Successful conversion from conventional immunosuppression to anti-CD154 monoclonal antibody costimulatory molecule blockade in rhesus renal allograft recipients.
BACKGROUND
Several conventional forms of immunosuppression have been shown to antagonize the efficacy of anti-CD154 monoclonal antibody- (mAb) based costimulatory molecule blockade immunotherapy. Our objective was to determine if allograft recipients treated with a conventional immunosuppressive regimen could be sequentially converted to anti-CD154 mAb monotherapy without compromising graft survival.


METHODS
Outbred juvenile rhesus monkeys underwent renal allotransplantation from MHC-disparate donors. After a 60-day course of triple therapy immunosuppression with steroids, cyclosporine, and mycophenolate mofetil, monkeys were treated with: (1) cessation of all immunosuppression (control); (2) seven monthly doses of 20 mg/kg hu5C8 (maintenance), or; (3) 20 mg/kg hu5C8 on posttransplant days 60, 61, 64, 71, 79, and 88 followed by five monthly doses (induction+maintenance). Graft rejection was defined by elevation in serum creatinine>1.5 mg/dl combined with histologic evidence of rejection.


RESULTS
Graft survival for the three groups were as follows: group 1 (control): 70, 75, >279 days; group 2 (maintenance): 83, 349, >293 days, and; group 3 (induction+maintenance): 355, >377, >314 days. Acute rejection developing in two of four monkeys after treatment with conventional immunosuppression was successfully reversed with intensive hu5C8 monotherapy.


CONCLUSIONS
Renal allograft recipients can be successfully converted to CD154 blockade monotherapy after 60 days of conventional immunosuppression. An induction phase of anti-CD154 mAb appears to be necessary for optimal conversion. Therefore, although concurrent administration of conventional immunosuppressive agents including steroids and calcineurin inhibitors has been shown to inhibit the efficacy of CD154 blockade, sequential conversion from these agents to CD154 blockade appears to be effective.
Cho
C S
CS
Department of Surgery, University of Wisconsin Hospital and Clinics, Madison 53792, USA.
Burkly
L C
LC
Fechner
J H
JH
Kirk
A D
AD
Oberley
T D
TD
Dong
Y
Y
Brunner
K G
KG
Peters
D
D
Tenhoor
C N
CN
Nadeau
K
K
Yagci
G
G
Ishido
N
N
Schultz
J M
JM
Tsuchida
M
M
Hamawy
M M
MM
Knechtle
S J
SJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D023201:CD40 Ligand / Q000276:immunology*; D006084:Graft Rejection / Q000188:drug therapy*; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation; D008253:Macaca mulatta; D019233:Retreatment; D016879:Salvage Therapy; D016038:Skin Transplantation; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D023201:CD40 Ligand