Intrathymic deletion of alloreactive T cells in mixed bone marrow chimeras prepared with a nonmyeloablative conditioning: Regimen
Intrathymic deletion of alloreactive T cells in mixed bone marrow chimeras prepared with a nonmyeloablative conditioning: Regimen
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DOI：
10.1097/00007890-199807150-00015
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发表时间：
1998-07-15
期刊：
影响因子：
6.2
通讯作者：
Sykes, M
中科院分区：
文献类型：
--
作者：
Manilay, JO;Pearson, DA;Sykes, M
背景非清髓性预处理诱导混合造血嵌合体导致供者特异性移植耐受识别内源性超抗原的特异性Vp承载T细胞家族的分析表明，供体特异性耐受性主要是由于这些混合嵌合体中的胸腺内缺失机制。然而，尚不知道超抗原表现为经典的移植抗原。因此，我们使用表达对同种异体主要组织相容性复合物抗原特异性的克隆型TCR的T细胞受体（TCR）转基因（Tg）受体来进一步评估缺失耐受性。2C TCR Tg小鼠（H2（B）），其Tg TCR识别主要组织相容性复合物I类Ld，在用耗尽的抗-CD 4和CD 8单克隆抗体、3戈伊全身照射和7戈伊胸腺照射预处理后用作Ld+骨髓细胞的受体。通过流式细胞术和免疫组化染色评估CD 8（+）2C受体T细胞的嵌合和缺失。通过体外细胞介导的淋巴细胞溶解试验和体内移植供体皮肤来检测耐受性。在混合嵌合体中，胸腺内和外周2C（+）CD 8单阳性T细胞的缺失是明显的，并且缺失与胸腺中具有树突状形态的供体型细胞的存在相关，并且与淋巴造血组织中的嵌合体相关。嵌合体在细胞介导的淋巴细胞溶解试验中显示出对供体的耐受性，并特异性地接受供体皮肤移植物。结论，通过非清髓性预处理方案和异基因骨髓移植制备的混合嵌合体中的供体反应性T细胞的胸腺内缺失，实现了对移植抗原的耐受。
Background. Mixed hematopoietic chimerism induced with a nonmyeloablative conditioning regimen leads to donor-specific transplantation tolerance. Analyses of specific Vp bearing T-cell families that recognize endogenous superantigens demonstrated that donor-specific tolerance is due mainly to an intrathymic deletional mechanism in these mixed chimeras. However, superantigens are not known to behave as classical transplantation antigens, We therefore used T-cell receptor (TCR) transgenic (Tg) recipients expressing a clonotypic TCR specific for an allogeneic major histocompatibility complex antigen to further assess deletional tolerance.Methods. 2C TCR Tg mice (H2(b)), whose Tg TCR recognizes major histocompatibility complex class I Ld, were used as recipients of Ld+ bone marrow cells after conditioning with depleting anti-CD4 and CD8 monoclonal antibodies, 3 Gy whole-body irradiation, and 7 Gy thymic irradiation. Chimerism and deletion of CD8(+) 2C recipient T cells was evaluated by flow cytometry and by immunohistochemical staining. Tolerance was tested with in vitro cell-mediated lympholysis assays and in vivo by grafting with donor skin.Results. Intrathymic and peripheral deletion of 2C(+) CD8-single-positive T cells was evident in mixed chimeras, and deletion correlated with the presence of donor-type cells with dendritic morphology in the thymus, and with chimerism in lymphohematopoietic tissues. Chimeras showed tolerance to the donor in cell-mediated lympholysis assays and specifically accepted donor skin grafts,Conclusions, Tolerance to transplantation antigens is achieved through intrathymic deletion of donor-reactive T cells in mixed chimeras prepared with a nonmyeloablative conditioning regimen and allogeneic bone marrow transplantation.