REGULATION OF MACROPHAGE ACTIVITY: IN VITRO VS IN VIVO

人单核细胞和巨噬细胞生物学反应的差异 广为人知，尽管人们对此知之甚少 其活性及其抗肿瘤活性的机制。 粒细胞巨噬细胞集落刺激因子(GM-CSF)是目前 在我们的癌症患者的临床试验中进行评估 机构。以前的工作已经证明GM-CSF可以诱导 单核细胞和肺泡巨噬细胞的独特反应。GM-CSF 激活肺泡巨噬细胞的细胞相关杀瘤活性 来自正常志愿者和癌症患者。相比之下， GM-CSF对血液细胞相关抗肿瘤活性影响不大 单核细胞，尽管其他与抗肿瘤活性有关的特性 (例如，超氧阴离子生产。分泌肿瘤坏死因子， 白介素6、干扰素)暴露后单核细胞表达上调 给GM-CSF。根据这些数据，成熟被假设为一种 GM-CSF诱导巨噬细胞杀瘤反应的关键决定因素。 第一个具体目标将决定不同的细胞机制 参与了单核细胞和单核细胞的GM-CSF反应 肺泡巨噬细胞。细胞因子基因的体外表达和产生 (白介素1、肿瘤坏死因子、白介素6、干扰素)将 被评估与细胞相关的杀瘤活性的相关性。 我们还将确定GM-CSF诱导的细胞因子是顺序还是 与GM-CSF同时进一步调节巨噬细胞/单核细胞基因 表达和功能活性。此外，对GM-CSF的反应 从切除的组织标本中提取的肿瘤内巨噬细胞 下定决心。第二个具体目标是将该项目与 评价体内暴露对人体健康影响的临床试验 GM-CSF在特定的细胞和/或分子过程中的作用 特异性靶点1与GM-CSF反应有关 单核/巨噬细胞。此外，还将在以下方面开展研究 在GM-CSF治疗前和治疗期间获得的肿瘤活检标本 确定GM-CSF诱导的变化在体内是否可检测到 肿瘤部位。这项调查将提供有关这两项法规的数据 人体杀瘤反应及抗肿瘤作用机制的研究进展 单核细胞和巨噬细胞。最终，这些发现将提供一种 为未来设计更有效的免疫方法奠定基础 为了癌症治疗。

Differences in biologic responses of human monocytes and macrophages are well recognized, although little is known about the regulation of activation and mechanisms of their antitumor activity. Granulocyte-macrophage colony stimulating factor (GM-CSF) is currently being evaluated in a clinical trial in patients with cancer at our institution. Previous work has demonstrated that GM-CSF induces distinctive responses in monocytes and alveolar macrophages. GM-CSF activates cell-associated tumoricidal activity in alveolar macrophages from both normal volunteers and patients with cancer. In contrast, GM-CSF has little effect on cell-associated antitumor activity of blood monocytes, although other properties associated with antitumor activity (e.g. superoxide anion production. secretion of tumor necrosis factor, interleukin-6, interferon) are upregulated in monocytes after exposure to GM-CSF. Based upon these data, maturation is hypothesized to be a critical determinant of GM-CSF induced macrophage tumoricidal response. The first specific aim will determine if divergent cellular mechanisms are involved in the contrasting GM-CSF responses of monocytes and alveolar macrophages. In vitro cytokine gene expression and production (interleukin-1, tumor necrosis factor, interleukin-6, interferon) will be assessed for correlation with cell-associated tumoricidal activity. We will also determine whether GM-CSF-induced cytokines sequentially or concurrently with GM-CSF further modulate macrophage/monocyte gene expression and functional activity. In addition, the response to GM-CSF of intratumor macrophages from resected tissue specimens will be determined. The second specific aim will be to link this project with the clinical trial by evaluating the effect of in vivo exposure to GM-CSF on the specific cellular and/or molecular processes shown in specific aim 1 to be associated with the GM-CSF responses of monocytes/macrophages. In addition, studies will be carried out with tumor biopsy specimens obtained prior to and during GM-CSF therapy to determine whether GM-CSF-induced changes are detectable in vivo at the tumor site. This investigation will provide data on both the regulation of tumoricidal responses and mechanisms of antitumor activity in human monocytes and macrophages. Ultimately such findings will provide a basis for the future design of more effective immunological approaches to cancer therapy.