Hill G R, Crawford J M, Cooke K R, Brinson Y S, Pan L, Ferrara J L
Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Blood. 1997 Oct 15;90(8):3204-13.
The influence of bone marrow transplantation (BMT) conditioning regimens on the incidence and severity of graft-versus-host disease (GVHD) has been suggested in clinical BMT. Using murine BMT models, we show here an increase in GVHD severity in several donor-recipient strain combinations after intensification of the conditioning regimen by increasing the total body irradiation (TBI) dose from 900 cGy to 1,300 cGy. Increased GVHD was mediated by systemic increases in tumor necrosis factor alpha (TNF alpha). Histologic analysis of gastrointestinal tracts showed synergistic damage by increased TBI and allogeneic donor cells that permitted increased translocation of lipopolysacharide (LPS) into the systemic circulation. In vitro, LPS triggered excess TNF alpha from macrophages primed by the GVH reaction. In addition, macrophages isolated within 4 hours of conditioning were primed in proportion to the TBI dose itself to secrete TNF alpha. Thus, the higher TBI dose increased macrophage priming and increased gut damage after allogeneic BMT, causing higher systemic levels of inflammatory cytokines and subsequent severe GVHD. These data highlight the importance of conditioning in GVHD pathophysiology and suggest that interventions to prevent LPS stimulation of primed macrophages may limit the severity of GVHD after intensive conditioning for allogeneic BMT.
在临床骨髓移植（BMT）中，有人提出BMT预处理方案对移植物抗宿主病（GVHD）的发生率和严重程度有影响。利用小鼠BMT模型，我们在此表明，在一些供体-受体品系组合中，当通过将全身照射（TBI）剂量从900 cGy增加到1300 cGy来强化预处理方案后，GVHD的严重程度有所增加。GVHD的加重是由肿瘤坏死因子α（TNFα）的全身水平升高介导的。胃肠道的组织学分析显示，增加的TBI和异基因供体细胞造成了协同损伤，使得脂多糖（LPS）向体循环的转运增加。在体外，LPS从由移植物抗宿主反应致敏的巨噬细胞中引发过量的TNFα。此外，在预处理后4小时内分离出的巨噬细胞按TBI剂量本身的比例被致敏，从而分泌TNFα。因此，更高的TBI剂量增加了巨噬细胞的致敏，并在异基因BMT后增加了肠道损伤，导致全身炎症细胞因子水平升高以及随后严重的GVHD。这些数据突出了预处理在GVHD病理生理学中的重要性，并表明防止LPS刺激致敏巨噬细胞的干预措施可能会限制异基因BMT强化预处理后GVHD的严重程度。
