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Interleukin-6 and the Lung
Published in Jason Kelley, Cytokines of the Lung, 2022
Ralph J. Zitnik, Jack A. Elias
Interleukin-6 may be involved in the pathogenesis of both Hodgkin’s (HL) and non-Hodgkin’s lymphoma (NHL). Cell lines from two patients with NHL expressed IL-6 protein and mRNA and proliferated in response to exogenous IL-6. The effects of IL-6 on these cells could be blocked with anti-IL-6 antibody, suggesting that a feedback loop involving IL-6 was responsible for their autonomous proliferation (Yee et al., 1989). The skin lesions of patients with mycosis fungoides also contain large amounts of IL-6 when compared with biopsy specimens of uninvolved skin (Lawlor et al., 1990). Tissue from patients with HL stain positively for IL-6 by immunocytochemical methods, and in situ hybridization reveals IL-6 mRNA transcripts over Hodgkin’s and Reed-Sternberg cells (Jucker et al., 1991). Additional investigation will be required, however, to determine the importance and potential therapeutic implications of IL-6 feedback loops in these disorders.
Drug Repurposing and Novel Antiviral Drugs for COVID-19 Management
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Shailendra Dwivedi, Aakanksha Rawat, Amit Ranjan, Ruchika Agrawal, Radhieka Misra, Sunil Kumar Gupta, Surekha Kishore, Sanjeev Misra
COVID-19–associated systemic inflammation and hypoxic respiratory failure can be associated with heightened cytokine release, as indicated by elevated blood levels of interleukin-6 (IL-6), C-reactive protein (CRP), D-dimer, and ferritin. It is hypothesized that modulating the levels of IL-6 or its effects may alter the course of disease. Several studies have indicated a “cytokine storm” with release of IL-6, IL-1, IL-12, and IL-18, along with tumor necrosis factor-alpha (TNFα) and other inflammatory mediators in COVID-19 patients as the main pathogenetic factor resulting in severe damage to lung tissues. The increased pulmonary inflammatory response may result in increased alveolar-capillary gas exchange, making oxygenation difficult in patients with severe illness. Interleukin inhibitors may ameliorate this damage caused by cytokine release. There are two classes of FDA-approved IL-6 inhibitors: anti-IL-6 receptor monoclonal antibodies (e.g., sarilumab, tocilizumab) and anti-IL-6 monoclonal antibodies (siltuximab). Currently, the NIH panel guidelines have recommended against the use of anti-IL-6 receptor monoclonal antibodies or anti-IL-6 monoclonal antibody for the treatment of COVID-19, except in a clinical trial [17].
Immunomodulation of Cytokines and T Cells by Biologicals in Rheumatoid Arthritis
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Ravinder N. Maini, Marc Feldmann
A murine monoclonal anti-IL-6 antibody has been given intravenously in open label studies [80, 81]. This antibody seemed to lead to significant improvement in pain, number of tender joints, and ESR. The lack of a placebo group, the small numbers of patients, and the absence of full documentation of validated measurement and response criteria make it difficult to assess these results. Preliminary data from Dr. Kishimoto’s group in Japan with an anti-IL-6 receptor antibody used in a trial on a small number of patients (personal communication) have given encouraging results. Fuller investigation of these antibodies in randomized placebo-controlled trials would be of interest in resolving whether IL-6 is pathogenic in RA.
Discovery and characterization of a monoclonal antibody targeting a conformational epitope of IL-6/IL-6Rα to inhibit IL-6/ IL-6Rα /gp130 hexameric signaling complex formation
Published in mAbs, 2022
Chun-Chi Chou, Kuo-Tai Hua, Min-Wei Chen, Chin-Jui Wu, Chun-Hua Hsu, Jann-Tay Wang, Michael Hsiao, Lin-Hung Wei
Sequential assembly of the IL-6/IL-6Rα/gp130 hexameric complex offers several alternatives for therapeutic intervention. Inhibitors that target different steps in the IL-6 signaling cascade have been developed. However, the question remains as to which of these modes of the blockade is superior and whether this difference can translate into clinical benefit. Tocilizumab, the first biologic targeting the IL-6 pathway to be approved by the Food and Drug Administration, recognizes both mIL-6Rα and sIL-6Rα and inhibits IL-6 signaling through competitive blockade of IL-6 binding.39 In comparison with anti-IL-6 antibodies, treatment of patients with anti-IL-6Rα antibodies prevents serum IL-6 accumulation and related adverse responses, such as fever, fatigue, and hypercalcemia.28 Nevertheless, targeting a receptor like IL-6Rα instead of the individual cytokine IL-6 already reduces the specificity. It has been shown that human IL-6Rα binds not only to IL-6, but also to human ciliary neurotrophic factor40 and IL-30,41 indicating that the blockade of IL-6Rα might also affect other signaling pathways. Likewise, experiments using olamkicept have shown that blocking IL-6 trans-signaling with sgp130Fc interferes with signaling elicited by the IL-11 trans-signaling pathway.42 C14mab’s blockade of the IL-6/IL-6Rα complex, but not IL-6Rα alone, enables the targeting of a single signaling entity and allows uninterrupted signaling of other cytokines in the IL-6 family.
Biologic and advanced immunomodulating therapeutic options for sarcoidosis: a clinical update
Published in Expert Review of Clinical Pharmacology, 2021
Ogugua Ndili Obi, Elyse E. Lower, Robert P. Baughman
There are two classes of anti-IL-6 biologic agents. Tocilizumab [312] and sarilumab [313,314] are non-chimeric IgG1monoclonal antibodies directed against the IL-6 receptor and are FDA approved for the treatment of moderate to severe rheumatoid arthritis refractory to anti-TNF therapy and other DMARDs [315]. Siltuximab is a chimeric/humanized monoclonal antibody that binds directly to circulating and membrane-bound IL-6 and prevents their binding to IL-6 receptor. Siltuximab is FDA approved for the treatment of multicentric Castleman’s disease [316]. Although siltuximab showed similar clinical efficacy to the anti-IL-6 receptor blockers, it was not approved for the treatment of rheumatoid arthritis due to an excess mortality in preclinical trials [317]. Sirukumab is another non-chimeric IgG1 kappa monoclonal antibody to circulating IL-6 that was not FDA approved for the treatment of rheumatoid arthritis due to safety concerns [318].
High sensitivity Troponin-T for prediction of adverse events in patients with COVID-19
Published in Biomarkers, 2020
Nikhil Singh, Rajeev K. Anchan, Stephanie A. Besser, Mark N. Belkin, Mark D. Cruz, Linda Lee, Dongbo Yu, Natasha Mehta, Ann B. Nguyen, Francis J. Alenghat
With this proposed mechanism, it would be of interest to know if targeted anti-inflammatory therapies, such as IL-6 inhibitors, decrease troponin elevation and if this response is predictive of improvement in outcomes. While we can speculate that use of IL-6 inhibitor therapy would decrease inflammation, as has been reported in other clinical scenarios, so far, no clear benefit for directed anti-IL-6 therapy has been found in COVID-19 patients with regards to our outcomes of interest (Kleveland et al.2016, Cortegiani et al.2020). Additionally, although we have identified the prognostic value of a cardiac biomarker, the outcomes we are reporting on are not limited to cardiovascular events. Our findings suggest that elevated hs-TnT serves as a marker of risk of future adverse events based on the current severity of the infectious disease and inflammatory process, but not necessarily as a marker of hard cardiovascular outcomes. Therefore, we are unable to comment on potential benefit, and no clear evidence currently exists, for cardiac-specific therapies in these patients (Sandoval et al.2020).