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是 众所周知，虽然对监管知之甚少， 激活和抗肿瘤活性的机制。 粒细胞-巨噬细胞集落刺激因子（GM-CSF）目前是 在我们的癌症患者的临床试验中进行评估， 机构。 先前的工作已经证明GM-CSF诱导 单核细胞和肺泡巨噬细胞的独特反应。 GM-CSF 激活肺泡巨噬细胞中细胞相关的杀肿瘤活性 来自正常志愿者和癌症患者。 与此相反， GM-CSF对血液细胞相关抗肿瘤活性无明显影响 单核细胞，虽然其他性质与抗肿瘤活性 (e.g.超氧阴离子产生。肿瘤坏死因子的分泌， 白细胞介素-6，干扰素）在暴露后在单核细胞中上调 转GM-CSF 根据这些数据，成熟被假设为一个 GM-CSF诱导的巨噬细胞杀肿瘤反应的关键决定因素。 第一个特定的目标将确定是否不同的细胞机制， 参与单核细胞的GM-CSF反应， 肺泡巨噬细胞 体外细胞因子基因表达和产生 （白细胞介素-1、肿瘤坏死因子、白细胞介素-6、干扰素）将 评估与细胞相关的杀肿瘤活性的相关性。 我们还将确定是否GM-CSF诱导的细胞因子顺序或 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 切除的组织标本中的肿瘤内巨噬细胞将 测定 第二个具体目标是将该项目与 临床试验通过评估体内暴露于 GM-CSF对特定细胞和/或分子过程的作用，如图10所示。 特异性目的1与以下患者的GM-CSF应答相关： 单核细胞/巨噬细胞。 此外，还将开展研究， 在GM-CSF治疗之前和期间获得的肿瘤活检标本， 确定GM-CSF诱导的变化是否可在体内检测到， 肿瘤部位。 这项调查将提供有关法规和 的杀瘤反应和抗肿瘤活性的机制 单核细胞和巨噬细胞。 最终，这些发现将提供一个 为今后设计更有效的免疫学方法奠定基础 到癌症治疗

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.