Interleukin-6 Receptor Blockade Research Articles

Tocilizumab does not ameliorate inflammation-induced left ventricular dysfunction in a collagen-induced arthritis rat model.

Interleukin-6 (IL-6) is an attractive therapeutic target due to its diverse roles in the pathogenesis of conditions characterized by systemic inflammation. IL-6 has also been implicated in the pathophysiology of heart failure. This study aimed to investigate the impact of IL-6 receptor blockade with tocilizumab on the molecular pathways underlying systemic inflammation-induced left ventricular (LV) dysfunction in a collagen-induced arthritis (CIA) rat model. Seventy-three Sprague-Dawley rats were divided into three groups: control (n=28), CIA (n=29), and CIA+IL-6 blocker (n=16). Inflammation was induced in the CIA and CIA+IL-6 blocker groups using bovine type II collagen emulsified in incomplete Freund's adjuvant. After arthritis onset, the CIA+IL-6 blocker group received tocilizumab for six weeks. Circulating inflammatory markers, relative LV mRNA gene expressions, and LV systolic and diastolic function were assessed. CIA rats developed LV diastolic and early-stage LV systolic dysfunction, which was not ameliorated by IL-6 blocker administration (p > 0.05). IL-6 blocker administration did not impact circulating inflammatory markers (all p > 0.05) or LV mRNA expression of inflammatory markers compared to the CIA group, nor did it reverse inflammation-induced increases in LV mRNA expression of genes involved in fibrosis and collagen turnover, regulation of titin phosphorylation, Ca2+ handling, mitochondrial function, or apoptosis (all p > 0.05). However, LV mRNA expressions of CD68 and LOX, genes involved in macrophage infiltration and collagen cross-linking, were increased in the CIA group (p = 0.03, p = 0.0004), but not in the CIA+IL-6 blocker group compared to controls (p > 0.05). These results suggest that although IL-6 blockade by tocilizumab may prevent inflammation-induced collagen cross-linking, the current treatment regimen may not protect against inflammation-induced LV dysfunction. Therefore, the role of IL-6 in the molecular mechanisms of inflammation-induced LV dysfunction remains inconclusive.

Exploring the therapeutic potential of interleukin-6 receptor blockade in autoimmune diseases using drug target mendelian randomization.

The blockade of the interleukin 6 receptor (IL-6R) demonstrates significant potential in various autoimmune diseases (ADs); however, the underlying therapeutic efficacy associated with this approach remains elusive.We conducted a comprehensive Mendelian randomization (MR) analysis based on large-scale genome-wide association studies to investigate the causal relationships between genetically proxied IL-6R blockade weighted by serum C-reactive protein levels and eighteen common ADs.Rheumatoid arthritis, COVID-19 infection, and COVID-19 critical illness were utilized as positive controls. The inverse-variance weighted (IVW) method was utilized as the primary analytical tool, while genetic colocalization analysis was conducted to further substantiate the causalities.Genetically proxied IL-6R blockade exhibited causally protective effects on all positive control diseases. After Bonferroni correction to IVW estimates, genetically proxied IL-6R blockade may significantly increase the risk of asthma (OR=1.031, P=2.15×10-12) and eczema (OR=1.066, P=5.92×10-22), while reducing the risk of ankylosing spondylitis (OR=0.341, P=1.39×10-5), Crohn's disease (OR=0.556, P=2.21×10-3), and type 1 diabetes (OR=0.410, P=1.78×10-7). Additionally, genetically proxied IL-6R blockade would suggestively reduce the risk of multiple sclerosis (OR=0.713,P=1.13×10-2). The results were robust under sensitivity analysis.For genetic colocalization analysis, we identified a shared causal variant rs531479718 linking serum C-reactive protein levels and asthma (posterior probability H4=0.998).Overall, our MR study demonstrated thatgenetically proxied IL-6R blockade may be causally associated with anincreased risk of asthma and eczema, while concurrently diminishing the risk of ankylosing spondylitis, Crohn's disease, type 1 diabetes, and multiple sclerosis. These findings carry substantial implications for informing the therapeutic utilization of IL-6R blockade in the management of ADs.

