Total body irradiation and acute graft-versus-host disease: The role of gastrointestinal damage and inflammatory cytokines
Total body irradiation and acute graft-versus-host disease: The role of gastrointestinal damage and inflammatory cytokines
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DOI：
10.1182/blood.v90.8.3204
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发表时间：
1997-10-15
期刊：
影响因子：
20.3
通讯作者：
Ferrara, JLM
中科院分区：
文献类型：
--
作者：
Hill, GR;Crawford, JM;Ferrara, JLM
在临床骨髓移植（BMT）中，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。使用小鼠BMT模型，我们在此显示，通过将全身照射（TBI）剂量从900 cGy增加到1，300 cGy来加强预处理方案后，几种供体-受体菌株组合中GVHD严重程度增加。增加的GVHD由肿瘤坏死因子α（TNF α）的全身性增加介导。胃肠道的组织学分析显示，TBI和同种异体供体细胞的增加导致了协同损伤，从而增加了脂多糖（LPS）进入体循环的易位。在体外，LPS触发过量的TNF α从巨噬细胞引发的GVH反应。此外，在调节4小时内分离的巨噬细胞与TBI剂量本身成比例地引发以分泌TNF α。因此，更高的TBI剂量增加了巨噬细胞引发和同种异体BMT后增加的肠道损伤，导致更高的全身炎症细胞因子水平和随后的严重GVHD。这些数据突出了在GVHD病理生理学中调节的重要性，并表明，干预措施，以防止LPS刺激引发的巨噬细胞可能会限制GVHD的严重程度后，强化调节同种异体BMI。(C)1997年，美国血液学会。
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 BMI. (C) 1997 by The American Society of Hematology.