Combination induction therapy with monoclonal antibodies specific for CD80, CD86, and CD154 in nonhuman primate renal transplantation.
BACKGROUND
Antibodies and fusion proteins specific for CD80, CD86, and CD154 have shown promise as agents capable of inducing donor-specific tolerance in rodents. These agents have also been shown to be synergistic with one another in many settings of counter-adaptive immunity. In the nonhuman primate, monoclonal antibodies specific for CD80 and CD86 have prolonged the time to rejection of renal allografts but have not resulted in tolerance. A monoclonal antibody specific for CD154 has resulted in markedly prolonged survival of kidney, islet, cardiac, and skin allografts, but again most animals have eventually developed rejection after prolonged periods of rejection-free survival off therapy.


METHODS
A combination of monoclonal antibodies specific for CD80, CD86, and CD154 were used in a mismatched nonhuman primate renal-allograft model. Doses used were based on optimized treatment protocols for each agent individually.


RESULTS
Treatment of four rhesus macaques with this combination yielded a mean rejection-free survival of 565 days (311-911 days), significantly greater than untreated controls (mean survival=7.0 days, P=0.001) and animals treated with only a combination of anti-CD80 and CD86 (mean survival=191 days, P=0.01). The survival of animals treated with this combination of monoclonal antibodies was not significantly greater than those treated with anti-CD154 alone, but the production of alloantibody was delayed compared with monotherapy anti-CD154.


CONCLUSIONS
These data suggest that a synergy exists between these agents, particularly with regard to T-dependent B-cell responses, but that they fail to induce durable tolerance in nonhuman primates.
Montgomery
Sean P
SP
The Department of Surgery, Walter Reed Army Medical Center, Washington, DC, USA.
Xu
He
H
Tadaki
Douglas K
DK
Celniker
Abbie
A
Burkly
Linda C
LC
Berning
Justin D
JD
Cruzata
Francis
F
Elster
Eric A
EA
Gray
Gary
G
Kampen
Robert L
RL
Swanson
S John
SJ
Harlan
David M
DM
Kirk
Allan D
AD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000917:Antibody Formation; D015703:Antigens, CD / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology* / Q000502:physiology; D051940:B7-2 Antigen; D023201:CD40 Ligand / Q000276:immunology*; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D016030:Kidney Transplantation / Q000276:immunology*; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D023201:CD40 Ligand