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Fetal pancreas as a donor organ

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Abstract

The use of the fetal pancreas as a donor organ for the treatment of diabetes has been explored in the rat and currently is being tried in minipigs. Growth and development of a fetal pancreas under the kidney capsule of a diabetic rat is sufficient to completely reverse streptozotocin diabetes; the organ contains 20–25% of the insulin content of a normal adult pancreas. The fetal pancreas grows and develops most fully in normoglycemic environment. Cryopreservation results in nearly complete survival of the pancreas and provides time for tissue and blood typing and testing for compatibility of donor and recipient lymphocytes using the Mixed Leucocyte Reaction. These methods have been developed in human systems. Removal of the pancreas from the fetus and transplantation prior to a critical period of exocrine development (18 days in the rat, 55 in the pig) are followed by atrophy of exocrine elements and a pure endocrine organ results. This obviates the problem of exocrine enzymes. Venous drainage of insulin from the transplanted pancreas into the liver provides the most effective response when the supply of insulin is limited. Metabolic studies in successfully-transplanted rats indicate complete reversal of the diabetic state to normal. These include blood glucose and insulin levels and responses to stimuli, the activity levels of 6 enzymes in the liver, glucagon levels, and the response to arginine stimulation and glucose metabolism during and after pregnancy.

Methods that have been used to prevent rejection, all of which have been partially effective, include donor liver pretreatment and short-term immunosuppression, total lymphoid irradiation combined with donor bone marrow, and treatment of the donor organ to eliminate immune cells by digestion and culture. Additional research will be required to develop an effective and safe method for prevention of allograft rejection in the minipig prior to application to diabetic humans.

Résumé

Le pancréas foetal est utilisé comme organe donneur pour le traitement du diabète chez le rat et est actuellement testé chez le cochon miniature. Un pancréas foetal greffé sous la capsule rénale d'un rat rendu diabétique croît et se différencie suffisamment pour faire régresser complètement le diabète induit par la streptozotocine; le contenu en insuline du pancréas foetal atteint 20 à 25% de celui d'un organe adulte normal. C'est en milieu normoglycémique que la croissance et la différenciation du pancréas foetal sont le plus complètes. La cryoconservation assure une survie de la quasi-totalité du pancréas et laisse un temps suffisant pour le typage sanguin et tissulaire et les tests de compatibilité des lymphocytes du donneur et du receveur en culture mixte de lymphocytes. Ces méthodes sont en cours d'élaboration pour les tissus humains. L'exérèse du pancréas foetal et sa greffe avant la période critique du développement exocrine (18 jours chez le rat, 55 chez le porc) provoque l'atrophie des éléments exocrines et il en résulte un organe purement endocrine, ce qui résoud le problème des enzymes des sécrétions exocrines. C'est le drainage portal de l'insuline du greffon qui donne le meilleur résultat lorsque la production d'insuline est limitée. Les paramètres métaboliques des rats diabétiques transplantés avec succès reviennent complètement à la normale; en particulier la glycémie et l'insulinémie et leur réponse aux stimuli, les activités de 6 enzymes hépatiques, les taux de glucagon et leur réponse à la stimulation par l'arginine et le métabolisme du glucose pendant et après une grossesse.

Parmi les méthodes utilisées pour prévenir le rejet, et qui toutes ont montré une efficacité partielle, figurent le prétraitement du foie du donneur et l'immunosuppression, l'irradiation lymphoïde totale associée à la moëlle osseuse de donneur, et le traitement de l'organe donneur pour éliminer les cellules immunitaires par digestion et mise en culture. Des recherches supplémentaires sont nécessaires pour mettre au point une méthode efficace et sûre de prévention du rejet des hétérogreffes chez le porc miniature avant l'application au diabète humain.

Resumen

El uso del páncreas fetal como órgano donante en el tratamiento de la diabetes ha sido explorado en la rata y actualmente está siendo ensayado en cerdos. El crecimiento y desarrollo del páncreas fetal colocado bajo la cápsula del riñón de una rata diabética son suficientes para revertir en forma completa la diabetes inducida por estreptozotocina; el órgano así transplantado exhibe un 20–25% del contenido de insulina de un páncreas adulto normal. El páncreas fetal se desarrolla al máximo en un ambiente normoglicémico. La criopreservación resulta en supervivencia casi completa del páncreas y representa ganancia de tiempo para la tipificación tisular y sanguínea y para realizar pruebas de compatibilidad de los linfocitos donantes y recipientes mediante la Reacción de Linfocitos Mixtos. Estos métodos han sido desarrollados en sistemas humanos. La excisión del pancreas del feto y su transplante antes del período crítico de desarrollo exocrino (18 días en la rata, 55 en el cerdo) produce atrofia de los elementos exocrinos y da como resultado un órgano endocrino puro, lo cual elimina el problema de la enzimas exocrinas. El drenaje venoso de la insulina que secreta el páncreas transplantado hacia el hígado hace posible la más efectiva respuesta en condiciones en las cuales la provisión de insulina es limitada. Estudios metabólicos en ratas exitosamente trasplantadas indican la reversión completa de la diabetes a un estado normal. Tales estudios incluyen niveles de glucosa y de insulina sanguínea y su respuesta a estímulos, niveles de actividad de 6 enzimas en el hígado, niveles de glucagón y su respuesta a estimulación con arginina y el metabolismo de glucosa durante y después del embarazo.

Los métodos utilizados para prevenir el rechazo, los cuales son parcialmente efectivos, incluyen el pretratamiento con inyecciones intravenosas de extracto de hígado adulto donante e inmunosupresión a corto término, la irradiación linfocítica total combinada con inyección de médula ósea adulta donante y el tratamiento del órgano donante, o sea el páncreas fetal, por medio de la digestión y el cultivo para eliminar las células inmunes. Se requiere realizar investigación adicional para el desarrollo de un método efectivo y seguro que logre prevenir el rechazo del alotransplante en el cerdo antes de su aplicación a diabéticos humanos.

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Authors and Affiliations

  1. Department of Medicine, School of Medicine, Dental Research Institute and Molecular Biology Institute, University of California at Los Angeles, California, USA

    Josiah Brown M.D., John A. Danilovs Ph.D., William R. Clark Ph.D. & Yoko S. Mullen M.D., Ph.D.

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  1. Josiah Brown M.D.
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  2. John A. Danilovs Ph.D.
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  3. William R. Clark Ph.D.
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  4. Yoko S. Mullen M.D., Ph.D.
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Additional information

Supported by NIH Grant AM 17980, AM 20827, The Kroc Foundation and the American Diabetes Association.

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Brown, J., Danilovs, J.A., Clark, W.R. et al. Fetal pancreas as a donor organ. World J. Surg. 8, 152–157 (1984). https://doi.org/10.1007/BF01655130

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