PDF(Pubmed)
Abstract：
Immune checkpoint pathways, i.e., coinhibitory pathways expressed as feedback following immune activation, are crucial for controlling an excessive immune response. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) are the central classical checkpoint inhibitory (CPI) molecules used for the control of neoplasms and some infectious diseases, including some fungal infections. As the immunosuppression of severe paracoccidioidomycosis (PCM), a chronic granulomatous fungal disease, was shown to be associated with the expression of coinhibitory molecules, we hypothesized that the inhibition of CTLA-4 and PD-1 could have a beneficial effect on pulmonary PCM. To this end, C57BL/6 mice were infected with Paracoccidioides brasiliensis yeasts and treated with monoclonal antibodies (mAbs) α-CTLA-4, α-PD-1, control IgG, or PBS. We verified that blockade of CTLA-4 and PD-1 reduced the fungal load in the lungs and fungal dissemination to the liver and spleen and decreased the size of pulmonary lesions, resulting in increased survival of mice. Compared with PBS-treated infected mice, significantly increased levels of many pro- and anti-inflammatory cytokines were observed in the lungs of α-CTLA-4-treated mice, but a drastic reduction in the liver was observed following PD-1 blockade. In the lungs of α-CPI and IgG-treated mice, there were no changes in the frequency of inflammatory leukocytes, but a significant reduction in the total number of these cells was observed. Compared with PBS-treated controls, α-CPI- and IgG-treated mice exhibited reduced pulmonary infiltration of several myeloid cell subpopulations and decreased expression of costimulatory molecules. In addition, a decreased number of CD4+ and CD8+ T cells but sustained numbers of Th1, Th2, and Th17 T cells were detected. An expressive reduction in several Treg subpopulations and their maturation and suppressive molecules, in addition to reduced numbers of Treg, TCD4+, and TCD8+ cells expressing costimulatory and coinhibitory molecules of immunity, were also detected. The novel cellular and humoral profiles established in the lungs of α-CTLA-4 and α-PD-1-treated mice but not in control IgG-treated mice were more efficient at controlling fungal growth and dissemination without causing increased tissue pathology due to excessive inflammation. This is the first study demonstrating the efficacy of CPI blockade in the treatment of pulmonary PCM, and further studies combining the use of immunotherapy with antifungal drugs are encouraged.
摘要：
免疫检查点途径，即，共抑制途径表达为免疫激活后的反馈，对于控制过度的免疫反应至关重要。细胞毒性T淋巴细胞抗原-4（CTLA-4）和程序性细胞死亡蛋白-1（PD-1）是用于控制肿瘤和一些感染性疾病的核心经典检查点抑制（CPI）分子。包括一些真菌感染.作为严重的副角菌病（PCM）的免疫抑制，慢性肉芽肿性真菌病,被证明与共抑制分子的表达有关，我们假设抑制CTLA-4和PD-1可能对肺PCM产生有益作用.为此,C57BL/6小鼠感染巴西副球菌酵母，并用单克隆抗体（mAb）α-CTLA-4，α-PD-1，对照IgG，或PBS。我们证实CTLA-4和PD-1的阻断减少了肺部的真菌负荷和真菌向肝脏和脾脏的播散，并减少了肺部病变的大小，增加小鼠的存活率。与PBS处理的感染小鼠相比，在α-CTLA-4处理的小鼠的肺中观察到许多促炎和抗炎细胞因子的水平显着增加，但在PD-1阻断后观察到肝脏急剧减少。在α-CPI和IgG处理的小鼠的肺中，炎性白细胞的频率没有变化，但是观察到这些细胞的总数显着减少。与PBS处理的对照相比，α-CPI和IgG处理的小鼠表现出几种骨髓细胞亚群的肺浸润减少和共刺激分子的表达减少。此外,检测到CD4+和CD8+T细胞数量减少,但Th1,Th2和Th17T细胞数量持续增加.几个Treg亚群及其成熟和抑制分子的表达减少，除了减少Treg的数量，TCD4+,和表达免疫共刺激和共抑制分子的TCD8+细胞，也被发现了。在α-CTLA-4和α-PD-1处理的小鼠的肺中而不是在对照IgG处理的小鼠中建立的新的细胞和体液谱在控制真菌生长和播散方面更有效,而不会由于过度炎症而导致组织病理学增加。这是第一项研究证明CPI阻断治疗肺部PCM的有效性，并鼓励将免疫治疗与抗真菌药物结合使用的进一步研究。
