Genes And Gene Products As Immunoadjuvants

作为免疫佐剂的基因和基因产物

• 批准号: 7301895
• 负责人: Steven M Holland
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7301895
• 关键词: Genes; Gene; Products; Immunoadjuvants

We are working on the identification, description, and treatment of congenital and acquired syndromes of increased susceptibility to infection. The syndromes in which we are interested primarily affect the phagocytes, and are most apparent in the increased susceptibility to nontuberculous mycobacteria. These organisms are important pathogens only in the immunocompromised host. Therefore, we have sought to identify patients without previously recognized forms of immunocompromise who have these infections and then determine the nature of their susceptibility. In this way we have identified and characterized the pathways involved in the control of mycobacteria and other intracellular pathogens, such as Salmonella. The abnormalities we have already identified center around macrophage/lymphocyte interactions leading to the production of or response to interferon gamma, IL-12, and tumor necrosis factor. In addition, the pathways regulating the response to tumor necrosis factor overlap with the interferon gamma signaling pathways and have been shown to be lesioned in patients with these infections. The study of these "experiments of nature" highlights the critical role of the macrophage/ lymphocyte interaction in control of mycobacteria and other intracellular pathogens. These observations have led us to explore cytokine therapies that may have broader application to the treatment of tuberculosis. Over the last year we have continued our focus on the importance of the regulation of inflammatory genes in mycobacterial infections through the study of patients with extrapulmonary tuberculosis. IN collaborations with groups in the United States and Brazil we have identified abnormalities in chemokine secretion that are associated with extrapulmonary but not pulmonary tuberculosis. Last year we initiated a national group for the study of pulmonary nontuberculous mycobacterial disease, the Nontuberculous Mycobacterial Consortium, to create national protocols for the study of nontuberculous infections in North America. This organization has continued to grow and has successfully created the first national treatment trial in pulmonary nontuberculous mycobacterial disease.

我们正在研究对感染易感性增加的先天性和可靠性综合征的识别，描述和治疗。我们感兴趣的综合征主要影响吞噬细胞，并且最明显地对增加无结核分枝杆菌的敏感性最为明显。这些生物仅在免疫功能低下的宿主中才是重要的病原体。因此，我们试图鉴定患有这些感染的免疫功能障碍形式的患者，然后确定其敏感性的性质。通过这种方式，我们已经确定并表征了控制分枝杆菌和其他细胞内病原体（例如沙门氏菌）所涉及的途径。我们已经在巨噬细胞/淋巴细胞相互作用周围确定的异常，导致对干扰素γ，IL-12和肿瘤坏死因子产生或反应。此外，调节对肿瘤坏死因子的反应与干扰素伽马信号通路重叠的途径已被证明在患有这些感染的患者中已病变。对这些“自然实验”的研究突出了巨噬细胞/淋巴细胞相互作用在控制分枝杆菌和其他细胞内病原体中的关键作用。这些观察结果使我们探索了可能在结核病治疗中更广泛应用的细胞因子疗法。在过去的一年中，通过研究肺外结核病患者的研究，我们继续关注炎症基因在分枝杆菌感染中的重要性。在与美国和巴西的群体的合作中，我们已经确定了趋化因子分泌异常，这些异常与肺外肺结核有关。去年，我们发起了一个全国性的肺化分枝杆菌疾病研究，即非结核分枝杆菌财团，为北美无术感染的研究创建了国家方案。该组织一直在增长，并成功地创建了第一项国家治疗肺部无结霉菌疾病的国家治疗试验。