CYTOTOXIC CELL REGULATION BY THE PULMONARY MACROPHAGE

我们假设肺巨噬细胞抑制了肺癌患者的抗癌免疫。 肺的病理作用具有侵袭性和难治性 肺癌的症状随着过继免疫疗法的出现， 了解细胞毒性淋巴细胞是如何 在宿主环境中进行调节。在初步工作中，我们证明， 肺泡巨噬细胞（AM）是其他功能性NK细胞的有效抑制剂 LAK细胞。该提案将量化以下方面的具体性和程度： 这种抑制现象，其时间要求和可逆性， 以及介导它的亚细胞机制。新鲜的人类Ams将 获得并测试它们抑制细胞毒性功能的能力， NK细胞、LAK细胞、抗原特异性细胞毒性T淋巴细胞（CTL）和 抗体介导的细胞毒性（ADCC）。通过比较 抑制这些不同的细胞毒性效应物，其具有不同的 目标识别，我们将深入了解机制和特异性 抑制。我们亦会研究辅助医疗队在防止 诱导抗癌反应。抑制动力学将是 确定，因为一旦淋巴细胞 从AM环境中删除。将检查IL-2的能力 恢复细胞毒活性，和GM-CSF，已被证明影响 单核细胞和LAK细胞之间的相互作用，将测试其 调节抑制的能力。间接证据表明， AM和LAK细胞之间的相互作用是抑制过程的核心。性质 和重要性的细胞与细胞的结合将研究使用抗LFA 抗体和温度调节。最后，我们观察到抑制性 活性在孤立的AM膜，我们将试图定量， 表征这种膜相关的抑制信号。我们的最终目标 是优化宿主免疫力和对自然史的影响， 肺肿瘤的治疗。

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.