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Total lymphoid irradiation in renal transplantation

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Abstract

Total lymphoid irradiation (TLI), used in the treatment of some patients with Hodgkin's disease, produces profound immunological changes. In small rodents, mice and rats, a modified version of TLI results in transplantation tolerance for skin and heart allografts. The concept has been expanded to large outbred animals. In baboons transplantation tolerance has been produced for kidney and liver transplantation. The tolerance meets the in vivo and in vitro immunological requirements of durability and specificity. Baboons are currently surviving with normal graft function more than 6 years after kidney transplantation. Kidney-donor derived skin grafts are accepted permanently, and third-party skin and kidney grafts are rejected by these tolerant animals. Late chronic rejection occurs in a minority of animals between 6 and 12 months after transplantation. No grafts have been rejected by baboons with normal graft function at 1 year. The most successful protocol in baboons has involved a low cumulative dose (800 cGy), twice a week fractionation regimen of irradiation administered to a wider field than that used in the treatment of Hodgkin's disease. Up to two-thirds of such animals are rendered tolerant. The role of adjuvant immunosuppressive drug therapy in increasing the tolerant fraction obtained is currently under evaluation. Encouraging results with the use of several methods of TLI in clinical renal transplantation are emerging from 5 centers. The prospect of achieving transplantation tolerance with TLI in the clinical context may be realized with further experience and modification of techniques.

Résumé

L'irradiation totale du tissu lymphoïde (TLI) employée pour traiter quelques malades atteints de maladie de Hodgkin entraîne des modifications immunologiques considérables. Chez les petits rongeurs, souris et rats, une modification technique de l'irradiation totale se traduit par la tolérance de l'allogreffe cutanée ou cardiaque. Il en est de même chez d'autres animaux d'élevage de plus grande taille. C'est ainsi que chez les babouins la tolérance à la transplantation rénale et hépatique a pu être crée. Elle répond aux exigences de l'immunologie en ce qui concerne la durée et la sensibilité aussi bien in vitro que in vivo. Les babouins survivent facilement plus de 6 ans après la transplantation en présentant des fonctions rénales normales. Les greffes de la peau des donneurs rénaux sont tolérées en permanence alors que les greffes de peau et de rein d'un tiers parti sont rejetés. Dans quelques cas la réjection chronique tardive se manifeste de 6 mois à 12 mois après la transplantation. Après 1 an de fonctionnement normal du transplant aucune greffe n'est rejetée. Le meilleur protocole consiste en l'administration d'une dose totale faible de rayons: 800 cGy à raison de 80 à 400 unités 2 fois par semaine le champ d'irradiation étant plus large que celui adopté pour le traitement de la maladie de Hodgkin. Le rôle de l'adjonction de drogue immunodépressives pour augmenter la tolérance est en cours d'études. Des résultats encourageants qui concernent plusieurs méthodes d'irradiation totale du tissu lymphoïde appliquées à la transplantation rénale proviennent de plusieurs centres. Le projet d'aboutir à une tolérance absolue de la greffe par le receveur grâce à cette méthode peut être envisagé en fonction d'une plus grande expérience et des modifications apportées aux modalités de l'irradiation.

Resumen

La irradiación linfoide total (ILT) utilizada en el tratamiento de algunos pacientes con enfermedad de Hodgkin produce profundas alteraciones immunológicas. En los roedores pequeños, ratones y ratas, una version modificada de la ILT resulta en tolerancia al aloinjerto de piel y de corazón. El concepto ha sido expandido para incluír animales grandes de vida exterior. La tolerancia al transplante en mandriles ha sido lograda para el transplante de riñón y de hígado. La tolerancia alcanza los límites de requerimiento inmunológico in vivo e in vitro en cuanto a durabilidad y especificidad. Los mandriles se mantienen en estado de supervivencia con función normal de los transplantes por más de 6 años después del transplante renal. Los transplantes de piel derivados de animales donantes de rinón son aceptados en forma permanente, mientras que injertos de piel y de riñón de un tercer animal son rechazados por estos recipientes tolerantes. El rechazo tardío crónico ha ocurrido en una minoría de los animales entre 6 y 12 meses después del transplante. No se ha producido ningún rechazo en los mandriles con función normal del transplante al cabo de un año. El protocolo más exitoso en los mandriles ha significado una dosis acumulativa baja (800 cGy), 2 veces a la semana en regimen de fraccionamiento de la irradiación administrado a un campo mas amplio del que se utilizó en el tratamiento de la enfermedad de Hodgkin. Hasta 2/3 partes de estos animales han sido convertidos a tolerancia. El papel de la terapia con droga immunosupresiva en cuanto al aumento de la fracción de tolerancia está en evaluación en el momento actual. Resultados promisorios con el uso de diversos métodos de ILT en el transplante clínico renal comienzan a surgir de 5 centros diferentes. La perspectiva de lograr la tolerancia del transplante mediante la ILT en el contexto clínico puede ser lograda mediante una mayor experiencia y modificación de estas técnicas.

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Authors and Affiliations

  1. Transplantation Research Unit, Department of Surgery, University of Witwatersrand, South Africa

    J. Albertus Myburgh M.B., Ch.M., F.R.C.S., F.A.C.S.(Hon), F.R.C.S.(Hon), Jacobus A. Smit D.Phil., Anthony M. Meyers M.B., B.Ch., F.C.P.(S.A.), J. René Botha M.B., Ch.B.,F.C.S.(S.A.), Selma Browde M.B., B.Ch., M.Med. (Rad.T) & Peter D. Thomson M.B., B.Ch., F.C.P. (Ped.) (S.A.)

  2. Departments of Medicine, Radiotherapy, and Pediatrics, University of the Witwatersrand, South Africa

    J. Albertus Myburgh M.B., Ch.M., F.R.C.S., F.A.C.S.(Hon), F.R.C.S.(Hon), Jacobus A. Smit D.Phil., Anthony M. Meyers M.B., B.Ch., F.C.P.(S.A.), J. René Botha M.B., Ch.B.,F.C.S.(S.A.), Selma Browde M.B., B.Ch., M.Med. (Rad.T) & Peter D. Thomson M.B., B.Ch., F.C.P. (Ped.) (S.A.)

  3. Johannesburg Hospital, Johannesburg, South Africa

    J. Albertus Myburgh M.B., Ch.M., F.R.C.S., F.A.C.S.(Hon), F.R.C.S.(Hon), Jacobus A. Smit D.Phil., Anthony M. Meyers M.B., B.Ch., F.C.P.(S.A.), J. René Botha M.B., Ch.B.,F.C.S.(S.A.), Selma Browde M.B., B.Ch., M.Med. (Rad.T) & Peter D. Thomson M.B., B.Ch., F.C.P. (Ped.) (S.A.)

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  1. J. Albertus Myburgh M.B., Ch.M., F.R.C.S., F.A.C.S.(Hon), F.R.C.S.(Hon)
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  2. Jacobus A. Smit D.Phil.
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  3. Anthony M. Meyers M.B., B.Ch., F.C.P.(S.A.)
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  4. J. René Botha M.B., Ch.B.,F.C.S.(S.A.)
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  5. Selma Browde M.B., B.Ch., M.Med. (Rad.T)
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  6. Peter D. Thomson M.B., B.Ch., F.C.P. (Ped.) (S.A.)
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Supported by the South African Medical Research Council and the Council of the University of the Witwatersrand.

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Myburgh, J.A., Smit, J.A., Meyers, A.M. et al. Total lymphoid irradiation in renal transplantation. World J. Surg. 10, 369–380 (1986). https://doi.org/10.1007/BF01655296

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