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 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.
Department of Surgery, Transplantation Unit, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. tkawai@partners.org
Tatsuo
T
Kawai
Hiroshi
H
Sogawa
Svetlan
S
Boskovic
Gregory
G
Abrahamian
Rex-Neal
RN
Smith
Siew-Lin
SL
Wee
David
D
Andrews
Ognjenka
O
Nadazdin
Ichiro
I
Koyama
Megan
M
Sykes
Henry J
HJ
Winn
Robert B
RB
Colvin
David H
DH
Sachs
A Benedict
AB
Cosimi
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D023201:CD40 Ligand / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D007108:Immune Tolerance; D016030:Kidney Transplantation / Q000276:immunology*; D008252:Macaca fascicularis; D023421:Models, Animal; D013923:Thromboembolism / Q000517:prevention & control; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning
D000911:Antibodies, Monoclonal; D023201:CD40 Ligand