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.
Kawai
Tatsuo
T
Department of Surgery, Transplantation Unit, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. tkawai@partners.org
Sogawa
Hiroshi
H
Boskovic
Svetlan
S
Abrahamian
Gregory
G
Smith
Rex-Neal
RN
Wee
Siew-Lin
SL
Andrews
David
D
Nadazdin
Ognjenka
O
Koyama
Ichiro
I
Sykes
Megan
M
Winn
Henry J
HJ
Colvin
Robert B
RB
Sachs
David H
DH
Cosimi
A Benedict
AB
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