The role of CD80, CD86, and CTLA4 in alloimmune responses and the induction of long-term allograft survival

Blocking the interaction of the CD28 costimulatory receptor with its ligand s, CD80 and CD86, inhibits in vivo immune responses, such as allograft reje ction, and in some instances induces tolerance. previously, we found that C TLA4Ig, which blocks the CD28/CTLA-4 (CD152) ligands CD80 and CD86, can be used to induce transplantation tolerance to vascularized allografts. Recent data suggest that an intact CD152-negative signaling pathway is essential for induction of tolerance to nominal Ags, Here, we show that blockade of C D152 using an anti-CD152 mAb at the time of transplantation prevents the in duction of long-term allograft survival by agents that target CD80 and CD86 , In contrast, CD152 signals are not required for the maintenance of establ ished graft survival. We also report for the first time that blockade of CD 86 alone can induce long-term graft survival. This requires that anti-CD86 mAb is given on the day of transplantation and also depends upon an intact CD152 pathway. This result, plus experiments using CD80-deficient mice, sug gests a dominant role for CD80 molecules on donor cells as the relevant lig and for CD152, We additionally find that blockade of CD152 at the time of t ransplantation does not interfere with the effectiveness of anti-CD154 mAbs , suggesting distinct mechanisms for inhibition of graft rejection by block ing the CD28 vs CD154 pathways.