Adjunctive immune modulation to improve TB treatment

描述（由申请人提供）：尽管有有效的化疗和实施直接观察治疗，短期策略，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需要至少6个月，耐药结核病患者需要一年以上。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来选择的，因此认为存在于患有活动性TB的患者的肺中的缓慢和/或非复制型结核分枝杆菌（Mtb）的亚群保持存活并且可以在治疗完成后显示表型耐受性，从而导致TB治疗的失败。此外，尽管细菌学治愈，结核病患者中仍报告了与疾病复发和再感染风险增加相关的残余慢性肺损伤。在这里，我们建议通过使用小分子磷酸二酯酶-4抑制剂（PDE 4 i）的连续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，我们将使用一个建立的Mtb感染的兔子模型，该模型非常模拟人类结核病的病理特征。我们已经证明，结核分枝杆菌分离株HN 878和CDC 1551在感染家兔后引起不同的临床结果。HN 878感染兔子导致慢性肺结核与空洞病类似，在人类活动性结核病。兔的Mtb CDC 1551感染产生了唯一的动物模型，其一致地导致细菌的完全和自发（即非药物介导的）清除并在肺中建立潜伏性TB感染（LTBI）。在先前使用PDE 4 i（CC 11050）在Mtb感染的兔中进行的研究中，我们表明该药物通常不具有免疫抑制性，改善了INH介导的Mtb杀伤，并减少了肺病理学。该药物已在人体I期临床试验中证明了安全性。然而，这些数据不足以启动人体研究，如果没有额外的知识，这种辅助治疗将如何发挥作用，在一个多药物结核病方案。本项目的目的是检测PDE 4 i（CC 11050）的以下能力：a）加速多药治疗方案中的Mt B清除; B）减少疾病病理以改善临床结局; c）通过增强多药治疗杀灭感染的能力来限制再激活风险。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PDE 4 i干预措施，帮助实现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。

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.