CD154 Blockade for Induction of Mixed Chimerism and Prolonged Renal Allograft Survival in Nonhuman Primates

Costimulatory blockade with anti‐CD154 monoclonal antibody (aCD154) prolongs allograft survival in nonhuman primates, but has not reliably induced tolerance when used alone. In the current studies, we evaluated the effect of adding CD154 blockade to a chimerism inducing nonmyeloablative regimen in p...

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Bibliographic Details
Published in:American journal of transplantation 2004-09, Vol.4 (9), p.1391-1398
Main Authors: Kawai, Tatsuo, Sogawa, Hiroshi, Boskovic, Svetlan, Abrahamian, Gregory, Smith, Rex‐Neal, Wee, Siew‐Lin, Andrews, David, Nadazdin, Ognjenka, Koyama, Ichiro, Sykes, Megan, Winn, Henry J., Colvin, Robert B., Sachs, David H., Cosimi, A. Benedict
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - therapeutic use
CD154 blockade
CD40 Ligand - immunology
Graft Survival - immunology
Immune Tolerance
kidney transplantation
Kidney Transplantation - immunology
Macaca fascicularis
mixed chimerism
Models, Animal
Thromboembolism - prevention & control
tolerance
Transplantation Chimera - immunology
Transplantation Conditioning
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Summary:Costimulatory blockade with anti‐CD154 monoclonal antibody (aCD154) prolongs allograft survival in nonhuman primates, but has not reliably induced tolerance when used alone. In the current studies, we evaluated the effect of adding CD154 blockade to a chimerism inducing nonmyeloablative regimen in primates. We observed a significant improvement of donor bone marrow (DBM) engraftment, which has been associated with a lower incidence of acute rejection and long‐term survival of renal allografts without the need for previously required splenectomy. Among the long‐term survivors, four never showed evidence of rejection, with the longest survival exceeding 1700 days following discontinuation of immunosuppression. Nevertheless, late chronic rejection was observed in three of eight recipients, indicating the necessity of further modifications of the regimen. Control recipients receiving no DBM or donor splenocytes in place of DBM rejected their allografts. Thus, DBM engraftment with, at least, transient mixed chimerism appears essential for induction of allograft tolerance using this conditioning regimen. Modification of the original mixed chimerism approach, by the addition of costimulatory blockade, has been shown to enhance mixed chimerism and induce renal allograft tolerance with less morbidity in nonhuman primates.
ISSN:1600-6135
1600-6143
DOI:10.1111/j.1600-6143.2004.00523.x