de Koning Barbara A E, van Dieren Jolanda M, Lindenbergh-Kortleve Dicky J, van der Sluis Maria, Matsumoto Tetsuya, Yamaguchi Keizo, Einerhand Alexandra W, Samsom Janneke N, Pieters Rob, Nieuwenhuis Edward E S
Division of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Dr Molewaterplein 60, PO Box 2060, 3000 GE Rotterdam, the Netherlands.
Int Immunol. 2006 Jun;18(6):941-9. doi: 10.1093/intimm/dxl030. Epub 2006 Apr 24.
The use of high doses of the anti-cancer drug methotrexate (MTX) is associated with intestinal damage. As a result, mucosal immune cells become increasingly exposed to a vast amount of microbial stimuli. We aimed at determining whether these cells are still functional during MTX treatment. Furthermore, we assessed if activation of the mucosal immune system would play a role in the pathogenesis of mucositis. A contributive role to mucositis for the adaptive immune system was established by showing that mucosal lymphocytes from MTX-treated mice secreted enhanced amounts of cytokines upon ex vivo polyclonal stimulation. Next, in vitro experiments revealed that macrophages were not affected by MTX in the capacity to produce tumor necrosis factor-alpha (TNF-alpha) and IL-10 after LPS exposure. Moreover, peritoneal macrophages from MTX-treated mice produced more IL-10 and TNF-alpha upon LPS stimulation, compared with cells derived from control mice. These data indicate a persistence of both innate and adaptive immune responses in this model. The clinical relevance of these findings was further established by the fact that LPS exposure prior to MTX treatment aggravated the course of mucositis. Furthermore, LPS-responsive mice recovered more slowly compared with LPS-unresponsive mice from MTX treatment. Finally, we found an increase in weight loss and intestinal damage upon MTX treatment in IL-10-deficient mice in comparison to wild-type controls, suggesting a protective role for IL-10 in mucositis. We conclude that mucosal immune responses remain resilient during MTX-induced mucositis. Whereas TNF-alpha production may contribute to mucosal damage, IL-10 may regulate by restricting excessive mucositis.
高剂量抗癌药物甲氨蝶呤（MTX）的使用与肠道损伤有关。因此，黏膜免疫细胞越来越多地暴露于大量的微生物刺激之下。我们旨在确定这些细胞在MTX治疗期间是否仍具有功能。此外，我们评估了黏膜免疫系统的激活是否会在黏膜炎的发病机制中发挥作用。通过证明来自MTX处理小鼠的黏膜淋巴细胞在体外多克隆刺激后分泌出更多的细胞因子，确定了适应性免疫系统对黏膜炎的促成作用。接下来，体外实验表明，巨噬细胞在接触脂多糖（LPS）后产生肿瘤坏死因子-α（TNF-α）和白细胞介素-10（IL-10）的能力不受MTX影响。此外，与来自对照小鼠的细胞相比，MTX处理小鼠的腹膜巨噬细胞在LPS刺激下产生更多的IL-10和TNF-α。这些数据表明在该模型中固有免疫和适应性免疫反应均持续存在。MTX治疗前接触LPS会加重黏膜炎病程这一事实进一步证实了这些发现的临床相关性。此外，与对LPS无反应的小鼠相比，对LPS有反应的小鼠从MTX治疗中恢复得更慢。最后，我们发现与野生型对照相比，IL-10缺陷小鼠在MTX治疗后体重减轻和肠道损伤增加，这表明IL-10在黏膜炎中具有保护作用。我们得出结论，在MTX诱导的黏膜炎期间，黏膜免疫反应保持弹性。虽然TNF-α的产生可能导致黏膜损伤，但IL-10可能通过限制过度的黏膜炎发挥调节作用。
