Adjunctive immune modulation to improve TB treatment

辅助免疫调节改善结核病治疗

• 批准号: 8659731
• 负责人: Selvakumar Subbian
• 金额: $ 23.85万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8659731
• 关键词: AIDS clinical trial group; Adrenal Cortex Hormones; Adult; Affect; Aftercare; Animal Model; Animals; Antibiotics; Antitubercular Agents; Bacillus (bacterium); Bacteria; Biological; Chronic; Clinical; Clinical Trials; Communicable Diseases; Cues; Data; Directly Observed Therapy; Disease; Drug Targeting; Drug resistance in tuberculosis; Effectiveness; Etanercept; Failure; Goals; Growth; HIV; Human; Immune; Immunity; Immunosuppression; Impairment; Infection; Inflammation; Intervention; Knowledge; Lung; Macrophage Activation; Measures; Mediating; Metabolic; Modeling; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; Oryctolagus cuniculus; Outcome; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase I Clinical Trials; Population; Pulmonary Tuberculosis; Recurrent disease; Regimen; Reporting; Research Design; Residual state; Resistance; Resolution; Respiratory physiology; Risk; Safety; Sputum; Sterilization; Steroids; T-Cell Activation; Testing; Therapeutic; Therapeutic Intervention; Time; Treatment Failure; Tuberculosis; Tumor Necrosis Factor Receptor; attributable mortality; biological adaptation to stress; chemotherapy; compliance behavior; design; disorder risk; high risk; immunoregulation; improved; in vitro Model; inhibitor/antagonist; isoniazid; killings; macrophage; novel; phosphodiesterase IV; preclinical study; public health relevance; small molecule; tuberculosis drugs; tuberculosis treatment

DESCRIPTION (provided by applicant): Despite the availability of effective chemotherapy and implementation of the Directly Observed Therapy, Short course strategy, tuberculosis (TB) remains a leading cause of adult deaths attributable to a single infectious disease. Standard multidrug therapy for TB requires a minimum of 6 months, and more than a year in drug resistant-TB patients. The long duration of chemotherapy has been associated with poor patient compliance and treatment failure. Since the antibiotics used to treat Mtb infection were selected for their ability to kill actively replicating bacilli, subpopulations of slow- and/or non-replicatng Mycobacterium tuberculosis (Mtb), thought to exist in the lungs of patients with active TB, remain alive and can show phenotypic tolerance after treatment completion, thus contributing to failure of TB treatment. Moreover, residual chronic lung damage, associated with increased risk for disease relapse and reinfection, has been reported in TB patients in spite of bacteriological cure. Here, we propose to improve the effectiveness of currently available anti-TB drugs through use of adjunctive immune modulation with a small molecule phosphodiesterase-4 inhibitor (PDE4i). For this study, we will use an established rabbit model of Mtb infection that closely mimics the pathologic features of TB disease in humans. We have demonstrated that Mtb isolates HN878 and CDC1551 elicit distinct clinical outcome following infection of rabbits. HN878 infection of rabbits results in chronic pulmonary TB with cavitary disease similar to what is seen in humans with active TB. Mtb CDC1551 infection of rabbits yields the only animal model that consistently results in full and spontaneous (i.e. not drug-mediated) clearance of bacteria and establishment of latent TB infection (LTBI) in the lungs. In previous studies using the PDE4i (CC11050) in Mtb infected rabbits, we showed that the drug is not generally immune suppressive, improves INH mediated Mtb killing, and reduces lung pathology. The drug has demonstrated safety in Phase I clinical trials in humans. However, these data are not sufficient to initiate human studies without the additional knowledge of how this adjunct treatment will act in a multi-drug TB regimen. The goal of this project is to test the ability of PDE4i (CC11050) to: a) accelerate Mtb clearance in a multi-drug regimen; b) reduce disease pathology to improve clinical outcome, and c) limit the risk of reactivation by enhancing the ability of multi-drug therapy to sterilize the infection. Results obtained from this preclinical study will facilitate th design and implementation of use of this novel PDE4i intervention in clinical trials, helping to achieve the ACTG's (AIDS Clinical Trial Group) agenda to develop shorter and more effective TB therapy.

描述（由申请人提供）：尽管可以使用有效的化疗并实施直接观察治疗、短期治疗策略，但结核病 (TB) 仍然是单一传染病导致成人死亡的主要原因。结核病的标准多药治疗至少需要 6 个月，而耐药结核病患者则需要一年以上。化疗持续时间长与患者依从性差和治疗失败有关。由于用于治疗 Mtb 感染的抗生素是根据其杀死活跃复制杆菌的能力而选择的，因此缓慢和/或非复制的结核分枝杆菌 (Mtb) 亚群（被认为存在于活动性结核病患者的肺部）仍然存活并且治疗完成后可表现出表型耐受性，从而导致结核病治疗失败。此外，据报道，尽管细菌学治愈，结核病患者仍存在残留的慢性肺损伤，与疾病复发和再感染的风险增加有关。在这里，我们建议通过使用小分子磷酸二酯酶 4 抑制剂 (PDE4i) 辅助免疫调节来提高现有抗结核药物的有效性。在本研究中，我们将使用已建立的结核分枝杆菌感染兔模型，该模型密切模仿人类结核病的病理特征。我们已经证明 Mtb 分离株 HN878 和 CDC1551 在感染兔子后会产生不同的临床结果。兔子感染 HN878 会导致慢性肺结核并伴有空洞病，与人类活动性结核病相似。兔子的 Mtb CDC1551 感染产生了唯一一致导致细菌完全自发（即非药物介导）清除并在肺部建立潜伏性结核感染 (LTBI) 的动物模型。在之前使用 PDE4i (CC11050) 对 Mtb 感染的兔子进行的研究中，我们表明该药物通常不具有免疫抑制作用，可改善 INH 介导的 Mtb 杀灭作用，并减少肺部病理。该药物已在人体 I 期临床试验中证明了安全性。然而，如果不了解这种辅助治疗在多药结核病治疗方案中如何发挥作用，这些数据不足以启动人体研究。该项目的目标是测试 PDE4i (CC11050) 的能力： a) 在多药方案中加速 Mtb 清除； b) 减少疾病病理以改善临床结果，以及 c) 通过增强多药治疗消除感染的能力来限制再激活的风险。从这项临床前研究中获得的结果将有助于在临床试验中设计和实施这种新型 PDE4i 干预措施，有助于实现 ACTG（艾滋病临床试验组）的议程，以开发更短、更有效的结核病治疗。