CYSTIC FIBROSIS LUNG IMMUNITY AND PSEUDOMONAS INFECTION

细菌性病原体慢性进行性肺部感染，特别是 铜绿假单胞菌，是负责大部分的发病率， 囊性纤维化（CF）患者的死亡率。 在初步研究中， 我们已经发现，铜绿假单胞菌感染患者的痰中 抑制淋巴细胞增殖反应。 的抑制活性 存在于痰中的是耐热的。 在平行研究中，我们发现 淋巴细胞增殖的强效耐热抑制因子， P.铜绿假单胞菌培养上清液。 这些抑制因素已经被 鉴定为吩嗪颜料。 这些低的抑制活性 分子量色素不被抗铜绿假单胞菌中和 抗体的 我们的第一个具体目标是鉴定 CF痰液中存在淋巴细胞增殖。 为此， 将使用高分辨率色谱法和其他分析方法。 CF痰液中抑制物的存在与细菌感染相关。 感染和功能抑制活性。 第二个具体目标是 确定铜绿假单胞菌吩嗪色素和抑制剂的作用 存在于CF中，对淋巴细胞活化和对吞噬细胞 多形核白细胞（PMN）和肺泡巨噬细胞的能力 （上午）。 这些方法包括活化标志物在细胞表面的表达， T淋巴细胞，B淋巴细胞分泌免疫球蛋白， 吞噬作用、硝基蓝四唑还原和铜绿假单胞菌摄取， 被PMN和AM杀害 这些研究的后续目标是 定义直接从CF痰液或支气管 灌洗。 第三个具体目标是确定CF淋巴细胞或 中性粒细胞更容易受到铜绿假单胞菌吩嗪的抑制 比正常的淋巴细胞或中性粒细胞的色素。 最后一个具体目标是 寻找P. 铜绿。 将使用以下方法寻求抑制-中和效应： 共价连接至载体的抑制剂的抗体，或通过 与类似但非抑制性化合物的竞争性抑制。 CF痰液中耐热抑制剂的存在可能 有助于CF肺部感染的慢性化和进展。 这种抑制肺阻力的机制需要了解 以便设计出具体的治疗方法来克服它。

Chronic progressive lung infection with bacterial pathogens, particularly Pseudomonas aeruginosa, is responsible for most of the morbidity and mortality in patients with cystic fibrosis (CF). In preliminary studies, we have found that the sputum of P. aeruginosa infected patients is highly inhibitory for lymphocyte proliferative responses. The inhibitory activity present in the sputum is heat resistant. In parallel studies we have found potent, heat resistant inhibitory factor(s) for lymphocyte proliferation in P. aeruginosa culture supernatants. These inhibitory factors have been identified as phenazine pigments. The inhibitory activity of these low molecular weight pigments is not neutralized by anti-P. aeruginosa antibodies. Our first specific aim is to identify the heat resistant inhibitor(s) of lymphocyte proliferation which are present in CF sputum. To this effect, high resolution chromatography and other analytical methods will be used. The presence of inhibitors in CF sputum will be correlated with bacterial infection and functional inhibitory activity. The second specific aim is to establish the effect of P. aeruginosa phenazine pigments and inhibitors present in CF sputa on lymphocyte activation, and on phagocytic capabilities of polymorphonuclear cells (PMN's) and alveolar macrophages (AM). These methods include surface expression of activation markers on T-lymphocytes, secretion of immunoglobulins by B-lymphocytes, and phagocytosis, nitrobluetetrazolium reduction and P. aeruginosa uptake and killing by PMN's and AMs. The subsequent goal of these studies is to define alterations in cells obtained directly from CF sputum or bronchial lavage. The third specific aim is to establish whether CF lymphocytes or PMN's are more susceptible to inhibition by P. aeruginosa phenazine pigments than are normal lymphocytes or PMN's. A last specific aim is to search for possible antagonists for lymphocytes inhibitors produced by P. aeruginosa. An inhibition-neutralizing effect will be sought using antibodies to an inhibitor covalently attached to a carrier, or through competitive inhibition with similar but non-inhibitory compounds. The presence of heat resistant inhibitors in CF sputum is likely to contribute to the chronicity and progression of CF pulmonary infection. This mechanism of inhibition of pulmonary resistance needs to be understood in order to design specific therapeutic approaches to overcome it.