CYTOTOXIC CELL REGULATION BY THE PULMONARY MACROPHAGE

在侵袭性和难治性中起着病理作用 患上了肺癌。随着过继免疫疗法的出现， 越来越重要的是要了解细胞毒性淋巴细胞 在宿主环境中进行调节。在前期工作中，我们证明了 肺泡巨噬细胞(AM)是其他功能性NK的有效抑制物 和LAK细胞。这项建议将量化 这种抑制现象，它的时间要求和可逆性， 以及调节它的亚细胞机制。新鲜的人类AMS将是 获得并测试其抑制细胞毒功能的能力 NK细胞、LAK细胞、抗原特异性细胞毒性T淋巴细胞(CTL)和 抗体定向细胞毒性(ADCC)。通过比较以下能力： 抑制这些不同的细胞毒效应，它们具有不同的机制 目标识别，我们将深入了解其机理和特异性 抑制力。我们亦会研究辅助队的能力，以防止 诱导抗癌反应。抑制的动力学将是 决定了，一旦淋巴细胞逆转抑制的可能性也会确定 从AM环境中删除。将检查IL-2的能力 以恢复细胞毒活性，以及GM-CSF，这已被证明影响 单核细胞与LAK细胞之间的相互作用，将被测试其 调节抑制的能力。间接证据表明，约束性 在AM和LAK细胞之间是抑制过程的中心。大自然 并将使用抗LFA来研究细胞间结合的重要性 抗体和温度调节。最后，我们观察到了抑制作用 在分离的AM膜中的活性，我们将尝试定量和 表征这个与膜相关的抑制信号。我们的终极目标 是优化宿主免疫力和对自然历史的影响 肺部肿瘤的治疗。

We hypothesize that pulmonary macrophages suppress anti-cancer immunity in the lung and play a pathologic role in the aggressive and refractory nature of lung cancer. With the advent of adoptive immunotherapies it is increasingly important to understand how cytotoxic lymphocytes are regulated in the host environment. In preliminary work we demonstrated that alveolar macrophages (AMs) are potent inhibitors of otherwise functional NK and LAK cells. This proposal will quantitate the specificity and extent of this inhibitory phenomenon, its temporal requirements and reversibility, and the subcellular mechanisms which mediate it. Fresh human Ams will be obtained and tested for their ability to inhibit the cytotoxic function of NK cells, LAK cells, antigen-specific cytotoxic T-lymphocytes (CTLs) and antibody-directed cell cytotoxicity (ADCC). By comparing the ability to inhibit these diverse cytotoxic effectors, which have varying mechanisms of target recognition, we will gain insight into the mechanism and specificity of inhibition. We will also examine the capacity of AMs to prevent the induction of an anti-cancer response. The kinetics of inhibition will be determined, as will the potential for reversing inhibition once lymphocytes are removed from the AM environment. IL-2 will be examined for its capacity to restore cytotoxic activity, and GM-CSF, which has been shown to affect the interaction between monocytes and LAK cells, will be tested for its ability to modulate inhibition. Indirect evidence suggests that binding between AMs and LAK cells is central to the inhibitory process. The nature and importance of cell-to-cell binding will be investigated using anti-LFA antibody and temperature modulation. Finally, we have observed inhibitory activity in isolated AM membranes and we will attempt to quantitate and characterize this membrane-associated inhibitory signal. Our ultimate goal is to optimize host immunity and impact on the natural history and treatment of pulmonary neoplasms.