Yamada K, Shimizu A, Utsugi R, Ierino F L, Gargollo P, Haller G W, Colvin R B, Sachs D H
Transplantation Biology Research Center and Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129, USA.
J Immunol. 2000 Mar 15;164(6):3079-86. doi: 10.4049/jimmunol.164.6.3079.
Previous studies in our laboratory have demonstrated that the presence of the thymus is essential for rapid and stable tolerance induction in allotransplant models. We now report an attempt to induce tolerance to kidney allografts by transplanting donor thymic grafts simultaneously with the kidney in thymectomized recipients. Recipients were thymectomized 3 wk before receiving an organ and/or tissues from a class I-mismatched donor. Recipients received 1) a kidney allograft alone, 2) a composite allogeneic thymokidney (kidney with vascularized autologous thymic tissue under its capsule), or 3) separate kidney and thymic grafts from the same donor. All recipients received a 12-day course of cyclosporine. Thymectomized animals receiving a kidney allograft alone or receiving separate thymic and kidney grafts had unstable renal function due to severe rejection with the persistence of anti-donor cytotoxic T cell reactivity. In contrast, recipients of composite thymokidney grafts had stable renal function with no evidence of rejection histologically and donor-specific unresponsiveness. By postoperative day 14, the thymic tissue in the thymokidney contained recipient-type dendritic cells. By postoperative day 60, recipient-type class I positive thymocytes appeared in the thymic medulla, indicating thymopoiesis. T cells were both recipient and donor MHC-restricted. These data demonstrate that the presence of vascularized-donor thymic tissue induces rapid and stable tolerance to class I-disparate kidney allografts in thymectomized recipients. To our knowledge, this is the first evidence of functional vascularized thymic grafts permitting transplantation tolerance to be induced in a large animal model.
我们实验室之前的研究表明，胸腺的存在对于同种异体移植模型中快速稳定地诱导免疫耐受至关重要。我们现在报告一项尝试，即在胸腺切除的受体中同时移植供体胸腺移植物和肾脏，以诱导对肾脏同种异体移植的耐受。受体在接受来自I类错配供体的器官和/或组织前3周进行胸腺切除。受体接受：1）单独的肾脏同种异体移植；2）复合异体胸腺肾（肾脏包膜下带有血管化自体胸腺组织）；或3）来自同一供体的单独肾脏和胸腺移植物。所有受体均接受为期12天的环孢素治疗。单独接受肾脏同种异体移植或接受单独胸腺和肾脏移植物的胸腺切除动物，由于严重排斥反应以及抗供体细胞毒性T细胞反应持续存在，肾功能不稳定。相比之下，复合胸腺肾移植物受体的肾功能稳定，组织学上无排斥反应迹象，且存在供体特异性无反应性。术后第14天，胸腺肾中的胸腺组织含有受体型树突状细胞。术后第60天，受体型I类阳性胸腺细胞出现在胸腺髓质，表明有胸腺生成。T细胞受受体和供体MHC限制。这些数据表明，血管化供体胸腺组织的存在可在胸腺切除的受体中诱导对I类不相合肾脏同种异体移植的快速稳定耐受。据我们所知，这是功能性血管化胸腺移植物在大型动物模型中诱导移植耐受的首个证据。
