Life science
Medicine / Healthcare, Drug discovery, Life science

Therapeutic efficacy of anti-IL-6 receptor antibody intreatment of cytokine release syndrome
Laboratory of Immune Regulation, WPI Immunology Frontier Research Center
Associate Professor Sujin Kang

Researchmap https://researchmap.jp/sujinkang?lang=en

Professor Tadamitsu Kishimoto

Researchmap https://researchmap.jp/read0013669?lang=en

Life science

Abstract
A hyperinflammatory response following infection or trauma cancause the lifethreatening condition cytokine release syndrome(CRS). Our research team found that IL-6 signaling induces theexpression of inflammatory cytokines and PAI-1 in CRS patients,
causing respiratory distress and multiple organ failure, which arealso observed in severe COVID-19 patients. Blockade of IL-6 signaling using a human monoclonal antibody reduced PAI-1 levels
and alleviated the clinical manifestations of disease in severe COVID-19 patients.

effects targeting IL-6 receptors are expected for acute inflammatory diseases such as acute respiratory distress syndrome and sepsis.

▍ Background & Results
Overstimulation of the inflammatory response has an array ofharmful complications, ranging from asthma to severe autoimmune diseases. One such complication, called cytokine release
syndrome (CRS), is seen in patients suffering a hyperimmune
response to microbial infection or trauma and can lead to multiple
organ failure and even death. Despite knowing which cytokines
are involved, there is still no specific immunotherapy for CRS andtreatment is limited to supportive care. To better understand themolecular mechanisms of CRS pathogenesis, we first studied
the cytokine profiles of 91 patients diagnosed with CRS associated with bacterial sepsis, acute respiratory distress syndrome,or burns. Strikingly, patients from all three groups had elevatedlevels of proinflammatory cytokines IL-6, IL-8, IL-10, and MCP-10,
as well as a protein called PAI-1, which causes small blood clots
in vessels throughout the body, including the lungs. Importantly,
increased PAI-1 levels are associated with more severe cases ofpneumonia, a common cause of death among COVID-19 patients.
Because IL-6 was positively associated with the levels of the othercytokines and PAI-1, the researchers concluded that IL-6 signaling
is crucial for the development of CRS following infection or trauma,
and may play a role in the pathogenesis of COVID-19. Examinationof cytokine profiles in severe COVID-19 patients revealed an increase in IL-6 early in the disease process, causing release of PAI1 from blood vessels. Interestingly, PAI-1 levels were significantly
higher in COVID-19 patients with severe respiratory impediment.
Most significantly though, when severe COVID-19 patients weretreated with a human monoclonal antibody to block IL-6 signaling,PAI-1 levels rapidly declined and severe disease symptoms werealleviated. IL-6 signaling blockade could therefore prove useful forthe treatment of both CRS and the severe respiratory complicationsof COVID-19.

Figure: How Actemra© suppresses inflammation IL-6 in blood promotes thrombus
formation via PAI-1. By suppressing IL-6, Actemra reduces the severity of pneumonia caused by the cytokine storm.
Actemra©; An humanized anti-IL-6 receptor antibody (tocilizumab)▍ Significance of the research and Future perspective
Based on the results of this research, the administration of anti-IL-6 receptor antibody drastically reduced the symptoms of cytokine storms, and recently it is recommended by WHO as a treatment for new coronavirus infection (COVID-19). Thus, therapeutic

P a t e n tKang, S; Tanaka, T; Inoue, H et al. IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome. Proc Natl Acad Sci USA. 2020; 117(36): 22351-22356. doi: 10.1073/pnas.2010229117
UR
L https://resou.osaka-u.ac.jp/ja/research/2020/20200824_1
K e y w o r d interleukin-6, tocilizumab, endothelial cell, cytokine release syndrome, COVID-19Tr e a t i s e