Cautionary Tale of Unopposed Prophylactic IL6 Receptor Blockade in Axicabtagene ciloleucel for Large B-Cell Lymphoma

Cautionary Tale of Unopposed Prophylactic IL6 Receptor Blockade in Axicabtagene ciloleucel for Large B-Cell Lymphoma

Exploring the therapeutic potential of interleukin-6 receptor blockade in cardiovascular disease treatment through Mendelian randomization

Interleukin-6 (IL-6) plays a crucial role in the pathogenesis of cardiovascular disease (CVD), and IL-6 receptor (IL-6R) blockade has emerged as a promising therapeutic option. However, their specific therapeutic effects in different types of CVDs remain unclear. This study aimed to assess the efficacy of IL-6R blockade in the management of various CVDs, including hypertension (HTN), coronary heart disease (CHD), myocardial infarction (MI), atrial fibrillation (AF), and heart failure (HF). The Mendelian randomization (MR) approach was utilized to investigate the therapeutic impact of IL-6R blockade on HTN, CHD, MI, AF, and HF based on the genome-wide association study (GWAS) summary statistics. MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis were used for sensitivity analysis to verify the reliability of the MR results. The Bonferroni method was used to correct for bias caused by multiple comparisons. Inverse variance weighted (IVW) results demonstrated that IL-6R blockade significantly influenced CHD (odds ratio (OR) = 0.757, 95% confidence interval (CI): 0.690 - 0.832, P = 5.804 × 10–9) and MI (OR = 0.840, 95% CI: 0.744 - 0.949, P = 0.005). However, IL-6R blockade had no significant effect on HTN (OR = 1.015, 95% CI: 0.950 - 1.084, P = 0.663), AF (OR = 0.905, 95% CI: 0.800 - 1.025, P = 0.116) and HF (OR = 1.012, 95% CI: 0.921 - 1.113, P = 0.805). Genetically predicted IL-6R blockade was associated with a protective effect on CHD and MI, but not HTN, AF and HF. This study's findings offer valuable insights for tailoring IL-6R blockade treatment for different types of CVD, and serve as a reference for future research.

Exploring the role of interleukin-6 receptor blockade in epilepsy and associated neuropsychiatric conditions through a mendelian randomization study

BACKGROUND The interplay between inflammation, immune dysregulation, and the onset of neurological disorders, including epilepsy, has become increasingly recognized. Interleukin (IL)-6, a pro-inflammatory cytokine, is suspected to not only mediate traditional inflammatory pathways but also contribute to neuroinflammatory responses that could underpin neuropsychiatric symptoms and broader psychiatric disorders in epilepsy patients. The role of IL-6 receptor (IL6R ) blockade presents an intriguing target for therapeutic intervention due to its potential to attenuate these processes. AIM To explore the potential of IL6R blockade in reducing the risk of epilepsy and investigate whether this pathway might also influence associated psychiatric and neuropsychiatric conditions due to neuroinflammation. METHODS Mendelian randomization (MR) analysis employing single nucleotide polymorphisms (SNPs) in the vicinity of the IL6R gene (total individuals = 408225) was used to evaluate the putative causal relationship between IL6R blockade and epilepsy (total cases/controls = 12891/312803), focal epilepsy (cases/controls = 7526/399290), and generalized epilepsy (cases/controls = 1413/399287). SNP weights were determined by their effect on C-reactive protein (CRP) levels and integrated using inverse variance-weighted meta-analysis as surrogates for IL6R effects. To address potential outlier and pleiotropic influences, sensitivity analyses were conducted employing a variety of MR methods under different modeling assumptions. RESULTS The genetic simulation targeting IL6R blockade revealed a modest but significant reduction in overall epilepsy risk [inverse variance weighting: Odds ratio (OR): 0.827; 95% confidence interval (CI): 0.685-1.000; P = 0.05]. Subtype analysis showed variability, with no significant effect observed in generalized, focal, or specific childhood and juvenile epilepsy forms. Beyond the primary inflammatory marker CRP, the findings also suggested potential non-inflammatory pathways mediated by IL-6 signaling contributing to the neurobiological landscape of epilepsy, hinting at possible links to neuroinflammation, psychiatric symptoms, and associated mental disorders. CONCLUSION The investigation underscored a tentative causal relationship between IL6R blockade and decreased epilepsy incidence, likely mediated via complex neuroinflammatory pathways. These results encouraged further in-depth studies involving larger cohorts and multifaceted psychiatric assessments to corroborate these findings and more thoroughly delineate the neuro-psychiatric implications of IL-6 signaling in epilepsy. The exploration of IL6R blockade could herald a novel therapeutic avenue not just for seizure management but also for addressing the broader psychiatric and cognitive disturbances often associated with epilepsy.

