An anti-human ICAM-1 antibody inhibits rhinovirus-induced exacerbations of lung inflammation.
An anti-human ICAM-1 antibody inhibits rhinovirus-induced exacerbations of lung inflammation.
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DOI：
10.1371/journal.ppat.1003520
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Johnston SL
中科院分区：
文献类型：
--
作者：
Traub S;Nikonova A;Carruthers A;Dunmore R;Vousden KA;Gogsadze L;Hao W;Zhu Q;Bernard K;Zhu J;Dymond M;McLean GR;Walton RP;Glanville N;Humbles A;Khaitov M;Wells T;Kolbeck R;Leishman AJ;Sleeman MA;Bartlett NW;Johnston SL
人鼻病毒（HRV）引起大多数普通感冒以及哮喘和慢性阻塞性肺病（COPD）的急性加重。迫切需要有效的治疗方法，但目前还没有获得许可的治疗方法或疫苗。在100种鉴定的血清型中，约90%结合人细胞间粘附分子-1（ICAM-1）的结构域1作为其细胞受体，使其成为开发治疗的有吸引力的靶点;然而，ICAM-1结构域1也是宿主防御和细胞运输调节所需的，主要通过其主要配体LFA-1。使用特异性结合人ICAM-1的结构域1的小鼠抗人ICAM-1抗体（14 C11），我们表明14 C11局部或全身给药可防止两组主要鼻病毒HRV 16和HRV 14的进入，并减少体内细胞炎症、促炎细胞因子诱导和病毒载量。14 C11还减少了主要组HRV诱导的哮喘恶化模型中的细胞炎症和Th 2细胞因子/趋化因子的产生。有趣的是，14 C11在体外不通过人ICAM-1/LFA-1相互作用阻止细胞粘附，表明14 C11靶向的表位对病毒进入具有特异性。因此，人ICAM-1结构域-1特异性抗体可以在体内防止主要组HRV进入和诱导气道炎症。病毒利用宿主细胞上的受体引起感染。旨在阻断病毒-受体相互作用的疗法有可能预防病毒性疾病。细胞受体对正常宿主细胞功能也很重要。因此，靶向这些受体以阻断病毒感染的新疗法也可能无意中改变宿主细胞的生理学。病毒病原体，如感冒病毒（鼻病毒），被认为是哮喘发作和慢性阻塞性肺疾病（COPD）恶化的主要原因。在这项研究中，我们表明，有可能确定新的治疗性抗体，阻止感染鼻病毒，而不损害受体的主要功能，细胞粘附。然后，我们使用动物模型，表明抗体可以抑制病毒诱导的肺部炎症和疾病。此外，我们发现这种抗体也可以抑制病毒引起的哮喘恶化。这项工作是相关的，因为它表明抗体可以针对病毒受体的不同区域进行定制，以阻止感染，而不会抑制受体的正常细胞功能。这对于开发新的治疗方法，预防鼻病毒感染引起的疾病，如哮喘和COPD的恶化非常重要。
Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ∼90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo. Viruses exploit receptors on the host cell to cause infection. Therapies aimed at blocking virus-receptor interactions have the potential to prevent viral disease. Cellular receptors are also important for normal host cell function. Therefore, new therapies targeting these receptors to block viral infection may also inadvertently alter the physiology of the host cell. Viral pathogens, such as the cold virus (rhinovirus), are believed to be the major cause of asthma attacks and exacerbations in chronic obstructive pulmonary disease (COPD). In this study, we show that it is possible to identify novel therapeutic antibodies that block infection with rhinovirus without impairing the receptors' main function of cell adhesion. We then use animal models that show that an antibody can inhibit virus-induced lung inflammation and disease. Moreover, we show that this antibody can also inhibit a virally induced asthma exacerbation. This work is relevant in that it shows that antibodies can be tailored to distinct regions of viral receptors to block infection without inhibiting the receptors' normal cellular function. This is important for the development of new treatments that will prevent diseases caused by infection with rhinovirus, such as exacerbations of asthma and COPD.
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DOI：
10.1183/09031936.00092410
发表时间：
2011-05
期刊：
The European respiratory journal
影响因子：
--
作者：
Bizzintino J;Lee WM;Laing IA;Vang F;Pappas T;Zhang G;Martin AC;Khoo SK;Cox DW;Geelhoed GC;McMinn PC;Goldblatt J;Gern JE;Le Souëf PN
通讯作者：
Le Souëf PN
影响因子：
4.9
作者：
Hayden, FG;Turner, RB;Zalman, LS
通讯作者：
Zalman, LS
影响因子：
105.7
作者：
Nicholson, KG;Kent, J;Cancio, E
通讯作者：
Cancio, E
影响因子：
9.6
作者：
Garbino, J;Gerbase, MW;Kaiser, L
通讯作者：
Kaiser, L
DOI：
10.1164/rccm.201006-0833oc
发表时间：
2011-03-15
影响因子：
24.7
作者：
Mallia, Patrick;Message, Simon D.;Johnston, Sebastian L.
通讯作者：
Johnston, Sebastian L.