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Pancreatic islet transplantation: Immuno-alteration with ultraviolet irradiation

Abstract

To circumvent rejection of allogeneic pancreatic islet grafts, we have examined the use of ultraviolet (UV) irradiation to inactivate allostimulatory cells in blood prior to their use for the induction of donor-specific tolerance and to decrease the immunogenicity of pancreatic islets by direct UV irradiation. UVB (280–320 nm) irradiation of blood can effectively abrogate lymphocyte stimulatory capacity in an MLC, while subsequent transfusions of appropriately UV irradiated blood have indefinitely prolonged islet allograft survival in the Lewis to ACI rat strain combination (greater than 250 days), without the use of immunosuppressive agents. This treatment is donor specific in that third-party W/F islet allograft survival is not prolonged in ACI rats transfused with UV-treated Lewis blood (MST, 7.5 days). When W/F rats are used as donors of blood, moderate prolongation of W/F islet allograft survival is obtained (MST of 21±12 days). When non-UV-treated W/F blood is transfused, rejection of W/F islets is accelerated (MST of 2 days versus no treatment control of 6.5 days) in the ACI recipient.

UV irradiation of rat dendritic cells can completely abrogate their powerful stimulatory activity in an MLC at a dose of 900 J/m2. Rat islets subjected to this same dose of UV irradiation do not exhibit any alteration in their endocrine function when transplanted into syngeneic diabetic animals. UV irradiated (900 J/m2) Lewis islets transplanted into non-immunosuppressed ACI rats showed marked prolongation of survival (greater than 80 days).

We conclude that UV irradiation is effective in immuno-alteration of the stimulatory cells in blood and can selectively decrease immunogenicity of pancreatic islets without being deleterious to their endocrine function. Both these methods are readily applicable to islet transplantation in other animals and eventually in humans.

Résumé

Nous avons étudié l'efficacité des radiations ultraviolettes (UV) dans la prévention du rejet des greffes d'îlots pancréatiques, afin d'inactiver les cellules sanguines activatrices, avant de les utiliser pour induire chez le receveur une tolérance spécifique du donneur; et diminuer l'immunogénicité des îlots pancréatiques.

L'irradiation UV (à 280–320 nm) du sang abolit le pouvoir activateur des lymphocytes en culture mixte de lymphocytes, et les transfusions faites ensuite avec du sang correctement traité prolongent indéfiniment la survie d'îlots de rat Lewis greffés chez des rats ACI (250 jours), sans besoin d'agent immunosuppresseur. Ce traitement est spécifique du donneur dans la mesure où la survie des hétérogreffes d'îlots de rat W/F n'est pas prolongée chez les rats ACI transfusés avec du sang de Lewis traité aux UV (durée moyenne de survie 7,5 jours). Lorsque des rats W/F sont utilisés comme donneurs de sang, on obtient une prolongation modeste de la survie d'hétérogreffes d'îlots W/F (survie moyenne 21±12 jours). Lorsque du sang de W/F non-traité par les UV est transfusé, le rejet est accéléré (durée moyenne de survie=2 jours contre 6,5 jours pour les témoins sans traitement) chez le receveur ACI.

L'irradiation UV des cellules dendritiques de rat à la dose de 900 J/m2 supprime complètement leur pouvoir stimulant en culture mixte de lymphocytes. Les îlots de rats soumis á cette même dose de rayons UV conservent intacte leur fonction endocrine lorsqu'ils sont transplantés chez des animaux de même lignée rendus diabétiques. Les greffes d'îlots pancréatiques de rat Lewis irradiés par les UV (900 J/m2), chez des rats ACI non-immunodéprimés, ont une survie nettement prolongée (> 80 jours).

Nous en concluons que l'irradiation UV réduit efficacement l'immunogénicité des cellules stimulatrices du sang et diminue sélectivement l'antigénicité des îlots pancréatiques, sans dommage pour leur fonction endocrine. Ces deux méthodes sont immédiatement applicables à la transplantation d'îlots d'autres espèces et ultérieurement chez l'homme.

Resumen

Con intención de eludir el rechazo en aloinjertos de islotes pancreáticos estudiamos el uso de la irradiación ultravioleta (UV) en la inactivación previa de células aloestimuladoras en sangre del donante con intención de inducir un estado de tolerancia específica al donante; y en la disminución de la inmunogenicidad de islotes pancreáticos con la irradiación UV directa de estos. La irradiación UVB (280–320 NM) sanguinea puede eliminar de forma efectiva la capacidad estimuladora de linfocitos en cultivo mixto de linfocitos (MLC) mientras que transfusiones subsecuentes de sangre irradeada con UV prolonga indefinidamente (más de 250 días) la supervivencia de aloinjertos de islotes de ratas Lewis a ratas ACI sin el uso de drogas inmunosupresoras. Este tratamiento es donante-específico ya que la supervivencia de aloinjertos de islotes W/F de tercer partido no es prolongada en ratas ACI transfundidas con sangre de ratas Lewis irradiadas con UV (promedio de supervivencia 7.5 días). El uso de ratas W/F como donantes de sangre resulta en una prolongación moderada en la supervivencia de aloinjertos de islotes de ratas W/F (21±12 días). La transfusión de sangre no irradiada de ratas W/F acelera el rechazo de aloinjertos de islotes de ratas W/F a recipientes ACI (2 días comparado con 6.5 días para el control no tratado).

La irradiación UV de las células dendríticas en ratas con una dosis de 900 J/M2 puede totalmente abolir su actividad estimuladora en MLC. Islotes de ratas sometidos a la misma dosis de irradiación UV no demuestran alteración en su función endocrina cuando son transplantados a un animal singénico diabético. El transplante de islotes de ratas Lewis, irradiadas con UV (900 J/M2), a ratas ACI no inmunosuprimidas resultó en una prolongación marcada en la supervivencia del aloinjerto (más de 80 días).

Concluímos que la irradiación UV es efectiva en la inmunoalteración de las células estimuladoras sanguíneas y que puede selectivamente disminuir la inmunogenicidad de islotes pancréaticos sin afectar la función endocrina. Ambos métodos son facilmente aplicables al transplante de islotes en otros animales y eventualmente en el humano.

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Correspondence to Mark A. Hardy M.D..

Additional information

Supported by NIH grants AM 30468 and HL 14799 and JDF grant CU 50190201.

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Hardy, M.A., Lau, H.T., Weber, C. et al. Pancreatic islet transplantation: Immuno-alteration with ultraviolet irradiation. World J. Surg. 8, 207–213 (1984). https://doi.org/10.1007/BF01655137

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Keywords

  • Pancreatic Islet
  • Islet Transplantation
  • Islet Graft
  • Pancreatic Islet Transplantation
  • Irradiate Blood