IL-2/Treg-based immunity to TB and AIDS-related TB

基于 IL-2/Treg 的结核病和艾滋病相关结核病免疫

• 批准号: 8282719
• 负责人: Zheng W Chen
• 金额: $ 69.97万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282719
• 关键词: Acquired Immunodeficiency Syndrome; Antitubercular Agents; CD8B1 gene; Chronic; Disease; Drug Resistant Tuberculosis; Drug resistance; Effector Cell; Equilibrium; Event; Extreme drug resistant tuberculosis; HIV; IL2RA gene; Immune; Immune response; Immunotherapeutic agent; Infection; Inflammatory; Interferons; Interleukin-2; Kinetics; Lesion; Macaca; Mediating; Modality; Morbidity - disease rate; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; Regulatory T-Lymphocyte; Research; Role; Site; Testing; Tissues; Tuberculosis; alternative treatment; base; cytokine; cytotoxic; in vivo; mortality; novel; novel vaccines; pandemic disease; public health relevance; respiratory; simian human immunodeficiency virus; tuberculosis immunity

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (M.tb)-induced tuberculosis (TB) remains the leading morbidity and mortality worldwide, and the magnitude of the problem continues to grow, due in part to HIV pandemics. Sustained increases in cases of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains are making TB extremely difficult to treat and globally control. Since drug resistance is likely to increase, there is a pressed need to develop new vaccines or immunotherapeutics. We have recently shown that IL-2 treatment of macaques can induce remarkable expansion of CD4+CD25(high)Foxp3+ T regulatory cells (Treg) in systemic and respiratory sites, and more importantly confers apparent homeostatic protection against TB lesions. This surprising finding suggests that Treg can function in vivo as homeostatic regulator against TB, far beyond simple inhibition of immune responses. Based on this novel observation, we hypothesize that IL-2-expanded Treg can orchestrate or balance host responses and suppress M.tb-mediated inflammatory events, leading to no or mild TB lesions, whereas IL-2-activated T effector cells producing IFN?; or cytotoxic cytokine may help to limit M.tb replication and dissemination. To test this hypothesis, we will: I. Perform mechanistic studies to determine a critical role of IL-2-expanded Foxp3+ Treg in anti-TB immunity in macaques. II. Determine if intermittent IL-2 treatments during chronic active M.tb infection can sustain Treg expansion, down-regulate TB-driven inflammatory events or associated M.tb replication, and confer immunotherapeutics against severe TB lesions and/or TB cavities. III. Examine kinetics and function of Treg during SHIV-induced reactivation of latent M.tb co-infection, and determine if combined ART and intermittent IL-2 treatment can expand Treg and ?d, CD8 T effector cells, and confer immunotherapeutics against AIDS-related reactivation TB. PUBLIC HEALTH RELEVANCE: This project is proposed based on our recent novel observation that cytokine IL-2 treatment of macaques induces remarkable expansion of CD4+Foxp3+ T regulatory cells (Treg), and confers apparent protection against tuberculosis disease or tissue damages. Studies will elucidate immune mechanisms for IL-2-induced anti-tuberculosis immunity, and explore IL-2-based treatment modalities for tuberculosis and AIDS-related tuberculosis. Findings will exert sustained, long-term impact on tuberculosis research and provide potential alternative treatment for tuberculosis, multi-drug resistant tuberculosis, and AIDS-related tuberculosis.

描述（由申请人提供）：结核分枝杆菌（M.TB）诱导的结核病（TB）仍然是全球领先的发病率和死亡率，并且问题的幅度不断增长，部分原因是HIV Pandemics。在耐多药TB（MDR-TB）和广泛的抗药性结核（XDR-TB）菌株中，持续增加的增加使结核病极为难以治疗和全球控制。由于耐药性可能会增加，因此需要开发新的疫苗或免疫治疗药。我们最近表明，猕猴的IL-2处理可以引起全身和呼吸部位中CD4+ CD25（高）FOXP3+ T调节细胞（TREG）的显着扩展，更重要的是，更重要的是赋予明显的稳态保护抗TB病变。这一令人惊讶的发现表明，Treg可以在体内起作用，作为对TB的体内稳态调节剂，远远超出了对免疫反应的简单抑制。基于这个新颖的观察，我们假设IL-2扩展的Treg可以协调或平衡宿主反应并抑制M.TB介导的炎症事件，从而导致没有或轻度的TB病变，而IL-2激活的T效应细胞产生IFN？或细胞毒性细胞因子可能有助于限制M.TB的复制和传播。为了检验这一假设，我们将：I。进行机械研究，以确定IL-2扩展的FOXP3+ Treg在猕猴中抗TB免疫中的关键作用。 ii。确定在慢性活性M.TB感染期间间歇性IL-2治疗是否可以维持TREG的扩张，下调TB驱动的炎症事件或相关的M.TB复制，并赋予针对严重TB病变和/或TB腔的免疫治疗剂。 iii。在SHIV诱导的潜在M.TB共同感染的重新激活过程中，检查Treg的动力学和功能，并确定合并的ART和间歇性IL-2处理是否可以扩大Treg和？D，CD8 T效应细胞，并赋予与AIDS相关的重新抗性TB的免疫治疗剂。 公共卫生相关性：基于我们最近的新观察结果，提出了该项目，即猕猴的细胞因子IL-2治疗可引起CD4+ FOXP3+ T调节细胞（TREG）的显着扩展，并赋予对结核病疾病或组织损害的明显保护。研究将阐明针对IL-2诱导的抗结核免疫的免疫机制，并探索基于IL-2的治疗方法，用于结核病和与AIDS相关的结核病。发现将对结核病研究产生持续的长期影响，并为结核病，多药耐药性结核病和与艾滋病相关的结核病提供潜在的替代治疗方法。