Cutting edge: Transplantation tolerance through enhanced CTLA-4 expression

Knockout and blocking studies have shown a critical role for CTLA-4 in peripheral tolerance, however, it is unknown whether augmenting CTLA-4 expression actually promotes tolerance. Here we demonstrate a specific and requisite role for CTLA-4 and its up-regulation in tolerance through anti-CD45RB. First, long-term murine islet allograft survival induced by anti-CD45RB is prevented by CTLA44g, which interferes with B7.-CTLA-4 interactions. Second, anti-CD45RB is ineffective in recipients lacking ng LA-4,B7-1, and B7-2. Incontrast, CTLA4-Ig, which targets B17 on allogeneic cells, promotes long-term engraftment in these mice. Moreover, anti-CD45Rb was effective in X-deficient controls expressing CTLA-4. Finally, in wildtype mice, CTLA-4 expression returned to baseline 17 days after receiving anti-CD45RB, and was refractory to further increase. Transplantation and anti-CD45RB therapy at this time could neither augment CTLA-4 nor prolong engraftment, These data demonstrate a specific role for CTLA-4 in anti-CD45RB-mediated tolerance and indicate that CTLA-4 up-regulation can directly promote allograft survival.