Prevention of kidney allograft rejection using anti-CD40 and anti-CD86 in primates.
BACKGROUND
Costimulation blockade has been proposed to induce allograft tolerance. We combined an antagonist anti-CD40 monoclonal antibody (mAb) with an antagonist anti-CD86 mAb in a rhesus monkey kidney allograft model. We chose this combination because it leaves CD80-CD152 signaling unimpaired, allowing for the down-regulatory effect of CD152 signaling to take place through this pathway.


METHODS
Rhesus monkeys underwent transplantation with a major histocompatibility complex-mismatched kidney. One group of animals received anti-CD40 alone, and a second group received the combination of anti-CD40 and anti-CD86, twice weekly for 56 days.


RESULTS
Three animals with low levels of anti-CD40 rejected the transplanted kidney while still receiving treatment. Three animals with high levels of anti-CD40 rejected at days 91, 134, and 217 with signs of chronic rejection. Animals treated with the combination of anti-CD40 and anti-CD86 mAbs rejected their kidneys at days 61, 75, and 78, shortly after cessation of treatment. Two animals were killed on days 71 and 116 with a blocked ureter. These animals developed virtually no signs of tubulitis or infiltration during treatment and no donor-specific alloantibodies.


CONCLUSIONS
Both treatment protocols prevented rejection for the duration of the treatment in most animals. Blocking costimulation by anti-CD40 or by anti-CD40 plus anti-CD86 may be an effective method to prevent graft rejection and may obviate the need for other immunosuppressive drugs, especially in the immediate posttransplantation period.
Haanstra
Krista G
KG
Biomedical Primate Research Centre, Rijswijk, The Netherlands.
Ringers
Jan
J
Sick
Ella A
EA
Ramdien-Murli
Seema
S
Kuhn
Eva-Maria
EM
Boon
Louis
L
Jonker
Margreet
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000917:Antibody Formation; D000918:Antibody Specificity; D015703:Antigens, CD / Q000276:immunology*; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000276:immunology*; D002678:Chimera / Q000276:immunology; D004338:Drug Combinations; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D006648:Histocompatibility; D007518:Isoantibodies / Q000032:analysis / Q000276:immunology; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000276:immunology*; D014019:Tissue Donors
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D051940:B7-2 Antigen; D019013:CD40 Antigens; D004338:Drug Combinations; D007518:Isoantibodies; D008562:Membrane Glycoproteins