Soheili Tayebeh, Durand Amandine, Sepulveda Fernando E, Rivière Julie, Lagresle-Peyrou Chantal, Sadek Hanem, de Saint Basile Geneviève, Martin Samia, Mavilio Fulvio, Cavazzana Marina, André-Schmutz Isabelle
Human Lymphohaematopoiesis Laboratory, INSERM U1163, Paris, France.
University of Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France.
Blood Adv. 2017 Dec 21;1(27):2781-2789. doi: 10.1182/bloodadvances.2017012088. eCollection 2017 Dec 26.
Patients with mutations in the gene (coding for Munc13-4 protein) suffer from familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a life-threatening immune and hyperinflammatory disorder. The only curative treatment is allogeneic hematopoietic stem cell (HSC) transplantation, although the posttreatment survival rate is not satisfactory. Here, we demonstrate the curative potential of gene correction of HSCs in a murine model of FHL3. We generated a self-inactivating lentiviral vector, used it to complement HSCs from -deficient (Jinx) mice, and transplanted the cells back into the irradiated Jinx recipients. This procedure led to complete reconstitution of the immune system (ie, to wild-type levels). The recipients were then challenged with lymphocytic choriomeningitis virus to induce hemophagocytic lymphohistiocytosis (HLH)-like manifestations. All the clinical and biological signs of HLH were significantly reduced in mice having undergone HSC gene correction than in nontreated animals. This beneficial effect was evidenced by the correction of blood cytopenia, body weight gain, normalization of the body temperature, decreased serum interferon-γ level, recovery of liver damage, and decreased viral load. These improvements can be explained by the restoration of the CD8 T lymphocytes' cytotoxic function (as demonstrated here in an in vitro degranulation assay). Overall, our results demonstrate the efficacy of HSC gene therapy in an FHL-like setting of immune dysregulation.
基因（编码Munc13 - 4蛋白）发生突变的患者患有3型家族性噬血细胞性淋巴组织细胞增生症（FHL3），这是一种危及生命的免疫和过度炎症性疾病。唯一的治愈性治疗方法是异基因造血干细胞（HSC）移植，尽管治疗后的生存率并不理想。在此，我们在FHL3小鼠模型中证明了对HSCs进行基因校正的治愈潜力。我们构建了一种自失活慢病毒载体，用它来补充来自缺陷型（Jinx）小鼠的HSCs，并将这些细胞回输到经辐照的Jinx受体小鼠体内。这一过程导致免疫系统完全重建（即达到野生型水平）。然后用淋巴细胞性脉络丛脑膜炎病毒攻击受体小鼠，以诱导噬血细胞性淋巴组织细胞增生症（HLH）样表现。与未治疗的动物相比，接受HSC基因校正的小鼠中HLH的所有临床和生物学体征均显著减轻。血细胞减少症的纠正、体重增加、体温正常化、血清干扰素 - γ水平降低、肝损伤恢复以及病毒载量降低都证明了这种有益效果。这些改善可以通过CD8 T淋巴细胞细胞毒性功能的恢复来解释（如在此体外脱颗粒试验中所示）。总体而言，我们的结果证明了HSC基因治疗在类似FHL的免疫失调情况下的疗效。
