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(申请人提供)：尽管可获得有效的化疗和实施直接观察疗法，短期治疗战略，结核病(结核病)仍然是成人死于一种单一传染病的主要原因。结核病的标准多药疗法至少需要6个月，耐药结核病患者需要一年以上。化疗持续时间长，患者依从性差，治疗失败。由于用于治疗结核分枝杆菌感染的抗生素是因为它们能够杀死主动复制的杆菌，所以被认为存在于活动性结核病患者肺部的慢复制和/或非复制结核分枝杆菌(Mtb)亚群仍然活着，并在治疗完成后表现出表型耐受，从而导致结核病治疗失败。此外，尽管进行了细菌治疗，但结核病患者仍有残留的慢性肺损伤，这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目前可用的抗结核药物的有效性。在这项研究中，我们将使用已建立的结核分枝杆菌感染的兔模型，该模型非常接近于人类结核病的病理特征。我们已经证明了结核分枝杆菌分离株HN878和CDC1551在兔感染后引起了不同的临床结果。感染HN878的兔会导致慢性肺结核病，并伴有空洞性疾病，与人类活动性结核病相似。结核分枝杆菌CDC1551感染兔产生了唯一的动物模型，持续地导致细菌完全和自发(即不是药物介导的)清除，并在肺部建立潜伏性结核病感染(LTBI)。在先前使用PDE4i(CC11050)对感染结核分枝杆菌的兔进行的研究中，我们发现该药一般不具有免疫抑制作用，可以改善异烟肼介导的结核分枝杆菌杀伤作用，并减少肺部病理。该药物已在人体I期临床试验中证明是安全的。然而，如果不进一步了解这种辅助治疗在多药结核病方案中的作用，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)在多种药物方案中加速结核分枝杆菌的清除；b)减少疾病病理以改善临床结果，以及c)通过增强多种药物疗法对感染进行消毒的能力来限制再激活的风险。这项临床前研究的结果将促进在临床试验中使用这种新型PDE4i干预措施的设计和实施，有助于实现ACTG(艾滋病临床试验小组)的议程，开发更短和更有效的结核病治疗方法。