MECHANISMS OF ACQUIRED THYMIC TOLERANCE: INDUCTION OF TRANSPLANT TOLERANCE BY ADOPTIVE TRANSFER OF IN VIVO ALLOMHC PEPTIDE ACTIVATED SYNGENEIC T CELLS 1

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Abstract
Our most recent observation that i.v. injection ofWistar-Furth (WF) major histocompatibility complex Class I peptide 5(P5)-pulsed self-myeloid or lymphoid dendritic cells (DC) inducestransplantation tolerance suggests that adoptive transfer of in vivoallopeptide-primed host T cells might induce acquired tolerance through theirinteraction with thymicDC. To examine this hypothesis, host myeloid DC cultured in ratgranulocyte/macrophage colony stimulating factor and interleukin 4 were pulsedin vitro with P5 and injected intravenously into syngeneic ACI rats. The Tcells primed to P5 via the indirect pathway of allorecognition were harvested7 days later and administered by either intravenously or intrathymically intosyngeneic ACI recipients of WF cardiacallografts. Syngeneic T cells obtained from the spleen of P5-primedrats had a high mixed lymphocyte reaction proliferative response to P5presented by self-DC. I.v. administration of2×10 7 P5-primed alloreactive purified hostsplenic T cells alone on day −7 significantly(P 200days). Thymectomy before i.v. injection of P5-activated syngeneic T cells ledto acute graft rejection, suggesting that the homing of in vivo activated Tcells to the host thymus might play a role in the induction of tolerance. Tofurther define the role of the recipient thymus in this model, we examined theeffects of intrathymic (i.t.) injection of P5-primed alloreactive T cells ongraft survival and found that i.t. administration of the P5-primed T cells onday −7 alone significantly prolonged graft survival (15.0±0.7days) and when combined with 0.5 ml ALS led to donor-specific permanent graftsurvival. The long-term unresponsive recipients permanently (>100 days)accepted second-set donor-specific cardiac allografts but not third-party(Lewis)grafts. These findings demonstrate that the adoptive transfer ofsplenic T cells primed to an indirectly presented donor peptide inducestransplantation tolerance in a transiently immunosuppressed secondarysyngeneic recipient. Our data suggest that the interaction of thymic DC withactivated peripheral T cells induces alloantigen (Ag)-specific T-celltolerance by either inactivation or deletion of alloreactive T cells in thethymus. This observation provides the first formal evidence that theinteraction between thymic DC and activated peripheral T cells thatcontinuously circulate through the thymus plays an important role in theinduction and maintenance of Ag-specifictolerance.