The NLRP3 inflammasome is essential for IL-18 production in a murine model of macrophage activation syndrome.

Hyperinflammatory disease is associated with an aberrant immune response resulting in cytokine storm. One such instance of hyperinflammatory disease is known as macrophage activation syndrome (MAS). The pathology of MAS can be characterised by significantly elevated serum levels of interleukin-18 (IL-18) and interferon gamma (IFNγ). Given the role for IL-18 in MAS, we sought to establish the role of inflammasomes in the disease process. Using a murine model of CpG-oligonucleotide-induced MAS, we discovered that the expression of the NLRP3 inflammasome was increased and correlated with IL-18 production. Inhibition of the NLRP3 inflammasome or the downstream caspase-1 prevented MAS-mediated upregulation of IL-18 in the plasma but, interestingly, did not alleviate key features of hyperinflammatory disease including hyperferritinaemia and splenomegaly. Furthermore blockade of IL-1 receptor with its antagonist IL-1Ra did not prevent the development of CpG-induced MAS, despite being clinically effective in the treatment of MAS. These data demonstrate that, during the development of MAS, the NLRP3 inflammasome was essential for the elevation in plasma IL-18 - a key cytokine in clinical cases of MAS - but was not a driving factor in the pathogenesis of CpG-induced MAS.

Monoclonal Antibody Treatment for Relapse Prevention in Neuromyelitis Optica Spectrum Disorder

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system that can lead to devastating neurological disabilities such as blindness and impaired mobility. Given that NMOSD can cause severe neurological deteriorations even with a single episode, exploring effective relapse prevention strategies in NMOSD is imperative. Recently, various biological monoclonal antibody therapies targeting diverse mechanisms have shown efficacy in preventing relapses in NMOSD, as evidenced by clinical trials. These monoclonal antibody therapies include complement inhibition (eculizumab and ravulizumab), B-cell depletion (rituximab and inebilizumab), and interleukin-6 receptor blockade (tocilizumab and satralizumab) mechanisms. Some of these therapies are now reimbursable, and this review summarizes their mechanisms, administration methods, reimbursement status in Korea, efficacy, and safety profiles in clinical practice.

Monoclonal Antibody Treatment for Relapse Prevention in Neuromyelitis Optica Spectrum Disorder

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system that can lead to devastating neurological disabilities such as blindness and impaired mobility. Given that NMOSD can cause severe neurological deteriorations even with a single episode, exploring effective relapse prevention strategies in NMOSD is imperative. Recently, various biological monoclonal antibody therapies targeting diverse mechanisms have shown efficacy in preventing relapses in NMOSD, as evidenced by clinical trials. These monoclonal antibody therapies include complement inhibition (eculizumab and ravulizumab), B-cell depletion (rituximab and inebilizumab), and interleukin-6 receptor blockade (tocilizumab and satralizumab) mechanisms. Some of these therapies are now reimbursable, and this review summarizes their mechanisms, administration methods, reimbursement status in Korea, efficacy, and safety profiles in clinical practice.

