ORGAN SPECIFIC CYTOKINE THERAPY - LOCAL ACTIVATION OF MONONUCLEAR PHAGOCYTES BY DELIVERY OF AN AEROSOL OF RECOMBINANT INTERFERON-GAMMA TO THE HUMAN LUNG
ORGAN SPECIFIC CYTOKINE THERAPY - LOCAL ACTIVATION OF MONONUCLEAR PHAGOCYTES BY DELIVERY OF AN AEROSOL OF RECOMBINANT INTERFERON-GAMMA TO THE HUMAN LUNG
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DOI：
10.1172/jci115291
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发表时间：
1991-07-01
影响因子：
15.9
通讯作者：
CRYSTAL, RG
中科院分区：
文献类型：
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作者：
JAFFE, HA;BUHL, R;CRYSTAL, RG
在肺泡巨噬细胞在呼吸道上皮表面的宿主防御中的核心作用以及IFN-γ激活单核吞噬细胞的能力的背景下，我们评估了使用rIFN-γ在体内激活人肺泡巨噬细胞的策略。 为了实现这一点，将rIFN-γ给予不吸烟的正常人，定量血清和呼吸道上皮衬里液（ELF）中IFN-γ的量，并通过定量IP-10（IFN-γ特异性诱导的基因）的mRNA转录物的表达来评价血液单核细胞和肺泡巨噬细胞的IFN-γ相关活化的状态。 全身性施用（皮下）最大耐受量的rIFN-γ（250 μ g）后，血清中IFN-γ的水平可检测，但ELF中不能检测，IP-10转录物在血液单核细胞中表达，但在肺泡巨噬细胞中不能表达，以及多种全身性不良反应。 为了避免全身给药不能到达呼吸ELF和激活肺泡巨噬细胞，rIFN-γ（250- 1，000 μ g）作为气雾剂吸入，每天一次，持续3天。 引人注目的是，虽然在血清中未检测到IFN-γ，但在呼吸ELF中以剂量依赖性方式可检测到。 此外，肺泡巨噬细胞，而不是血液单核细胞，表达IP-10 mRNA转录，重要的是，吸入雾化rIFN-γ与局部或全身不良反应无关。 因此，使用rIFN-γ通过将细胞因子直接靶向肺来激活肺泡巨噬细胞是可行的。 这些数据表明，有针对性的细胞因子治疗的潜在策略，没有全身副作用，以增强呼吸道防御的风险或与肺部感染的个人。
In the context of the central role of the alveolar macrophage in host defense of the respiratory epithelial surface, and the ability of IFN-gamma to activate mononuclear phagocytes, we have evaluated strategies to use rIFN-gamma to activate human alveolar macrophages in vivo. To accomplish this, rIFN-gamma was administered to nonsmoking normals, the amounts of IFN-gamma quantified in serum and respiratory epithelial lining fluid (ELF) and the status of IFN-gamma related activation of blood monocytes and alveolar macrophages was evaluated by quantifying the expression of mRNA transcripts of IP-10, a gene induced specifically by IFN-gamma. Systemic administration (subcutaneous) of maximally tolerated amounts of rIFN-gamma (250-mu-g) was followed by detectable levels of IFN-gamma in serum but not ELF, the expression of IP-10 transcripts in blood monocytes but not alveolar macrophages, and multiple systemic adverse effects. To circumvent the inability of systemic administration to reach respiratory ELF and activate alveolar macrophages, rIFN-gamma (250-1,000-mu-g) was inhaled as an aerosol once daily for 3 d. Strikingly, while IFN-gamma was not detected in serum it was detectable in respiratory ELF in a dose-dependent fashion. Further, alveolar macrophages, but not blood monocytes, expressed IP-10 mRNA transcripts and, importantly, inhalation of aerosolized rIFN-gamma was not associated with local or systemic adverse effects. Thus, it is feasible to use rIFN-gamma to activate alveolar macrophages by targeting the cytokine directly to the lung. These data suggest a potential strategy for targeted cytokine therapy, without systemic side effects, to augment respiratory tract defenses in individuals at risk for or with lung infection.