Pretransplant portal venous adoptive transfer in conjunction with sirolimus prolongs renal allograft survival in non-human primates

Abstract

Abstract Introduction: Portal venous inoculation of alloantigen has been demonstrated to induce hyporesponsiveness in multiple rodent models and has been suggested as a preferred method of donor specific transfusion (DST) for human tolerance protocols. Portal infusion of donor splenocytes and/or bone marrow has also been shown to induce tolerance to skin transplants across complete MHC barriers in mice. The objective of this study was to determine if portal DST had a demonstrable graft-sparing effect in a non-human primate renal allograft model. Methods: Outbred rhesus monkeys were used as donor-recipient pairs based on genetic non-identity at MHC and pretransplant MLR responsiveness. Perioperative DST was administered portally using splenocytes or bone marrow cells on day -7. A similar number of splenocytes or bone marrow cells were infused via a peripheral vein on day -2. On day 0, a kidney transplant was performed. Between the first exposure to alloantigen and the time of kidney transplant, the monkeys were maintained on FK506 1 mg/kg PO BID or sirolimus 1 mg/kg PO qD. No immunosuppression was used thereafter. Results: Histological examination of the transplant kidney at the time of euthanasia was consistent with acute cellular rejection. Group 4 had a significantly longer survival than either group 3 (p = 0.037), group 5 (p = 0.025) or group 6 (p = 0.001). GroupPV infusionIV infusionImmuno- suppressantSurvivalMean survival1SplenocyteSplenocyteFK5065, 1392SplenocyteBone marrowFK5065, 149.53Bone marrowBone marrowFK5064, 12, 14, 1511.254Bone marrowBone marrowSirolimus14, 26, 28, 40275——Sirolimus7, 7, 776———5, 5, 6, 7, 8, 86.5 Conclusions: Portal venous donor bone marrow inoculation with sirolimus adjuvant therapy resulted in prolonged renal allograft survival in this non-human primate model. Additional study is under way to determine humoral immune response and transcriptional analysis of the liver in response to portal inoculation.