Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154

Norma S Kenyon, M. Chatzipetrou, M. Masetti, A. Ranuncoli, M. Oliveira, J. L. Wagner, A. D. Kirk, D. M. Harlan, L. C. Burkly, Camillo Ricordi

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Abstract

Reported effects of anti-CD154 treatment on autoimmunity, alloreactivity, and inflammatory events mediated by macrophages and endothelial cells indicated that it might be an ideal agent for the prevention of intrahepatic islet allograft failure. This hypothesis was tested in MHC-mismatched rhesus monkeys. Transplantation of an adequate number of viable islets resulted in engraftment and insulin independence in six of six recipients treated with anti-CD154 (hu5c8) induction plus monthly maintenance therapy (postoperative day >125, >246, >266, >405, >419, >476). AntiCD154 (hu5cS) displayed no inhibitory effect on islet cell function. For monkeys followed for >100 days, continued improvement in graft function, as determined by first phase insulin release in response to intravenous glucose, was observed after the first 100 days post-transplant. No evidence of toxicity or infectious complications has been observed. All recipients treated with anti-CD154 became specifically nonresponsive to donor cells in mixed lymphocyte reactions. Furthermore, three monkeys are now off therapy (> 113, >67, and >54 days off anti-CD154), with continued insulin independence and donor-specific mixed lymphocyte reaction hyporeactivity. In striking contrast to all previously tested strategies, transplantation of an adequate number of functional islets under the cover of anti-CD154 (hu5c8) monotherapy consistently allows for allogeneic islet engraftment and long-term insulin independence in this highly relevant preclinical model.

Original languageEnglish
Pages (from-to)8132-8137
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number14
DOIs
StatePublished - Jul 6 1999

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Macaca mulatta
Allografts
Insulin
Mixed Lymphocyte Culture Test
Haplorhini
Transplantation
Transplants
Autoimmunity
Islets of Langerhans
Endothelial Cells
Macrophages
Glucose
Therapeutics

ASJC Scopus subject areas

  • Genetics
  • General

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Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154. / Kenyon, Norma S; Chatzipetrou, M.; Masetti, M.; Ranuncoli, A.; Oliveira, M.; Wagner, J. L.; Kirk, A. D.; Harlan, D. M.; Burkly, L. C.; Ricordi, Camillo.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 14, 06.07.1999, p. 8132-8137.

Research output: Contribution to journalArticle

Kenyon, Norma S ; Chatzipetrou, M. ; Masetti, M. ; Ranuncoli, A. ; Oliveira, M. ; Wagner, J. L. ; Kirk, A. D. ; Harlan, D. M. ; Burkly, L. C. ; Ricordi, Camillo. / Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154. In: Proceedings of the National Academy of Sciences of the United States of America. 1999 ; Vol. 96, No. 14. pp. 8132-8137.
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