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Pulmonary macrophage transplantation therapy

机译：肺巨噬细胞移植治疗

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摘要

Bone-marrow transplantation is an effective cell therapy but requires myeloablation, which increases infection risk and mortality. Recent lineage-tracing studies documenting that resident macrophage populations self-maintain independently of haematological progenitors prompted us to consider organ-targeted, cell-specific therapy. Here, using granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor-β-deficient (Csf2rb~(-/-)) mice that develop a myeloid cell disorder identical to hereditary pulmonary alveolar proteinosis (hPAP) in children with CSF2RA or CSF2RB mutations, we show that pulmonary macrophage transplantation (PMT) of either wild-type or Csf2rb-gene-corrected macrophages without myeloablation was safe and well-tolerated and that one administration corrected the lung disease, secondary systemic manifestations and normalized disease-related biomarkers, and prevented disease-specific mortality. PMT-derived alveolar macrophages persisted for at least one year as did therapeutic effects. Our findings identify mechanisms regulating alveolar macrophage population size in health and disease, indicate that GM-CSF is required for phenotypic determination of alveolar macrophages, and support translation of PMT as the first specific therapy for children with hPAP.%"粒细胞一巨噬细胞群刺激因子"(GM-CSF)的受体发生的突变会造成"肺泡蛋白沉积症"(PAP)。这是一种遗传病,会由于表面活性剂的积累而导致呼吸衰竭。这种病目前还没有治疗药物,必须通过肺灌洗将表面活性剂清除。PAP在小鼠模型中可以通过基因矫正的造血干细胞的骨髓移植治愈,但这种方法由于在必要的骨髓清除/免疫抑制过程中的感染此前还没有被证明对人类可行。现在,Bruce Trapnell及同事报告了在将基因矫正的巨噬细胞一次性直接转移到肺中之后小鼠PAP所发生的矫正。基因矫正的巨噬细胞持续存在了至少了一年。自体基因矫正的巨噬细胞的这种肺移植,将会免除对骨髓清除和免疫抑制的需要,对于人类PAP的治疗来说也应当更为可行。
机译：骨髓移植是一种有效的细胞疗法，但需要骨髓消融术，这会增加感染风险和死亡率。最近的谱系追踪研究表明，常驻巨噬细胞群体能够独立于血液祖细胞进行自我维持，这促使我们考虑针对器官的细胞特异性疗法。在这里，使用粒细胞-巨噬细胞集落刺激因子（GM-CSF）受体-β缺陷型（Csf2rb〜（-/-））小鼠，可在患有CSF2RA或CSF2RA的儿童中发生与遗传性肺泡蛋白沉着症（hPAP）相同的骨髓细胞疾病CSF2RB突变，我们表明野生型或经Csf2rb基因校正的巨噬细胞的肺巨噬细胞移植（PMT）无骨髓消融是安全且耐受性良好的，并且一次给药可以纠正肺部疾病，继发性系统表现和与疾病相关的生物标记正常化，并预防特定疾病的死亡率。 PMT衍生的肺泡巨噬细胞和治疗效果持续至少一年。我们的发现确定了在健康和疾病中调节肺泡巨噬细胞种群大小的机制，表明GM-CSF是肺泡巨噬细胞表型确定所必需的，并支持PMT的翻译作为hPAP患儿的首个特异性疗法。％“粒细胞一巨噬细胞群刺激因子”（GM-CSF）的受体发生的突变会造成“肺泡蛋白沉积症”（PAP）。这是一种遗传病，会由于表面活性剂的积累而导致呼吸衰竭。 PAP在小鼠模型中可以通过基因矫正的造血干细胞的骨髓移植治愈，但这种方法由于在必要的骨髓清除/免疫抑制过程中现在，布鲁斯·特拉普内尔（Bruce Trapnell）和同事报告了在将基因矫正的巨噬细胞一次性直接转移到肺中之后小鼠PAP所发生的矫正。基因矫正的巨噬细胞持续自体基因矫正的巨噬细胞的这种肺移植，将免除对生殖器官清除和免疫抑制的需要，对于人类PAP的治疗来说也可以更为可行。

著录项

  • 来源
    《Nature》 |2014年第7523期|450-454B1|共6页
  • 作者

    Takuji Suzuki; Paritha Arumugam; Takuro Sakagami; Nico Lachmann; Claudia Chalk; Anthony Sallese; Shuichi Abe; Cole Trapnell; Brenna Carey; Thomas Moritz; Punam Malik; Carolyn Lutzko; Robert E. Wood; Bruce C. Trapnell;

  • 作者单位

    Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA;

    Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA;

    Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA;

    RG Reprograming and Gene Therapy, Institute of Experimental Hematology, Hannover Medical School, Carl Neuberg-Str. 1,30625 Hannover, Germany;

    Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA;

    Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA;

    Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA;

    Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA,Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02138, USA;

    Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA;

    RG Reprograming and Gene Therapy, Institute of Experimental Hematology, Hannover Medical School, Carl Neuberg-Str. 1,30625 Hannover, Germany;

    Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA;

    Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA;

    Division of Pulmonary Medicine,Cincinnati Children's Hospital Medical Center,3333 Burnet Avenue,Cincinnati,Ohio 45229, USA;

    Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA,Division of Pulmonary Medicine,Cincinnati Children's Hospital Medical Center,3333 Burnet Avenue,Cincinnati,Ohio 45229, USA,Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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