Treatments of autoimmune diseases, chronic inflammation, cancer, and COVID-19 can all find their clues in our understanding of cytokines
Chinese original by Hui-Chen Lin
English translation by Wei-Hsin Lin (of the Tang Prize Foundation)
Illustration by Sun Shan
Since the COVID pandemic broke out, hundreds of millions of people around the globe have fallen victim to this virus. The severity of COVID-19, however, varies substantially from patients to patients. Researchers found out that except for the damage caused by the virus itself, “cytokine storms” that can occur when a patient’s immune system fails to rein in the release of cytokines are the main culprit of serious complications such as pneumonia and multiple organ failure. So, the question we should ask is: can we prevent the progression of COVID-19 by developing therapeutics to target cytokines?
Cytokines are small proteins secreted by several types of cells. They are involved in many physiological effects and are responsible for delivering messages between immune cells. When our bodies are invaded by pathogens, immune cells will release cytokines, which will then bind to the surface receptors of targeted cells, triggering a cascade of immune and inflammatory responses to combat these pathogens. But if the immune system cannot properly regulate the release of cytokines, inflammations can persist, impairing bodily functions and even causing organ failures.
In the 1950s, cytokines were discovered when scientists were studying the factors secreted by immune cells as well as their functions. Subsequently, more was unveiled about the role cytokines play in autoimmune diseases, inflammatory diseases, and even chronic diseases such as brain or heart diseases and cancer. These groundbreaking discoveries enabled us to achieve major breakthroughs in the diagnosis, prevention and treatment of many maladies. For this reason, three renowned cytokine codebreakers were jointly awarded the 2020 Tang Prize in Biopharmaceutical Science.
Dr. Charles Dinarello, professor of medicine at the University of Coloardo, identified the first cytokine, interleukin-1β (IL-1β), and developed IL-1 inhibitors for the treatment of rheumatoid arthritis and inflammatory diseases. Dr. Marc Feldmann of the University of Oxford focuses on the mechanism underlying rheumatoid arthritis. He identified tumor necrosis factor (TNF) as the key cytokine in the diseased joints of those with this debilitating disease. He then worked with pharmaceutical companies to develop drugs to block TNF. Dr. Tadamitsu Kishimoto specializes in the basic research related to interleukin-6 (IL-6) and its receptor. He is credited with converting the cytokine field into modern molecular medicine, a transformation that has brought about many great clinical advances. In addition, he helped developed tocilizumab, an anti-IL-6 receptor antibody now being used to treat rheumatoid arthritis and systemic idiopathic juvenile arthritis.
According to Dr. Fu-Tong Liu, vice president of Academia Sinica, these three laureates “facilitated the development of cytokine-targeting biologic therapies. Though these important discoveries were made decades ago, the products that came out of them still have huge impact on us today.” Medications that either inhibit or regulate the functions of cytokines became available for sale one after another because of the development of cytokine research. As a result, many people suffering from autoimmune or chronic inflammatory diseases can now opt for drugs with higher efficacy and fewer adverse side effects. For example, anti-TNF antibodies have been widely used to treat autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, psoriasis, and so on. Currently, they hold the largest market share among this type of drugs. Further research also proved IL-1’s involvement in other chronic diseases. Therefore, IL-1 inhibitors have been developed into a powerful tool to tackle myocardial infraction, diabetes and cancer.
IL-6 and IL-1 inhibitors are now our new hope for lowing the death rate in patients with severe COVID-19. Both the US Food and Drug Administration and the World Health Organization have granted an Emergency Use Authorization for tocilizumab for the treatment of COVID-19. It has also been included in Taiwan’s treatment guidelines for COVID-19. Moreover, Dr. Dinarello pointed out that IL-1 inhibitors can effectively reduce mortality among patients with respiratory failure.
During the years when cytokine biology expanded rapidly, people wanted to know how these molecules affect our immune system and other aspects of human physiology. However, after early experiments in humans, the history of cytokines being used as a treatment change considerably and the focus was shifted to the inhibition of cytokines. But it doesn’t mean we have effective inhibitors for all the cytokine-related chronic diseases. Some brain and heart diseases, for instance, are the exceptions. Dr. Fu-Tong Liu suggested that “maybe there are other cytokines or their receptors that are more suitable targets for therapies.” Besides cytokine storms, there are many frontiers in cytokine biology that are yet to be explored, and it is in these known unknowns where modern medicine’s hope lies.
The Chinese original was published on the 2021 November edition of the Scientific America.