Targeted Immunotherapy for Tuberculosis and HIV co-infection

项目摘要 结核病的惊人蔓延以及艾滋病毒相关结核病的共同流行是全球卫生问题。 尽管有效的抗分枝杆菌和抗病毒治疗的可用性，日益增长的耐药性， 与艾滋病毒合并感染相关的发病率和死亡率增加，促使迫切需要制定 创新疗法宿主对结核分枝杆菌（M.tb）的免疫应答的一个关键特征是免疫应答的免疫应答。 形成称为肉芽肿的免疫细胞聚集体，主要在肺中， 微环境，其中包含感染，但也允许病原体的持久性和最终 休眠感染的重新激活，如在艾滋病毒中所见。我们假设通过抑制宿主的免疫抑制 由调节性T细胞（T细胞）和髓源性抑制细胞（MDSC）介导的应答，以及由 消除吞噬和窝藏结核分枝杆菌的免疫细胞，宿主的免疫反应可能会倾向于 主要是抗分枝杆菌的，最终导致根除感染。在这项研究中，我们建议 测试新的和改进的DAB 389 mIL-2（Ontak®）和DAB 389 mIL-4制剂的功效， 白喉毒素为基础的细胞因子受体靶向融合蛋白在我们的实验室产生的，在选择性 消除分别表达IL-2-R和IL-4 R的细胞，例如Treg和MDSC。我们会评估他们 作为TB和结核分枝杆菌/HIV共感染小鼠模型中的宿主定向治疗剂， 用于灵长类动物模型研究和人类临床试验。 .

PROJECT SUMMARY The alarming spread of tuberculosis (TB), and co-epidemic of HIV-associated TB, are global health concerns. Despite the availability of effective anti-mycobacterial and anti-viral therapy, growing drug-resistance, and increased morbidity and mortality associated with HIV co-infection, have prompted an exigent need to develop innovative therapies. A key feature of host immune response to Mycobacterium tuberculosis (M.tb) is the formation of aggregates of immune cells called granulomas, predominantly in the lungs, which provide the microenvironment in which infections are contained, but which also allow for pathogen persistence and ultimate reactivation of dormant infection, as seen in HIV. We hypothesize that by dampening host immunosuppressive responses mediated by regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSC), and by eliminating immune cells that engulf and harbor M.tb, the host immune response could be tipped towards a predominantly anti-mycobacterial one leading ultimately to eradication of infection. In this study, we propose to test the efficacy of new and improved preparations of DAB389mIL-2 (Ontak®) and DAB389mIL-4, specific diphtheria toxin-based cytokine receptor targeted fusion proteins generated in our laboratory, in the selective elimination of cells, such as Tregs and MDSC, expressing IL2-R and IL-4R respectively. We will evaluate them as host directed therapeutics in mouse models of TB and of M.tb/HIV co-infection in order to develop them further for primate model studies and human clinical trials. .