предыдущий|следующий

Перепрофилирование вредного эпитопа антитела в целевые терапевтические средства для сепсиса и ревматоидного артрита

  • role： Contribute equally, First author同等贡献者, 第一作者
  • Affiliation：

    The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA

    Departments of Emergency Medicine and/Or Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/North-well, Hempstead, NY 11549, USA

Wei-Qiang Chen12,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA

Li Lou1,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA

    Departments of Emergency Medicine and/Or Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/North-well, Hempstead, NY 11549, USA

Xiao-Ling Qiang12,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA

    Departments of Emergency Medicine and/Or Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/North-well, Hempstead, NY 11549, USA

Cassie Shu Zhu12,  
  • Affiliation：

    The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA

Jian-Hua Li1,  
  • Affiliation：

    The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA

Shu-Jin Chen1,  
  • Affiliation：

    The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA

Brian Xiong1,  
  • Affiliation：

    The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA

Huan Yang1,  
  • Affiliation：

    The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA

    Departments of Emergency Medicine and/Or Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/North-well, Hempstead, NY 11549, USA

Ping Wang12,  
  • Affiliation：

    The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA

    Departments of Emergency Medicine and/Or Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/North-well, Hempstead, NY 11549, USA

Kevin J. Tracey12,  
  • role： Corresponding author通信作者
  • Affiliation：

    The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA

    Departments of Emergency Medicine and/Or Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/North-well, Hempstead, NY 11549, USA

  • Email：hwang@northwell.edu
  • Introduction：* Hai-Chao Wang hwang@northwell.edu
Hai-Chao Wang12*

реферат

Предпосылки: Сепсис и ревматоидный артрит (РА) — различные, но механистически связанные состояния, часто вызванные дисрегулированными воспалительными реакциями. В данной работе мы исследовали парадоксальную гипотезу, что эпитоп вредного антитела против тетранекина (mAb9) может обладать неожиданным терапевтическим потенциалом. Методы: Путем картирования эпитопа mAb9 на регион P2 (остатки 55–70), ключевой для защитных функций тетранекина, мы разработали P2-1 — водорастворимый производный пептид в качестве целевой терапии. Затем использовали животные модели сепсиса (перевязка и пунктирование слепой кишки) и артрита (артрит, вызванный антителами к коллагену) для оценки терапевтических эффектов P2, P2-1 и нейтрализующего антитела к прокатепсину L (pCTS-L) путем оценки выживаемости при сепсисе, тяжести артрита, чувствительности к боли и гистологии суставных тканей. Параллельно применяли метод поверхностного плазмонного резонанса (SPR) и компьютерное моделирование для изучения взаимодействия P2-1 с высокомобильной группой 1 (HMGB1). В заключение, мы выяснили влияние P2-1 на индуцированный HMGB1 высвобождение pCTS-L и других цитокинов и хемокинов с использованием первичных человеческих периферических мононуклеарных клеток (PBMC). Результаты: P2-1 значительно улучшал выживаемость и снижал системное воспаление в модели сепсиса, снижал тяжесть артрита и чувствительность к боли в модели РА, даже при терапевтическом применении после начала заболевания. Механистически P2-1 имел высокое сродство к HMGB1 и селективно подавлял HMGB1-индуцированную экспрессию мРНК катепсина L (Ctsl) и секрецию pCTS-L из человеческих иммунных клеток, при этом не влияя на другие HMGB1-индуцированные цитокины и хемокины. Мы дополнительно подтвердили pCTS-L как терапевтическую мишень, показав, что нейтрализующее антитело оказывает мощные антиартритические эффекты, снижая воспаление суставов, боль и структурные повреждения. Выводы: Наши результаты представляют инновационную стратегию открытий лекарств, превращающую понимание вредного действия антител в целевые препараты для оси HMGB1-pCTS-L. Этот подход не только предоставляет P2-1 как мощное средство, но и устанавливает pCTS-L как критический медиатор воспалительных заболеваний, таких как сепсис и РА.

ключеви́че слова́

Высокомобильная группа 1 (HMGB1);Прокатепсин L;Тетранекин;сепсис;Ревматоидный артрит (РА);антитело;миметический пептид;эпитоп;врожденные иммунные клетки

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