PREVENTING ALLOGRAFT-REJECTION WITH CTLA4IG - EFFECT OF DONOR-SPECIFIC TRANSFUSION ROUTE OR TIMING

Background: Tolerance to alloantigen in transplant recipients could re move life-long dependence on immunosuppression. Evidence suggests that T-cell responses to alloantigen are dependent not only on T-cell rece ptor activation but also on costimulation by means of the CD28 recepto r. The natural ligands for CD28, expressed on antigen-presenting cells , are B7 family members. CTLA4Ig (a soluble CD28 receptor analog) pref erentially binds B7-1 and B7-2 and inhibits CD28 activation. Theoretic ally, T-cell receptor activation in the presence of alloantigen during CTLA4Ig blockade of CD28-B7 costimulation could render T cells tolera nt to that specific alloantigen. In vivo CTLA4Ig significantly increas es allograft survival times and can lead to transplantation tolerance. In the rat cardiac allograft model, donor-specific transfusion must b e combined with CTLA4Ig to induce tolerance. Previously our laboratory has shown that timing is crucial in the induction of tolerance. Metho ds: We examined the effect of differing routes (intravenous, portal ve in, or intrathymic), as well as timing (before, at, and after transpla ntation), of donor-specific transfusion on its ability to synergize wi th CTLA4Ig using a rat heterotopic major histocompatibility complex-mi smatch heart transplant model. Results: We found that tolerance induce d by CTLA4Ig and donor-specific transfusion was antigen specific and t hat timing, but not route of donor-specific transfusion had a benefici al effect on allograft survival equal to portal vein and intrathymic r outes, which have been believed to be more tolerogenic. Conclusions: A lmost universal engraftment can be induced with a combination of intra venous donor-specific transfusion at transplantation plus inhibition o f CD28 activation by CTLA4Ig 48 hours after transplantation-a regimen which could have clinical application.