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Transplantation of organ-cultured fetal pancreas: Experimental studies and potential clinical application in diabetes mellitus

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Abstract

Transplantation of organ-cultured fetal islets of Langer-hans may be one way of overcoming the dual difficulties of finding a suitable source of tissue and controlling graft rejection. Experiments in mice have clearly shown that fetal pancreas is an excellent source of islets. Tissue from one donor can be used to treat one or more recipients and provides excellent control of drug-induced diabetes, including prevention of diabetic renal microangiopathy. The fetal islets display selective survival in vitro and organ culture can be used to obtain large amounts of tissue for transplantation. In addition, growth in “normoglycemic” media results in functional maturation of the fetal tissue.

Culture conditions can be modified to eliminate from the putative graft immunogenic “passenger leukocytes,” the cells responsible for initiating graft rejection. Such immunogenic cell—depleted grafts can be transplanted across histocompatibility barriers without the need for recipient immunosuppression.

Fetal human pancreas shares many properties in common with fetal mouse pancreas. Continuing growth and differentiation occur in vitro and following xenotransplantation into athymic mice. However, fetal human pancreas is frequently damaged by ischemia before it can be used, and also appears to be more susceptible to oxygen toxicity than is fetal mouse pancreas. Nevertheless, when fresh human tissue is available, it may be a suitable source of islets for transplantation in type I diabetics.

Résumé

La greffe d'îlots de Langerhans foetaux mis en culture est susceptible de résoudre deux des problèmes posés par la transplantation pancréatique: celui de la source de tissu, et celui du contrôle du rejet. Les études faites chez la souris ont clairement démontré que le pancréas foetal est une excellente source d'îlots. Le tissu d'un seul donneur suffit à traiter un ou plusieurs receveurs et assure un équilibre parfait du diabète expérimental induit par les drogues et la prévention des complications rénales de la microangiopathie diabétique. Les îlots foetaux survivent sélectivement in vitro et la culture de tissu fournit de grandes quantités de tissu pour la greffe. En outre, la culture en milieu “normoglycémique” entraîne la maturation fonctionnelle du tissu foetal.

Les conditions de culture peuvent être modifiées pour éliminer des futurs greffons les “leucocytes passagers”, cellules responsables de la mise en route du processus de rejet. De tels greffons déplétés en cellules immunogéniques peuvent être transplantés en transgressant les barrières de la compatibilité tissulaire, sans besoin d'immunosuppression chez le receveur.

Le pancréas foetal humain a beaucoup de caractères en commun avec le pancréas foetal de souris. Sa croissance et sa différenciation se poursuivent in vitro et après xénogreffe chez la souris athymique. Néanmoins le pancréas foetal humain présente souvent des lésions d'ischémie avant de pouvoir être utilisé, et paraît aussi plus sensible à la toxicité de l'oxygène que le pancréas foetal de souris. Toutefois, quand du tissu humain frais sera disponible, il pourra constituer une source convenable d'îlots pour la transplantation chez des diabétiques insulinodépendants.

Resumen

El injerto de islotes fetales cultivados puede representar una manera de sobrepasar la dificultad en encontrar fuente apropiada de tejido y el control del rechazo del injerto. Experimentos en ratones han claramente demonstrado que el pancreas fetal es una fuente excelente de islotes. Tejido derivado de un donante puede ser utilizado en el transplante de más de un recipiente y provee control excelente de diabetes inducida por medicamentos y causa la prevención de la microangiopatia renal diabética. Los islotes fetales demuestran supervivencia selectiva en vitro y su cultivo puede ser utilizado para obtener grandes cantidades de tejido para transplante. Similarmente el crecimiento normoglicémico resulta en la maduración funcional del tejido fetal.

Las condiciones de cultivo pueden modificarse para eliminar del injerto los “linfocitos pasajeros,” células responsables por iniciar el rechazo de injerto. Estos injertos faltos de taies células inmunogénicas pueden ser transplantados a través barreras de histocompatibilidad sin necesidad de utilizar inmunosupresión. El páncreas fetal humano tiene muchas características en común con el páncreas fetal del ratón. El crecimiento y la diferenciación continua en vitro y después de xenoinjerto en ratones atímicos. Sin embargo el páncreas fetal humano sostiene frecuentemente daño isquémico antes de transplantarlo y aparenta ser más susceptible a la toxicidad de oxígeno que el pancreas fetal del ratón. Tejido pancreático fetal humano puede ser fuente apropiada de islotes para injerto en diabéticos insulino-dependientes.

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Correspondence to Dr. T. E. Mandel M.B., B.S..

Additional information

Supported by the National Health and Medical Research Council of Australia, NIH Grant AM 27683; and grants from J.B. Were & Sons, Perpetual Trustees and Executors Association of Australia, the Gavemer Foundation, and the John Claude Kellion Foundation.

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Mandel, T.E. Transplantation of organ-cultured fetal pancreas: Experimental studies and potential clinical application in diabetes mellitus. World J. Surg. 8, 158–168 (1984). https://doi.org/10.1007/BF01655131

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Keywords

  • Graft Rejection
  • Athymic Mouse
  • Potential Clinical Application
  • Functional Maturation
  • Suitable Source