Genes And Gene Products As Immunoadjuvants

我们正在致力于鉴定、描述和治疗先天性和获得性综合征，这些综合征对分枝杆菌和细胞内真菌感染的易感性增加。我们感兴趣的综合征主要影响吞噬细胞，最明显的是对非结核分枝杆菌的易感性增加。这些生物体被认为是仅在免疫功能低下的宿主中的重要病原体。因此，我们试图确定患者没有以前公认的形式的免疫功能低下谁有这些感染，然后确定其易感性的性质。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（如沙门氏菌、组织胞浆菌病和球孢子菌病）的途径。我们已经发现的异常是围绕巨噬细胞/淋巴细胞相互作用，导致干扰素γ、IL-12和肿瘤坏死因子的产生或对其产生反应。此外，调节对肿瘤坏死因子的反应的途径与干扰素γ信号传导途径重叠，并且已显示在患有这些感染的患者中受损。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（包括真菌）中的关键作用。这些观察结果使我们探索可能在结核病治疗中具有更广泛应用的细胞因子疗法。在过去的一年里，我们通过对肺外真菌患者的研究，继续关注炎症基因在分枝杆菌感染中的重要性。我们已经发现组织胞浆菌病、球孢子菌病和分枝杆菌病患者细胞因子受体和信号传导异常。

We are working on the identification, description, and treatment of congenital and acquired syndromes of increased susceptibility to mycobacterial and intracellular fungal infections. 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 thought to be 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, histoplasmosis, and coccidioidomycosis. 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, including fungi. 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 fungi. We have identified abnormalities in cytokine receptors and signaling in those with histoplasmosis and coccidioidomycosis as well as as mycobacteria.