Dey B, Yang Y G, Preffer F, Shimizu A, Swenson K, Dombkowski D, Sykes M
Transplantation Biology Research Center/Surgical Service, and Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston 02129, USA.
Transplantation. 1999 Jul 15;68(1):141-9. doi: 10.1097/00007890-199907150-00026.
The expansion of transgenic donor CD8+ T-cells with known allospecificity against a host MHC class I alloantigen was examined in a murine graft-versus-host disease (GVHD) model.
Lethally irradiated, Ld+ BALB/c mice received bone marrow cells and spleen cells from anti-Ld 2C T-cell receptor (TCR)-transgenic B6 mice, alone or with normal B6 spleen cells. Transgenic TCR-bearing T-cell expansion, apoptosis, and function were monitored at various time points and were correlated with clinical outcome.
Fifteen-fold clonal expansion of 2C CD8 cells occurred by day 4 after bone marrow transplantation. Between days 4 and 7, increasing proportions of 2C CD8 cells underwent apoptotic cell death, coincident with a 7-15-fold decline in their numbers. CD8 and TCR expression were down-regulated on 2C CD8 cells by day +4 after bone marrow transplantation, and they were anergic to TCR-mediated stimulation. Clinically, the BALB/c recipients of 2C spleen cells exhibited only minimal chronic GVHD. In contrast, lethally irradiated BALB/c mice receiving similar numbers of non-transgenic B6 bone marrow cells and spleen cells exhibited severe GVHD (median survival time: 28 days). The addition of a small number of 2C spleen cells to the inoculum accelerated GVHD mortality, and 2C CD8 cells showed a similar time course of expansion and decline to that observed in recipients of larger numbers of 2C cells alone.
Initial clonal expansion, down-regulation of CD8 and TCR, anergy, and later deletion of graft-versus-host-reactive CD8 cells via apoptosis occurs in lethally irradiated recipients. Expansion of a single CD8 clone produces much less severe GVHD than that induced by a polyclonal, mixed CD4 plus CD8 response. These results have implications for GVHD pathogenesis and its sometimes self-limited nature.
在小鼠移植物抗宿主病（GVHD）模型中，研究了对宿主MHC I类同种抗原具有已知同种特异性的转基因供体CD8 + T细胞的扩增情况。
接受致死剂量照射的Ld + BALB/c小鼠单独或与正常B6脾细胞一起接受来自抗Ld 2C T细胞受体（TCR）转基因B6小鼠的骨髓细胞和脾细胞。在不同时间点监测携带转基因TCR的T细胞扩增、凋亡和功能，并将其与临床结果相关联。
骨髓移植后第4天，2C CD8细胞发生了15倍的克隆扩增。在第4天至第7天之间，越来越多比例的2C CD8细胞发生凋亡性细胞死亡，与此同时其数量下降了7至15倍。骨髓移植后第4天，2C CD8细胞上的CD8和TCR表达下调，并且它们对TCR介导的刺激无反应。临床上，接受过2C脾细胞的BALB/c受体仅表现出轻微的慢性GVHD。相比之下，接受相似数量非转基因B6骨髓细胞和脾细胞的接受致死剂量照射的BALB/c小鼠表现出严重的GVHD（中位生存时间：28天）。向接种物中添加少量2C脾细胞会加速GVHD死亡率，并且2C CD8细胞的扩增和下降时间过程与仅接受大量2C细胞的受体中观察到的相似。
在接受致死剂量照射的受体中，发生了初始克隆扩增、CD8和TCR下调、无反应性以及随后通过凋亡清除移植物抗宿主反应性CD8细胞的情况。单个CD8克隆的扩增所产生的GVHD严重程度远低于多克隆混合CD4加CD8反应所诱导的GVHD。这些结果对GVHD发病机制及其有时的自我限制性质具有启示意义。
