 died on day 12 from small bowel intussusception. Liver and sternomastoid muscle biopsies showed well-preserved porcine islets, staining positive for insulin and glucacon, without signs of rejection. In baboon #5, viable islets were detected in the sternomastoid muscle biopsy on day 14, but not on day 28 or thereafter. A progressive mononuclear cell and macrophage infiltration was seen in the biopsies. In conclusion, conventional immunosuppression allowed survival of porcine islets in baboons for < 24 h. The non-myeloablative regimen prolonged survival of porcine islets for > 14 days. However, despite depletion of T cells, anti-Gal antibody and complement, and CD154-hlockade, porcine islets were rejected by day 28. These results suggest that powerful innate immune responses are involved in rejection of discordant xenogencic islets.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adult porcine islet transplantation in baboons treated with conventional immunosuppression or a non‐myeloablative regimen and CD154 blockade

Bühler

Deng

O’Neil

et al. 2002

Xenotransplantation

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“…There is a great need to learn more about how these cells develop so as to maximize growth capacity and optimize function when they are transplanted. Much work has been done on pancreases removed at the mid-fetal stage of 60-90 days' gestation, which can normalize glucose levels in recipient mice with diabetes (27,28). Although the wait for the maturation of the islet tissue is problematic and the final yield of p-cells limited, neither of these impediments seems insurmountable.…”

Section: Scientific Impediments Current State Of the Art For Islet Trmentioning

confidence: 99%

Scientific and Political Impediments to Successful Islet Transplantation

Bonner-Weir²

1997

Diabetes

130

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Islet transplantation is a treatment for diabetes that has the potential to normalize glucose levels and prevent the development of complications. In spite of the simplicity of the concept and the urgent need to provide such a treatment to patients, there has been a frustrating lack of progress. This perspective delves into the scientific and political impediments to success. The scientific barriers are the need to find a satisfactory source of insulin-producing tissue and the requirement to prevent this tissue from being destroyed by immune rejection and autoimmunity. The problems and potential of allografts, xenografts, and the development of cell lines are discussed. Multiple approaches to the prevention of immune destruction are considered, including immunobarrier devices, immunosuppression, development of tolerance, and genetic manipulation. The political barriers discussed include the problems of high expectations, the controversy surrounding targeted research, the balance between basic and applied research, the roles of industry and academia, the concerns about xenotransplantation, and the difficulties in developing a planned approach to the problem.

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“…The optimal age within the first month of life may or may not be important. Most studies carried out in neonatal pig-to-NHP islet transplantation 1 to 3 NICCs were exposed to hypoxia during culture Immunodeficient NOD-rag-1 À/À mice NICCs exposed to hypoxia remained moderately responsive to glucose stimulation and recovered after reoxygenation Emamaullee Park [121] 1 to 3 Glycoantigen study on NICCs cultured for 1, 5 and 9 days in vitro NS On day 1, NICCs expressed more mannose and fucose than after 5 or 9 days of culture Nakatsu [122] ( Table 2) and in neonatal pig-to-mouse islet transplantation models [81][82][83]102] have utilized pigs in the first week of life (Table 4). Is there any published evidence suggesting that this age is optimal?…”

Section: Discussionmentioning

confidence: 99%