key: cord-0757910-djlvsfmq
authors: Kishimoto, Tadamitsu
title: Interleukin-6: From arthritis to CAR-T cell therapy and COVID-19
date: 2021-03-14
journal: Int Immunol
DOI: 10.1093/intimm/dxab011
sha: 56fab5c93081156b731803779e70db9f82f0cac9
doc_id: 757910
cord_uid: djlvsfmq

Blockade of interleukin (IL)-6 function by an anti-IL-6 receptor (IL-6R) antibody (tocilizumab, trade name Actemra) has been shown to be effective for the treatment of chronic autoimmune inflammatory diseases including rheumatoid arthritis. Interestingly, treatment with tocilizumab has also been found to alleviate the cytokine storm induced by chimeric antigen receptor (CAR)-T cell therapy. Patients with serious cases of coronavirus disease 2019 (COVID-19) exhibit cytokine release syndrome (CRS), which suggested that tocilizumab might be an effective therapeutic for serious cases of COVID-19. In the first part of this short review, the therapeutic effect of tocilizumab for the disease induced by IL-6 overproduction is described. CRS induced by CAR-T cell therapy and COVID-19 is then discussed.

A c c e p t e d M a n u s c r i p t 4 autoimmune inflammatory diseases or CRSs. Furthermore, as shown in Figure 2 , gp130 functions as a signal transducer for not only IL-6 but also several other cytokines, such as leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neutrophic factor (CNTF), IL-11, IL-27, IL-31 and cardiotrophin (CTF). Consequently, all these cytokines show similar redundant and pleiotropic functions (6) .

Several clinical observations have suggested that IL-6 overproduction induces various inflammatory phenomena. For example, in a patient with cardiac myxoma (7) who showed a high fever and elevated CRP levels, all their inflammatory symptoms disappeared after the myxoma was surgically removed, and the myxoma tissue showed a high IL-6 titer.

Additionally, in a case of Castleman's disease (8) where the patient exhibited high fever and anemia with an elevated CRP level and swelling of multiple lymph nodes, a biopsy of the affected lymph nodes revealed a high IL-6 titer in B cells within the germinal centers. Since these initial observations, IL-6 overproduction has been described in various autoimmune inflammatory diseases (Table 1 ).

An antibody directed against the 80-kDa IL-6R was prepared to treat these chronic inflammatory diseases. The humanized anti-IL-6R antibody is called tocilizumab. As shown in Figure 2 , tocilizumab can block the binding of IL-6 with IL-6R as well as interfere with the formation of IL-6-soluble IL-6R complexes and inhibit gp130 dimerization. This signaling system is called IL-6 trans-signaling (3), and tocilizumab almost completely blocks IL-6 signals by these two pathways (Fig. 2) . The clinical effect of tocilizumab is dramatic. It has been successfully used to treat patients with Castleman's disease, juvenile idiopathic arthritis A c c e p t e d M a n u s c r i p t 5 (9), rheumatoid arthritis (10) and giant cell arteritis (11) . Currently, over one million patients in more than 100 countries are treated with this antibody.

One regulatory mechanism of IL-6 production occurs at the mRNA level. Two molecules, endonucleases Regnase-1 (12) and Arid5A (13) , act at the stem-loop of the 3′untranslated region of IL-6 mRNA. Regnase-1 is involved in the degradation of mRNA, and it downregulates IL-6 production. Arid5A binds to the same portion of the IL-6 mRNA,

where it competes with Regnase-1 to protect the mRNA from degradation. Under normal conditions, Arid5A is present mainly in nuclei, but when inflammation occurs, it moves to the cytoplasm and stabilizes IL-6 mRNA, resulting in the overproduction of IL-6.

B precursor-acute lymphoblastic leukemia (B-ALL) is one of the most common childhood malignancies. The recently reported strategy of using chimeric antigen receptor (CAR)modified T cells directed against the B-cell antigen cluster differentiation 19 (CD19) can effectively treat refractory B-ALL in children (14) . CAR binding with CD19 B-ALL results in T-cell activation, antigen-mediated cell killing, and T-cell proliferation.

