Mechanisms of acquired thymic tolerance: Induction of transplant tolerance by adoptive transfer of in vivo alloMHC peptide activated syngeneic T cells

被引:17
作者
Ali, A [1 ]
Garrovillo, M [1 ]
Oluwole, OO [1 ]
Depaz, HA [1 ]
Gopinathan, R [1 ]
Engelstad, K [1 ]
Hardy, MA [1 ]
Oluwole, SF [1 ]
机构
[1] Columbia Univ, Coll Phys & Surg, Dept Surg, New York, NY 10032 USA
关键词
D O I
10.1097/00007890-200105270-00015
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background. Our most recent observation that i.v. injection of Wistar-Furth (WF) major histocompatibility complex Class I peptide 5 (P5)-pulsed self-myeloid or lymphoid dendritic cells (DC) induces transplantation tolerance suggests that adoptive transfer of in vivo allopeptide-primed host T cells might induce acquired tolerance through their interaction with thymic DC. Methods. To examine this hypothesis, host myeloid DC cultured in rat granulocyte/macrophage colony stimulating factor and interleukin 4 were pulsed in vitro with P5 and injected intravenously into syngeneic ACI rats. The T cells primed to P5 via the indirect pathway of allorecognition were harvested 7 days later and administered by either intravenously or intrathymically into syngeneic ACI recipients of WF cardiac allografts. Results. Syngeneic T cells obtained from the spleen of PB-primed rats had a high mixed lymphocyte reaction proliferative response to P5 presented by self-DC. I.v. administration of 2x10(7) PB-primed alloreactive purified host splenic T cells alone on day -7 significantly (P <0.001) prolonged cardiac allograft survival from 10.5 +/-1.0 days to 18.6 +/-1.8 days in the WF-to-ACI rat combination, I.v. injection of P5-activated host T cells combined with 0.5 ml antilymphocyte serum (ALS)-transient immunosuppression on day -7 led to 100% donor-specific permanent graft survival (> 200 days). Thymectomy before i.v. injection of P5-activated syngeneic T cells led to acute graft rejection, suggesting that the homing of in vivo activated T cells to the host thymus might play a role in the induction of tolerance. To further define the role of the recipient thymus in this model, we examined the effects of intrathymic (i.t.) injection of P5-primed alloreactive T cells on graft survival and found that i.t. administration of the P5-primed T cells on day -7 alone significantly prolonged graft survival (15.0 +/-0.7 days) and when combined with 0.5 ml ALS led to donor-specific permanent graft survival. The long-term unresponsive recipients permanently (> 100 days) accepted second-set donor-specific cardiac allografts hut not third-party (Lewis) grafts. Conclusions. These findings demonstrate that the adoptive transfer of splenic T cells primed to an indirectly presented donor peptide induces transplantation tolerance in a transiently immunosuppressed secondary syngeneic recipient. Our data suggest that the interaction of thymic DC with activated peripheral T cells induces alloantigen (Ag)-specific T-cell tolerance by either inactivation or deletion of alloreactive T cells in the thymus. This observation provides the first formal evidence that the interaction between thymic DC and activated peripheral T cells that continuously circulate through the thymus plays an important role in the induction and maintenance of Ag-specific tolerance.
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页码:1442 / 1448
页数:7
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