Institut National de la Santé et de la Recherche Médicale, Unité U768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire, Paris, France.
EMBO Mol Med. 2009 May;1(2):112-24. doi: 10.1002/emmm.200900009.
Hereditary haemophagocytic lymphohistiocytosis (HLH) is a fatal inflammatory disease and treatments currently may lead to serious side effects. There is a pressing need for effective, less toxic treatments for this disease. Previous reports have suggested that interferon gamma (IFNgamma) has a role in the pathogenesis of HLH. Here, we report that blocking IFNgamma had a therapeutic effect in two different murine models of human hereditary HLH (perforin-deficient and Rab27a-deficient mice, both infected with lymphocytic choriomeningitis virus). Therapeutic administration of an anti-IFNgamma antibody induced recovery from haemophagocytosis in both genetic models, as evidenced by increased survival in perforin-deficient mice and correction of blood cytopenia, moderation of body temperature changes, decreased cytokinaemia, restoration of splenic architecture and reduced haemophagocytosis in the liver of both murine models. Involvement of the central nervous system in Rab27a-deficient mice was prevented by anti-IFNgamma therapy. Hepatic T-cell infiltrates and virus persisted, with no detectable harm during the time course of these studies. These data strongly suggest that neutralization of IFNgamma could be used in humans to safely alleviate the clinical manifestations of haemophagocytosis.
遗传性噬血细胞性淋巴组织细胞增生症（HLH）是一种致命的炎症性疾病，目前的治疗方法可能会导致严重的副作用。因此，迫切需要针对这种疾病的有效、毒性更低的治疗方法。先前的报告表明，干扰素γ（IFNγ）在 HLH 的发病机制中起作用。在这里，我们报告称，阻断 IFNγ 在两种不同的人类遗传性 HLH （穿孔素缺陷和 Rab27a 缺陷小鼠，均感染淋巴细胞性脉络丛脑膜炎病毒）的小鼠模型中具有治疗作用。抗 IFNγ 抗体的治疗性给药在两种遗传模型中均诱导噬血细胞作用的恢复，这表现在穿孔素缺陷小鼠的存活率增加和血液细胞减少症得到纠正、体温变化得到缓解、细胞因子血症减少、脾脏结构得到恢复以及两种小鼠模型的肝脏噬血作用减少。抗 IFNγ 治疗可预防 Rab27a 缺陷小鼠中枢神经系统受累。肝 T 细胞浸润和病毒持续存在，但在这些研究的时间过程中没有检测到明显的危害。这些数据强烈表明，中和 IFNγ 可用于人类以安全缓解噬血细胞的临床表现。
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