In vitro and in vivo antivirus activity of an anti-programmed death-ligand 1 (PD-L1) rat-bovine chimeric antibody against bovine leukemia virus infection.
In vitro and in vivo antivirus activity of an anti-programmed death-ligand 1 (PD-L1) rat-bovine chimeric antibody against bovine leukemia virus infection.
复制标题
DOI：
10.1371/journal.pone.0174916
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Ohashi K
中科院分区：
文献类型：
--
作者：
Nishimori A;Konnai S;Okagawa T;Maekawa N;Ikebuchi R;Goto S;Sajiki Y;Suzuki Y;Kohara J;Ogasawara S;Kato Y;Murata S;Ohashi K
程序性死亡-1（PD-1）是T细胞上的一种免疫抑制受体，已知在许多慢性疾病中通过与PD-配体1（PD-L1）结合参与免疫逃避。我们先前发现，PD-L1表达在感染牛白血病病毒（BLV）的牛中上调，并且阻断PD-1/PD-L1相互作用的抗体在体外重新激活T细胞功能。因此，本研究评价了其体内抗病毒活性。首先，我们将抗牛PD-L1大鼠单克隆抗体4G 12接种到BLV感染的奶牛中。然而，在试验期间，这并不诱导T细胞增殖或BLV前病毒负荷的减少，并且仅结合循环IgM+ B细胞直到接种后一周。我们假设体内作用的缺乏是由于其在牛中的稳定性较低，因此建立了抗PD-L1大鼠-牛嵌合抗体（Boch 4G 12）。Boch 4G 12能够与牛PD-L1特异性结合，中断PD-1/PD-L1相互作用，并在体外激活健康和BLV感染牛的免疫应答。因此，我们实验性地用BLV感染健康小牛，并且一旦其达到白细胞减少（AL）阶段，就静脉内接种1 mg/kg Boch 4G 12。从测试小牛分离的外周血单核细胞（PBMC）的培养表明，Boch 4G 12接种增加了CD 4 + T细胞的增殖，而BLV前病毒载量显著降低，清楚地表明该处理诱导抗病毒活性。因此，需要使用大量动物进行进一步研究，以支持其临床应用的有效性。
Programmed death-1 (PD-1), an immunoinhibitory receptor on T cells, is known to be involved in immune evasion through its binding to PD-ligand 1 (PD-L1) in many chronic diseases. We previously found that PD-L1 expression was upregulated in cattle infected with bovine leukemia virus (BLV) and that an antibody that blocked the PD-1/PD-L1 interaction reactivated T-cell function in vitro. Therefore, this study assessed its antivirus activities in vivo. First, we inoculated the anti-bovine PD-L1 rat monoclonal antibody 4G12 into a BLV-infected cow. However, this did not induce T-cell proliferation or reduction of BLV provirus loads during the test period, and only bound to circulating IgM+ B cells until one week post-inoculation. We hypothesized that this lack of in vivo effects was due to its lower stability in cattle and so established an anti-PD-L1 rat-bovine chimeric antibody (Boch4G12). Boch4G12 was able to bind specifically with bovine PD-L1, interrupt the PD-1/PD-L1 interaction, and activate the immune response in both healthy and BLV-infected cattle in vitro. Therefore, we experimentally infected a healthy calf with BLV and inoculated it intravenously with 1 mg/kg of Boch4G12 once it reached the aleukemic (AL) stage. Cultivation of peripheral blood mononuclear cells (PBMCs) isolated from the tested calf indicated that the proliferation of CD4+ T cells was increased by Boch4G12 inoculation, while BLV provirus loads were significantly reduced, clearly demonstrating that this treatment induced antivirus activities. Therefore, further studies using a large number of animals are required to support its efficacy for clinical application.