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 toler ance can be achieved in a mouse heart model if recipients are pretreat ed with a donor-specific blood transfusion (DST) in combination with a depleting anti-CD4 antibody. The advantage of this approach instead o f simply using the antibody alone at the time of transplantation is th at the nonspecific immunosuppressive effects of the antibody have larg ely decayed by the time of transplant such that donor-specific, rather than total, unresponsiveness results. However, this approach would no t be applicable to clinical cadaveric transplantation since donor-spec ific transfusion at a specified time before transplant would not be po ssible. In an attempt to address these problems we have sought to dete rmine (A) whether the state of unresponsiveness established by the ant i-CD4/DST protocol could be maintained by repeated exposure only to th e tolerizing antigen; (B) whether unrelated or random transfusion (RT) could substitute for DST in the anti-CD4/antigen pretreatment protoco l, 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 recha llenge without further antibody treatment can maintain a state of unre sponsiveness to alloantigen; second, that random blood transfusion giv en under the cover of anti-CD4 monoclonal antibody leads to indefinite allograft survival and true tolerance in the longterm; and third, tha t once established by random transfusion under anti-CD4 cover, unrespo nsiveness can be maintained for an extended period by random transfusi on alone. These results suggest that random blood transfusion combined with anti-CD4 monoclonal antibody therapy might be considered as a po ssible approach to the induction of specific unresponsiveness in clini cal transplantation.