Degauque Nicolas, Lair David, Dupont Alexandre, Moreau Anne, Roussey Gwénaelle, Moizant Frédérique, Hubert François Xavier, Louvet Cédric, Hill Marcelo, Haspot Fabienne, Josien Régis, Usal Claire, Vanhove Bernard, Soulillou Jean Paul, Brouard Sophie
Institut National de la Santé et de la Recherche Médicale-Université de Nantes, Unité Mixte de Recherche 643, France.
J Immunol. 2006 Apr 1;176(7):3915-22. doi: 10.4049/jimmunol.176.7.3915.
Allograft acceptance can be induced in the rat by pretransplant infusion of donor blood or spleen cells. Although promoting long-term acceptance, this treatment is also associated with chronic rejection. In this study, we show that a single administration of anti-donor MHC class II alloimmune serum on the day of transplantation results in indefinite survival of a MHC-mismatched kidney graft. Long-term recipients accept a donor-type skin graft and display no histological evidence of chronic rejection. The kidney grafts of tolerant animals display an accumulation of TCR Cbeta, FoxP3, and IDO transcripts. Moreover, as compared with syngeneic recipients, tolerant recipients harbor a large infiltrate of MHC class II(+) cells and CD103(+) cells. In vitro, splenocytes from tolerant recipients exhibit decreased donor-specific proliferation, which is restored by depletion of non-T cells and partially restored by the blockade of IDO. Finally, splenocytes from tolerant recipients, but not purified T cell splenocytes, transfer donor-specific infectious tolerance without chronic rejection, after infusion into naive recipients, over two generations. However, splenocytes depleted of T cells or splenocytes depleted of CD103(+) cells fail to transfer tolerance. Collectively, these data show that a single administration of anti-donor MHC class II alloimmune serum induces a tolerant state characterized by an infiltration of the kidney graft by regulatory T cells and CD103(+) cells. These data also show that the transfer of tolerance requires the presence of both T cells and CD103(+) dendritic cells. The precise mechanism of cooperation of these two cell subsets remains to be defined.
通过移植前输注供体血液或脾细胞可诱导大鼠接受同种异体移植。尽管这种治疗可促进长期接受，但也与慢性排斥反应相关。在本研究中，我们发现移植当天单次给予抗供体MHC II类同种异体免疫血清可使MHC不匹配的肾移植长期存活。长期接受者可接受供体类型的皮肤移植，且无慢性排斥反应的组织学证据。耐受动物的肾移植中出现TCR Cβ、FoxP3和IDO转录本的积累。此外，与同基因接受者相比，耐受接受者体内有大量MHC II类(+)细胞和CD103(+)细胞浸润。在体外，耐受接受者的脾细胞表现出供体特异性增殖降低，去除非T细胞后可恢复，IDO阻断可部分恢复。最后，将耐受接受者的脾细胞（而非纯化的T细胞脾细胞）输注给未接触过抗原的接受者后，可在两代内传递供体特异性感染性耐受且无慢性排斥反应。然而，去除T细胞的脾细胞或去除CD103(+)细胞的脾细胞无法传递耐受。总体而言，这些数据表明，单次给予抗供体MHC II类同种异体免疫血清可诱导一种耐受状态，其特征为调节性T细胞和CD103(+)细胞浸润肾移植。这些数据还表明，耐受的传递需要T细胞和CD103(+)树突状细胞同时存在。这两个细胞亚群协同作用的确切机制仍有待确定。
