Xu Hong, Chilton Paula M, Huang Yiming, Schanie Carrie L, Ildstad Suzanne T
Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202, USA.
J Immunol. 2004 Feb 1;172(3):1463-71. doi: 10.4049/jimmunol.172.3.1463.
Nonmyeloablative conditioning has significantly reduced the morbidity associated with bone marrow transplantation. The donor hemopoietic cell lineage(s) responsible for the induction and maintenance of tolerance in nonmyeloablatively conditioned recipients is not defined. In the present studies we evaluated which hemopoietic stem cell-derived components are critical to the induction of tolerance in a total body irradiation-based model. Recipient B10 mice were pretreated with mAbs and transplanted with allogeneic B10.BR bone marrow after conditioning with 100-300 cGy total body irradiation. The proportion of recipients engrafting increased in a dose-dependent fashion. All chimeric recipients exhibited multilineage donor cell production. However, induction of tolerance correlated strictly with early production of donor T cells. The chimeras without donor T cells rejected donor skin grafts and demonstrated strong antidonor reactivity in vitro, while possessing high levels of donor chimerism. These animals lost chimerism within 8 mo. Differentiation into T cells was aborted at a prethymic stage in recipients that did not produce donor T cells. Moreover, donor Ag-driven clonal deletion of recipient T cells occurred only in chimeras with donor T cells. These results demonstrate that donor T cell production is critical in the induction of transplantation tolerance and the maintenance of durable chimerism. In addition, donor T cell production directly correlates with the deletion of potentially alloreactive cells.
非清髓性预处理显著降低了与骨髓移植相关的发病率。在接受非清髓性预处理的受者中，负责诱导和维持耐受的供体造血细胞谱系尚未明确。在本研究中，我们评估了在基于全身照射的模型中，哪些造血干细胞衍生成分对于诱导耐受至关重要。受体B10小鼠先用单克隆抗体进行预处理，然后在接受100 - 300 cGy全身照射预处理后，移植同种异体B10.BR骨髓。受体植入的比例呈剂量依赖性增加。所有嵌合受体均表现出多谱系供体细胞生成。然而，耐受的诱导与供体T细胞的早期生成严格相关。没有供体T细胞的嵌合体排斥供体皮肤移植，并在体外表现出强烈的抗供体反应性，同时具有高水平的供体嵌合率。这些动物在8个月内失去了嵌合性。在不产生供体T细胞的受体中，T细胞分化在胸腺前阶段就被阻断。此外，供体抗原驱动的受体T细胞克隆清除仅发生在有供体T细胞的嵌合体中。这些结果表明，供体T细胞的生成对于诱导移植耐受和维持持久嵌合性至关重要。此外，供体T细胞的生成与潜在的同种反应性细胞的清除直接相关。
