دورية أكاديمية
أعرض في EDS

A single-domain antibody targeting factor XII inhibits both thrombosis and inflammation.

التفاصيل البيبلوغرافية
العنوان: A single-domain antibody targeting factor XII inhibits both thrombosis and inflammation.
المؤلفون: Xu P; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Zhang Y; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Guo J; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.; College of Life Science, Zhejiang Normal University, Jinhua, Zhejiang, China., Li H; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Konrath S; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany., Zhou P; Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China., Cai L; Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Rao H; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Chen H; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Lin J; Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China., Cui Z; Renal Division, Peking University First Hospital, Beijing, China., Ji B; Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Wang J; MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Li N; Department of Medicine-Solna, Cardiovascular Medicine Unit, Karolinska Institute, Stockholm, Sweden., Liu DP; Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China., Renné T; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.; Center for Thrombosis and Hemostasis (CTH), Johannes Gutenberg University Medical Center, Mainz, Germany.; Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland., Wang M; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. miao.wang@pumc.edu.cn.; Clinical Pharmacology Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. miao.wang@pumc.edu.cn.; National Health Commission Cardiovascular Disease Regenerative Medicine Research Key Laboratory, Central China Subcenter of National Center for Cardiovascular Diseases, Henan Cardiovascular Disease Center, Fuwai Central-China Cardiovascular Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China. miao.wang@pumc.edu.cn.
المصدر: Nature communications [Nat Commun] 2024 Sep 12; Vol. 15 (1), pp. 7898. Date of Electronic Publication: 2024 Sep 12.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Thrombosis*/immunology , Thrombosis*/metabolism , Single-Domain Antibodies*/pharmacology , Single-Domain Antibodies*/immunology , Factor XII*/metabolism , Factor XII*/antagonists & inhibitors , Inflammation*/metabolism , Neutrophils*/immunology , Neutrophils*/metabolism , Neutrophils*/drug effects , Mice, Knockout*, Animals ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Disease Models, Animal ; Platelet Aggregation/drug effects ; Factor XIIa/metabolism ; Factor XIIa/antagonists & inhibitors ; Fibrin/metabolism ; Fibrin Fibrinogen Degradation Products/metabolism
مستخلص: Factor XII (FXII) is the zymogen of the plasma protease FXIIa that activates the intrinsic coagulation pathway and the kallikrein kinin-system. The role of FXII in inflammation has been obscure. Here, we report a single-domain antibody (nanobody, Nb) fused to the Fc region of a human immunoglobulin (Nb-Fc) that recognizes FXII in a conformation-dependent manner and interferes with FXIIa formation. Nb-Fc treatment inhibited arterial thrombosis in male mice without affecting hemostasis. In a mouse model of extracorporeal membrane oxygenation (ECMO), FXII inhibition or knockout reduced thrombus deposition on oxygenator membranes and systemic microvascular thrombi. ECMO increased circulating levels of D-dimer, alkaline phosphatase, creatinine and TNF-α and triggered microvascular neutrophil adherence, platelet aggregation and their interaction, which were substantially attenuated by FXII blockade. Both Nb-Fc treatment and FXII knockout markedly ameliorated immune complex-induced local vasculitis and anti-neutrophil cytoplasmic antibody-induced systemic vasculitis, consistent with selectively suppressed neutrophil migration. In human blood microfluidic analysis, Nb-Fc treatment prevented collagen-induced fibrin deposition and neutrophil adhesion/activation. Thus, FXII is an important mediator of inflammatory responses in vasculitis and ECMO, and Nb-Fc provides a promising approach to alleviate thrombo-inflammatory disorders.
(© 2024. The Author(s).)
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معلومات مُعتمدة: 82320108002 National Natural Science Foundation of China (National Science Foundation of China); 92149305 National Natural Science Foundation of China (National Science Foundation of China); A11/SFB 877, B8/SFB 841 and P6/KFO 306 Deutsche Forschungsgemeinschaft (German Research Foundation)
المشرفين على المادة: 0 (Single-Domain Antibodies)
9001-30-3 (Factor XII)
EC 3.4.21.38 (Factor XIIa)
9001-31-4 (Fibrin)
0 (Fibrin Fibrinogen Degradation Products)
تواريخ الأحداث: Date Created: 20240912 Date Completed: 20240912 Latest Revision: 20240915
رمز التحديث: 20240915
مُعرف محوري في PubMed: PMC11393108
DOI: 10.1038/s41467-024-51745-4
PMID: 39266545
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-024-51745-4