Therapeutic blockade of CXCR2 rapidly clears inflammation in arthritis and atopic dermatitis models: demonstration with surrogate and humanized antibodies.
Therapeutic blockade of CXCR2 rapidly clears inflammation in arthritis and atopic dermatitis models: demonstration with surrogate and humanized antibodies.
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DOI：
10.1080/19420862.2020.1856460
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发表时间：
2020-01
期刊：
影响因子：
5.3
通讯作者：
Robert R
中科院分区：
文献类型：
--
作者：
Alam MJ;Xie L;Ang C;Fahimi F;Willingham SB;Kueh AJ;Herold MJ;Mackay CR;Robert R
中性粒细胞是先天免疫系统中最丰富的效应细胞，代表着抵御感染的第一道防线。然而，在许多常见的病理学中，包括自身免疫性疾病，中性粒细胞的过度募集和激活可以驱动慢性炎症反应，导致不必要的组织破坏。已经研究了几种策略来解决病理性中性粒细胞生物学问题，从而为慢性炎症性疾病提供新的治疗方法。趋化因子受体CXCR2在调节中性粒细胞稳态中发挥着至关重要的作用，是一个有前途的药物靶点。在这项研究中，我们报告了人源化抗人 CXCR2 单克隆抗体的发现和验证。为了进行体内研究，我们开发了一种替代抗小鼠 CXCR2 抗体，以及人类敲入 CXCR2 小鼠。当在特应性皮炎（AD）和类风湿性关节炎（RA）模型中施用时，这些抗体可以迅速清除炎症。我们的研究结果支持进一步开发抗 CXCR2 mAb 方法，不仅适用于 RA 和 AD，还适用于其他中性粒细胞介导的炎症性疾病，其中中性粒细胞是致病性且医疗需求未得到满足。
Neutrophils are the most abundant effector cells of the innate immune system and represent the first line of defense against infection. However, in many common pathologies, including autoimmune diseases, excessive recruitment and activation of neutrophils can drive a chronic inflammatory response leading to unwanted tissue destruction. Several strategies have been investigated to tackle pathologic neutrophil biology, and thus provide a novel therapy for chronic inflammatory diseases. The chemokine receptor CXCR2 plays a crucial role in regulating neutrophil homeostasis and is a promising pharmaceutical target. In this study, we report the discovery and validation of a humanized anti-human CXCR2 monoclonal antibody. To enable in vivo studies, we developed a surrogate anti-mouse CXCR2 antibody, as well as a human knock-in CXCR2 mouse. When administered in models of atopic dermatitis (AD) and rheumatoid arthritis (RA), the antibodies rapidly clear inflammation. Our findings support further developments of anti-CXCR2 mAb approaches not only for RA and AD, but also for other neutrophil-mediated inflammatory conditions where neutrophils are pathogenic and medical needs are unmet.
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DOI：
10.1124/jpet.108.145862
发表时间：
2009-04-01
影响因子：
3.5
作者：
Farooq, Shukkur Muhammed;Stillie, RoseMarie;Stadnyk, Andrew W.
通讯作者：
Stadnyk, Andrew W.
影响因子：
16.6
作者：
Akitsu A;Ishigame H;Kakuta S;Chung SH;Ikeda S;Shimizu K;Kubo S;Liu Y;Umemura M;Matsuzaki G;Yoshikai Y;Saijo S;Iwakura Y
通讯作者：
Iwakura Y
炎性关节炎需要中性粒细胞的白细胞B4。
DOI：
10.1084/jem.20052371
发表时间：
2006-04-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
--
影响因子：
--
作者：
Jacobs, Jonathan P.;Ortiz-Lopez, Adriana;Campbell, James J.;Gerard, Craig J.;Mathis, Diane;Benoist, Christophe
通讯作者：
Benoist, Christophe
影响因子：
14.2
作者：
Guttman-Yassky, Emma;Nograles, Kristine E.;Krueger, James G.
通讯作者：
Krueger, James G.