Wolf Dennis, Anto-Michel Nathaly, Blankenbach Hermann, Wiedemann Ansgar, Buscher Konrad, Hohmann Jan David, Lim Bock, Bäuml Marina, Marki Alex, Mauler Maximilian, Duerschmied Daniel, Fan Zhichao, Winkels Holger, Sidler Daniel, Diehl Philipp, Zajonc Dirk M, Hilgendorf Ingo, Stachon Peter, Marchini Timoteo, Willecke Florian, Schell Maximilian, Sommer Björn, von Zur Muhlen Constantin, Reinöhl Jochen, Gerhardt Teresa, Plow Edward F, Yakubenko Valentin, Libby Peter, Bode Christoph, Ley Klaus, Peter Karlheinz, Zirlik Andreas
Cardiology and Angiology I, University Heart Center, and Medical Faculty, University of Freiburg, Freiburg, 79106, Germany.
Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA.
Nat Commun. 2018 Feb 6;9(1):525. doi: 10.1038/s41467-018-02896-8.
Integrin-based therapeutics have garnered considerable interest in the medical treatment of inflammation. Integrins mediate the fast recruitment of monocytes and neutrophils to the site of inflammation, but are also required for host defense, limiting their therapeutic use. Here, we report a novel monoclonal antibody, anti-M7, that specifically blocks the interaction of the integrin Mac-1 with its pro-inflammatory ligand CD40L, while not interfering with alternative ligands. Anti-M7 selectively reduces leukocyte recruitment in vitro and in vivo. In contrast, conventional anti-Mac-1 therapy is not specific and blocks a broad repertoire of integrin functionality, inhibits phagocytosis, promotes apoptosis, and fuels a cytokine storm in vivo. Whereas conventional anti-integrin therapy potentiates bacterial sepsis, bacteremia, and mortality, a ligand-specific intervention with anti-M7 is protective. These findings deepen our understanding of ligand-specific integrin functions and open a path for a new field of ligand-targeted anti-integrin therapy to prevent inflammatory conditions.
基于整合素的疗法在炎症的医学治疗中引起了相当大的关注。整合素介导单核细胞和中性粒细胞快速募集到炎症部位，但也是宿主防御所必需的，这限制了它们的治疗用途。在此，我们报告一种新型单克隆抗体——抗-M7，它能特异性阻断整合素Mac-1与其促炎配体CD40L的相互作用，同时不干扰其他配体。抗-M7在体外和体内均能选择性减少白细胞募集。相比之下，传统的抗Mac-1疗法不具有特异性，会阻断广泛的整合素功能，抑制吞噬作用，促进细胞凋亡，并在体内引发细胞因子风暴。传统的抗整合素疗法会加重细菌性败血症、菌血症和死亡率，而抗-M7这种配体特异性干预则具有保护作用。这些发现加深了我们对配体特异性整合素功能的理解，并为预防炎症性疾病的配体靶向抗整合素治疗新领域开辟了道路。
