LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation
LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation
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DOI：
10.1172/jci12156
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发表时间：
2001-06-01
影响因子：
15.9
通讯作者：
Ferrara, JLM
中科院分区：
文献类型：
--
作者：
Cooke, KR;Gerbitz, A;Ferrara, JLM
急性移植物抗宿主病（GVHD）和白血病复发仍然是异基因骨髓移植（BMT）成功的两个主要障碍。最近的研究表明，胃肠道完整性的丧失，特别是LPS易位到体循环中，对诱导细胞因子失调是至关重要的，导致GVHD。利用小鼠BMT模型，我们研究了直接LPS拮抗对GVHD严重程度和移植物抗白血病（GVL）活性的影响。从第0天至第+6天给予B 975（一种合成脂质-A类似物），降低了血清TNF-α水平，减少了肠道组织病理学，并导致生存率显著提高和临床减少。GVHD，与对照治疗的动物相比。重要的是，B 975在体内或体外对供体T细胞对宿主抗原的应答没有影响。当小鼠在BMT时接受致死剂量的P815肿瘤细胞时，给予B 975不会损害GVL活性，并导致显著改善的无白血病存活率。这些发现揭示了LPS在导致GVHD的早期炎症事件中的关键作用，并表明一类新的药理学药物LPS拮抗剂可能有助于预防GVHD，同时保留T细胞对宿主抗原和GVL活性的应答。
Acute graft-versus-host disease (GVHD) and leukemic relapse remain the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT). Recent studies have demonstrated that the loss of gastrointestinal tract integrity, and specifically the translocation of LPS into the systemic circulation, is critical to the induction of cytokine dysregulation that contributes to GVHD. Using a mouse BMT model, we studied the effects of direct LPS antagonism on GVHD severity and graft-versus-leukemia (GVL) activity. Administration of B975, a synthetic lipid-A analogue from day 0 to day +6, reduced serum TNF-alpha levels, decreased intestinal histopathology, and resulted in significantly improved survival and a reduction in clinical. GVHD, compared with control-treated animals. Importantly, B975 had no effect on donor T cell responses to host antigens in vivo or in vitro. When mice received lethal doses of P815 tumor cells at the time of BMT, administration of B975 did not impair GVL activity and resulted in significantly improved leukemia-free survival. These findings reveal a critical role for LPS in the early inflammatory events contributing to GVHD and suggest that a new class of pharmacologic agents, LPS antagonists, may help to prevent GVHD while preserving T cell responses to host antigens and GVL activity.