Prevention of renal allograft rejection in primates by blocking the B7/CD28 pathway.
BACKGROUND
There is accumulating evidence that blockade of the costimulatory pathways offers a valid approach for immune suppression after solid organ transplantation. In this study, the efficacy of anti-CD80 and anti-CD86 monoclonal antibodies (mAbs) in combination with cyclosporine (CsA) to prevent renal allograft rejection was tested in non-human primates.


METHODS
Rhesus monkeys were transplanted with a partly major histocompatibility complex-matched kidney on day 0. Anti-CD80 and anti-CD86 mAbs were administered intravenously daily for 14 days starting at day - 1. CsA was given intramuscularly for 35 days starting just after transplantation. The kidney function was monitored by determining serum creatinine levels.


RESULTS
The combination of anti-CD80 and anti-CD86 mAbs completely abrogated the mixed lymphocyte reaction. Untreated rhesus monkeys rejected the kidney allograft in 5-7 days. Treatment with anti-CD80 plus anti-CD86 mAbs resulted in a significantly prolonged graft survival of 28+ 7 days (P=0.025). There were no clinical signs of side effects or rejection during treatment. Kidney graft rejection started after the antibody therapy was stopped. The anti-mouse antibody response was delayed from day 10 to 30 after the first injection. No difference in graft survival was observed between animals treated with CsA alone or in combination with anti-CD80 and anti-CD86 mAbs. However, treatment with anti-CD80 and anti-CD86 mAbs reduced development of vascular rejection.


CONCLUSIONS
In combination, anti-CD80 and antiCD86 mAbs abrogate T-cell proliferation in vitro, delay the anti-mouse antibody response in vivo, and prevent graft rejection and development of graft vascular disease in a preclinical vascularized transplant model in non-human primates.
Ossevoort
M A
MA
Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
Ringers
J
J
Kuhn
E M
EM
Boon
L
L
Lorré
K
K
van den Hout
Y
Y
Bruijn
J A
JA
de Boer
M
M
Jonker
M
M
de Waele
P
P
D000818:Animals; D019138:Antibodies, Blocking / Q000097:blood / Q000276:immunology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control*; D007519:Isoantigens / Q000276:immunology; D007668:Kidney / Q000098:blood supply / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D018984:Epitopes, T-Lymphocyte; D007519:Isoantigens; D008562:Membrane Glycoproteins