PROLONGED SURVIVAL WITHOUT POSTTRANSPLANT IMMUNOSUPPRESSION IN A LARGE ANIMAL-MODEL

Background. T cells that receive T-cell antigen receptor signals but d o not undergo mitosis become unresponsive to subsequent antigenic stim ulation. This cart be achieved by antigen presentation to T cells in t he absence of critical costimulatory signals from antigen-presenting c ells (APC) or in the presence of the antiproliferative drug rapamycin. In mice, peritransplant infusion of adherent APC-depleted splenocytes , which do not provide costimulatory signals to T cells in vitro, lead s to T-cell unresponsiveness in vivo and specifically prolongs the sur vival of skin grafts that express the major histocompatibility complex (MHC) molecules expressed by the transfused cells. Our goal was to de termine whether in vivo infusion of adherent APC-depleted donor periph eral blood mononuclear cells (PBMC), with or without rapamycin, induce s prolonged kidney allograft survival in a large animal model. Methods . MHC homozygous inbred miniature swine (SLA(cc)) were transfused with dendritic cell-monocyte-depleted (G10-passed) PBMC (2.5 X 10(8) cells ) from MHC disparate SLA(dd) donors, with and without three peritransf usion injections of rapamycin (0.25 mg/i2g/day intramuscularly) the da y before, the day of, and the day after the transfusion. SLA(cc) recip ients received an SLA(dd) kidney transplant 6 days Inter. No posttrans plant immunosuppression was given. Results. In contrast to donor-speci fic whole blood transfusions, which uniformly resulted in sensitizatio n and hyperacute rejection (less than ? day), renal allograft survival in animals that received a transfusion of G10-passed PBMC from their eventual kidney donor was similar (mean, 8.1 +/- 4.5 days) to untreate d controls (mean, 7.8 +/- 5.0 days). Pretransplant rapamycin alone als o had no effect on survival (mean, 7.7 +/- 8.1 days) versus controls. The combination of G10-passed blood and peritransfusion rapamycin, how ever, increased survival significantly (mean, 27.3 +/- 10.4 days) (p = 0.01 versus untreated recipients or recipients of only G10-passed PBM C; p = 0.03 versus recipients of rapamycin alone). Conclusions. Pretra nsplant transfusion with costimulntor-deficient donor PBMC plus peritr ansfusion rapamycin treatment, but neither alone, prolongs renal allog raft survival in pigs without posttransplant immunosuppression. This s trategy, once optimized, may be applicable to human transplant toleran ce.