Can immunotherapy be used to deal with COVID-19?

New study examines the role of the immune response in severe COVID-19 and whether immunotherapy could be used to treat COVID-19 patients.

The body's immune response is largely controlled by signaling molecules known as cytokines. In the presence of an infection, pro-inflammatory cytokines promote the accumulation of immune cells at the infection site. This can often lead to inflammation at the infection site. However, in some disease states, including COVID-19, the immune response produced becomes too great. A disease known as cytokine release syndrome (CRS) has been documented in many COVID-19 patients, but also in other disease states such as sepsis. In this scenario, extremely high cytokine levels led to a hyperimmune response. This reaction can be extremely harmful and in some cases lead to clotting problems, leakage of vascular fluid, and even death.

Finding an effective therapy to fight CRS could significantly improve patient outcomes in a wide variety of diseases, including some of the more severe COVID-19 patients. A new study published by the Proceeding of the National Academy of Sciences examines in detail the mechanisms by which CRS occurs and causes harm (1). It is also studying the effects of tocilizumab, an immunotherapy drug, on CRS and possibly on the treatment of COVID-19.

The study recruited patients from various disease states (sepsis, acute respiratory distress syndrome and burns) as well as healthy control patients. With the exception of the healthy controls, CRS was diagnosed in all patients. The research team collected and analyzed serum samples from all participants. They discovered a number of interesting CRS features in the various disease states. The cytokines were generally elevated in all patients, but the specific cytokines varied slightly between disease states. However, certain cytokines such as IL-6, IL-8 and IL-10 were elevated in all CRS patients. In addition, levels of a specific protein called plasminogen activator inhibitor (PAI-1) were consistent with the clinical severity of systemic inflammation. Elevated PAI-1 levels have been found in numerous disease states and are known to increase the risk of blood clots forming. PAI-1 has been found to be elevated in CRS, but in patients with chronic autoinflammatory diseases such as rheumatoid arthritis. As a result, PAI-1 could be a useful and selective marker for CRS progression.

Similarly, serum IL-6 levels in CRS patients correlated positively with a number of other cytokines (and also PAI-1), meaning that as IL-6 levels increase, so do the levels of these other molecules. Another experiment found that IL-6 actually increased PAI-1 levels, but only in the presence of a protein known as the soluble IL-6 receptor (sIL-6R), a process known as trans signaling is. This finding suggests that IL-6 forms an inflammatory circuit in endothelial cells through the trans-signaling process. In this cycle, increased IL-6 levels (due to infection / sepsis, etc.) lead to the production of PAI-1 in the endothelial cells that line the inside of the blood vessels. This in turn causes inflammation in these cells, which produce more IL-6.

As a result, IL-6 represents a promising target for therapy in CRS. Researchers investigated the effects of using an IL-6 receptor-inhibiting drug called tocilizumab. Seven patients with severe COVID-19 infections were recruited and each received tocilizumab injections. All seven patients showed significant improvements after the injection. In addition, tocilizumab has been shown to lower PAI-1 levels as well as IL-10 levels in these patients.

The results of this study are of immediate relevance as they suggest that PAI-1 may be responsible for the coagulation complications seen in many COVID-19 patients. It suggests that elevated PAI-1 is caused by the IL-6 cytokine and that blocking the effects of IL-6 with the use of tocilizumab immunotherapy may be of clinical benefit in the treatment of COVID-19.

It should be noted that the study relied on a very small sample size and while it showed an association between IL-6 and PAI-1, this association cannot be explained. Further research is needed to examine and replicate the results of this study.

Written by Michael McCarthy

1. Kang S, Tanaka T, Inoue H, Ono C, Hashimoto S, Kioi Y. et al. IL-6 trans signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome. Procedure of the National Academy of Sciences. 2020: 202010229.

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