The robust expansion and sustained proliferation of the modified CAR-T cell population can eradicate leukemic cells and appears to sustain remission in many patients. However, this robust T-cell proliferation also activates macrophages to produce inflammatory cytokines, particularly IL-6, which causes a unique, significant side effect of CAR-T cell therapy, cytokine release syndrome (CRS). However, tocilizumab administration was found to effectively treat the CAR-T cell-induced CRS, which likely saved CAR-T therapy. In the initial case for which the use of tocilizumab was tested, the patient's high fever went down, A c c e p t e d M a n u s c r i p t 6 low blood pressure went up, and serum IL-6 and CRP levels returned to normal only a couple of hours after tocilizumab administration (15) . Figure 3 , tocilizumab blocks the function of large amounts of IL-6 secreted from T cell-stimulated macrophages and prevents CRS. Importantly, although steroid hormones such as dexamethasone can also prevent CRS, they block the antitumor effect of CAR-T cells. CAR-T cell therapy has now been approved for clinical use in combination with tocilizumab for preventing CRS (15) .

Excessive immune responses to bacterial or viral infections or tissue injury induce the overproduction of various cytokines, including IL-6, IL-10, interferon (IFN)-γ, monocyte Our retrospective data also indicate that patients with severe COVID-19 display a mild elevation in their levels of IL-6 and several other cytokines, along with a striking elevation of PAI-1 levels similar to those seen in patients with bacterial sepsis or ARDS (Fig.   4) . Notably, tocilizumab treatment decreased the levels of both IL-6 and PAI-1 and also improved some clinical pneumonia symptoms in patients with severe COVID-19 (16) . These data indicate that IL-6 signaling in the vascular endothelium plays pivotal roles in coagulation activation and thrombosis during the cytokine storm observed in patients with COVID-19.

Numerous clinical trials of tocilizumab as a COVID-19 treatment have now been conducted, but their results are inconsistent. In patients with moderate cases of COVID-19, no support was found for beneficial effects of tocilizumab treatment (18) . For patients who were critically ill with COVID-19, the EMPACTA trial reported that tocilizumab treatment was associated with a reduction in the requirement for mechanical ventilation but did not improve the overall mortality (19). However, the REMAP-CAP trials in the United Kingdom, which assessed the effectiveness of a blockade of IL-6R signaling via tocilizumab or another anti-IL-6R antibody, sarilumab, found that both antibodies improved survival in patients with severe COVID-19 (21) . These results suggest the beneficial efficacy of IL-6R antagonists in patients with COVID-19.

As mentioned, a complex of IL-6 and IL-6R transduces signals into the inside of cells through gp130. Dimerization of gp130 activates JAK-STAT3 signaling pathways. As expected, blockade of JAK-STAT3 signaling pathway by the anti-JAK kinase, baricitinib shows beneficial effects together with remdesivir in hospitalized patients (20).

Compared with the CRS associated with CAR-T cell therapy and other causes, the elevated serum IL-6 levels in patients with COVID-19 are 100-fold lower, but the PAI-1 A c c e p t e d M a n u s c r i p t 9 levels are comparable. Thus, although the beneficial effect of tocilizumab for treating COVID-19 remains controversial, the treatment appears to be effective for vascular damage.

The network of signal transduction between IL-6 and PAI-1 remains an interesting question to be addressed in future work.

As described here, IL-6 not only exhibits a wide variety of biological activities but also is involved in chronic autoimmune inflammation and can induce the acute shock condition known as a cytokine storm. A blockade of IL-6 signals produces significant clinical benefits for both autoimmune diseases and CRSs. In this respect, the blockade of IL-6 signals with a steroid hormone has similar effects, as demonstrated by the clinical benefit of dexamethasone in the treatment of severe COVID-19. However, unlike treatment with steroid hormones, IL-6 signal inhibition does not globally suppress immune function. At present, how IL-6 can induce both acute and chronic inflammation remains incompletely understood. It is also unknown how IL-6 production is regulated, which is important because constitutive IL-6 production occurs in various diseases. This review conveys the contents of my lecture given for the Japanese Society of Immunology in 2020.

A c c e p t e d M a n u s c r i p t 10 Acknowledgements I thank Dr. S. Kang for assistance in preparing the manuscript and M. Okawa for providing secretarial help. I also thank Katie Oakley, PhD, from Edanz Group (https://en-authorservices.edanz.com/ac) for editing a draft of this manuscript.

The author declares that T.K. holds the patent for Actemra. . Scheme of anti-IL-6R antibody treatment in the COVID-19 induced cytokine storm. SARS-CoV-2 directly infects vascular endothelial cells, leading to excessive proinflammatory cytokines and PAI-1 production. Tocilizumab treatment can inhibit these inflammatory circuits as an effective therapy for the cytokine storm.

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