Improved Mycobacterium tuberculosis clearance after the restoration of IFN-γ+ TNF-α+ CD4+ T cells: Impact of PD-1 inhibition in active tuberculosis patients.,European Journal of Immunology

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Improved Mycobacterium tuberculosis clearance after the restoration of IFN-γ+ TNF-α+ CD4+ T cells: Impact of PD-1 inhibition in active tuberculosis patients.
European Journal of Immunology ( IF 4.5 ) Pub Date : 2020-03-24 , DOI: 10.1002/eji.201948283
Divya Kamboj ₁ , Pushpa Gupta ₂ , Mandira Varma Basil ₃ , Anant Mohan ₄ , Randeep Guleria ₄ , Anuj Bhatnagar ₅ , Girija Mehta ₁ , Prabin Kumar ₁ , Abhinav Saurabh ₁ , Rakesh Deepak ₁ , Deepshi Thakral ₁ , Pragya Misra ₁ , Rati Tandon ₆ , Umesh D Gupta ₂ , Dipendra Kumar Mitra ₁

Affiliation

Prolonged therapy, drug toxicity, noncompliance, immune suppression, and alarming emergence of drug resistance necessitate the search for therapeutic vaccine strategies for tuberculosis (TB). Such strategies ought to elicit not only IFN-γ, but polyfunctional response including TNF-α, which is essential for protective granuloma formation. Here, we investigated the impact of PD-1 inhibition in facilitating protective polyfunctional T cells (PFTs), bacillary clearance, and disease resolution. We have observed PD-1 inhibition preferentially rescued the suppressed PFTs in active tuberculosis patients. In addition, polyfunctional cytokine milieu favored apoptosis of infected MDMs over necrosis with markedly reduced bacillary growth (≪CFU) in our in vitro monocyte-derived macrophages (MDMs) infection model. Furthermore, the animal study revealed a significant decline in the bacterial burden in the lungs and spleen of infected mice after in vivo administration of α-PD-1 along with antitubercular treatment. Our findings suggest that rescuing polyfunctional immune response by PD-1 inhibition works synergistically with antituberculosis chemotherapy to confer improved control over bacillary growth and dissemination. In summary, our data strongly indicate the therapeutic potential of α-PD-1 as adjunct immunotherapy that can rejuvenate suppressed host immunity and enhance the efficacy of candidate therapeutic vaccine(s).

中文翻译：

恢复IFN-γ+TNF-α+ CD4 + T细胞后结核分枝杆菌的清除率提高：PD-1抑制对活动性肺结核患者的影响。

长期的治疗，药物毒性，不合规，免疫抑制和耐药性的出现令人震惊，因此必须寻找治疗结核病（TB）的疫苗策略。此类策略不仅应引起IFN-γ，而且应引起包括TNF-α在内的多功能反应，这对保护性肉芽肿的形成至关重要。在这里，我们研究了PD-1抑制作用在促进保护性多功能T细胞（PFT），细菌清除率和疾病缓解方面的作用。我们已经观察到PD-1抑制作用优先挽救了活动性肺结核患者中抑制的PFT。此外，在我们的体外单核细胞衍生巨噬细胞（MDMs）感染模型中，多功能细胞因子环境比坏死更有利于感染MDM的凋亡，而细菌生长（growthCFU）明显减少。此外，这项动物研究显示，在体内施用α-PD-1并进行抗结核治疗后，感染小鼠的肺和脾脏细菌负荷显着降低。我们的研究结果表明，通过PD-1抑制来挽救多功能免疫反应与抗结核化疗具有协同作用，从而可以更好地控制细菌的生长和传播。总而言之，我们的数据有力地表明了α-PD-1作为辅助免疫疗法的治疗潜力，可以恢复受抑制的宿主免疫力并增强候选治疗疫苗的功效。我们的研究结果表明，通过PD-1抑制来挽救多功能免疫反应与抗结核化疗具有协同作用，从而可以更好地控制细菌的生长和传播。总而言之，我们的数据有力地表明了α-PD-1作为辅助免疫疗法的治疗潜力，可以恢复受抑制的宿主免疫力并增强候选治疗疫苗的功效。我们的研究结果表明，通过PD-1抑制来挽救多功能免疫反应与抗结核化疗具有协同作用，从而可以更好地控制细菌的生长和传播。总而言之，我们的数据有力地表明了α-PD-1作为辅助免疫疗法的治疗潜力，可以恢复受抑制的宿主免疫力并增强候选治疗疫苗的功效。

更新日期：2020-03-24

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