Signaling pathways in the regulation of cytokine release syndrome in human diseases and intervention therapy

Abstract

Cytokine release syndrome (CRS) embodies a mixture of clinical manifestations, including elevated circulating cytokine levels, acute systemic inflammatory symptoms and secondary organ dysfunction, which was first described in the context of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation and was later observed in pandemics of influenza, SARS-CoV and COVID-19, immunotherapy of tumor, after chimeric antigen receptor T (CAR-T) therapy, and in monogenic disorders and autoimmune diseases. Particularly, severe CRS is a very significant and life-threatening complication, which is clinically characterized by persistent high fever, hyperinflammation, and severe organ dysfunction. However, CRS is a double-edged sword, which may be both helpful in controlling tumors/viruses/infections and harmful to the host. Although a high incidence and high levels of cytokines are features of CRS, the detailed kinetics and specific mechanisms of CRS in human diseases and intervention therapy remain unclear. In the present review, we have summarized the most recent advances related to the clinical features and management of CRS as well as cutting-edge technologies to elucidate the mechanisms of CRS. Considering that CRS is the major adverse event in human diseases and intervention therapy, our review delineates the characteristics, kinetics, signaling pathways, and potential mechanisms of CRS, which shows its clinical relevance for achieving both favorable efficacy and low toxicity.

Acute Neurological Involvement after Donor Lymphocyte Infusion for Post-Transplant Viral Infection: The Same Pattern of Novel Cancer Immunotherapy-Related CNS Toxicity?

“…In this paper, we have presented three cases of patients with clinical manifestations that we can identify as belonging to CRS, and due to the neurological symptoms, to ICANS. Several pieces of evidence support the involvement of pro-inflammatory cytokines in the pathogenesis of CRS/ICANS, characterized by high levels of circulating pro-inflammatory cytokines, acute systemic inflammatory manifestations and secondary organ involvement [ 43 ]. In this context, our results have demonstrated that a cytokine blockade was able to relieve neurological manifestations in three patients who exhibited neuroinflammation associated with viral infections after HSCT.…”

Panax notoginseng Alleviates Sepsis-Induced Acute Kidney Injury by Reducing Inflammation in Rats

“…Thus, therapeutic targeting of TNF- α signaling has been extensively used for the treatment of several inflammatory diseases [ 26 , 27 ]. TNF- α can induce the expression of IL-6, IL-10, and IL-18, which can be used as an inflammatory marker for the development of sepsis [ 28 ]. Consistent with this previous study, our present study also revealed that the protective role of PNP in AKI was mediated through inhibition of inflammatory responses.…”

Immunotherapy and CRISPR Cas Systems: Potential Cure of COVID-19?

“… 137 Cytokine release syndrome (CRS) could lead to multiorgan dysfunction, which can occur in COVID-19, and after chimeric antigen receptor T (CAR-T) therapy, which is clinically characterized high fever, hyperinflammation, and severe organ dysfunction. 138 According to the website clinicaltrials.gov there are currently at least 16 clinical trials ongoing to assess the efficacy of blocking IL-6R in COVID-19 patients with cytokine storm syndrome. 139 Tocilizumab, is used for rheumatic conditions and is also co-labelled by the US Food and Drug Administration (FDA) for treatment with CAR-T therapy, which might be repurposed for treatment for COVID-19.…”