Induction of operational tolerance by random blood transfusion combined with anti-CD4 antibody therapy. A protocol with significant clinical potential.

Previous work from this laboratory has shown that donor-specific tolerance can be achieved in a mouse heart model if recipients are pretreated with a donor-specific blood transfusion (DST) in combination with a depleting anti-CD4 antibody. The advantage of this approach instead of simply using the antibody alone at the time of transplantation is that the nonspecific immunosuppressive effects of the antibody have largely decayed by the time of transplant such that donor-specific, rather than total, unresponsiveness results. However, this approach would not be applicable to clinical cadaveric transplantation since donor-specific transfusion at a specified time before transplant would not be possible. In an attempt to address these problems we have sought to determine (A) whether the state of unresponsiveness established by the anti-CD4/DST protocol could be maintained by repeated exposure only to the tolerizing antigen; (B) whether unrelated or random transfusion (RT) could substitute for DST in the anti-CD4/antigen pretreatment protocol, and (C) whether these two approaches could be successfully combined to provide an "umbrella unresponsiveness" that could be maintained until the time of transplant. Our data show, first, that antigen rechallenge without further antibody treatment can maintain a state of unresponsiveness to alloantigen; second, that random blood transfusion given under the cover of anti-CD4 monoclonal antibody leads to indefinite allograft survival and true tolerance in the long-term; and third, that once established by random transfusion under anti-CD4 cover, unresponsiveness can be maintained for an extended period by random transfusion alone. These results suggest that random blood transfusion combined with anti-CD4 monoclonal antibody therapy might be considered as a possible approach to the induction of specific unresponsiveness in clinical transplantation.