Interleukin-6 receptor blockade with tocilizumab to reduce immune-related toxicity with ipilimumab and nivolumab in metastatic melanoma.

9538 Background: Interleukin-6(IL-6) blockade has reversed steroid-refractory immune-related toxicity in patients receiving immune checkpoint blockade (ICB). IL-6 and its downstream acute phase reactants are also associated with short survival and therapeutic resistance in patients receiving single agent or combination ICB. We undertook a phase II trial of IPI, NIVO and the IL-6 receptor blocking antibody tocilizumab (TOCI) in unresectable melanoma. Methods: In a phase II, Simon-design two-stage trial, 70 patients with untreated metastatic melanoma received IPI at 1 mg/kg and NIVO at 3 mg/kg for 4 induction doses to week 12, and TOCI at 4 mg/kg every 6 weeks up to week 24. Maintenance NIVO was administered at 240 mg intravenously (IV) from weeks 12 to 24, then at a dose of 480 mg IV every 4 weeks for up to 2 years of treatment. To proceed past the first stage of 18 patients, 12/18 RECIST responses or more and/or a grade 3-5 treatment related immune-related adverse event (irAE) rate of ≤5/18 were required. Those criteria were both fulfilled, and in the second stage 49 patients were treated, with 3 additional patients accrued. Serum and peripheral blood samples were collected for biomarker assays at baseline and week 7. Results: There were 40/70 RECIST responders with a 57% best overall response rate (BORR), (exact 95% confidence interval (CI) of 44-68%) of partial response (PR) or complete response (CR); 6 patients had stable disease (SD), 24 with progression, at a median of 2.4 years of follow-up. A total of 46 patients had clinical benefit (CR+PR+SD) = 65% (exact 95% CI 37-81%). Median progression-free survival was 13 months. The expected BORR was 47% in the randomized Checkmate-511 trial at the same doses of IPI/NIVO. There have been 16 cases of grades 3-4 irAE including 3 episodes of colitis for a total of 16/71 patients eligible for toxicity = 22% (exact 95% CI: 12-31%), all grade 3/4; the expected rate of grades 3-5 TRAEs was 34% per Checkmate-511. The rate of irAE leading to discontinuation was 14%; it was 25% for CheckMate 511. Twenty-one deaths (30%) occurred, all due to progression. All grade 3-4 irAES were reversible and no grade 5 toxicity was seen. Osteopontin+IL6+CD45RAnegclassical monocytes were associated with response, and higher levels of naive CD8 T cells were associated with progression. CD16+CD56+CD57+ mature natural killer cells were significantly lower in patients with grade 3-4 immune-related toxicity. Conclusions: Prophylactic TOCI resulted in a low rate of grade 3-4 irAEs by week 24 in patients with stage IV melanoma receiving induction IPI 1 mg/kg and NIVO 3 mg/kg while maintaining a favorable overall response rate and survival. Novel biomarkers of response and toxicity including NK cells and monocytes as well as naïve and effector memory CD8 T cells were defined by high-resolution flow cytometry. Additional correlative data will be presented. Clinical trial information: NCT03999749 .

Phase II trial of weekly or bi-weekly tocilizumab with ipilimumab and nivolumab in advanced melanoma: Clinical outcomes and biomarker analysis.

9553 Background: Combination immune-checkpoint inhibitors (ICIs) improved outcomes in a plethora of cancer subtypes. However, up to 60% of patients (pts) receiving ipilimumab (ipi) plus nivolumab (nivo) experience grade 3/4 (G 3/4) immune-related adverse events (irAEs), often leading to treatment discontinuation. We evaluated two therapeutic strategies targeting interleukin-6 receptor (IL-6R) to reduce irAEs while enhancing ICls efficacy. Methods: Phase Il trial (NCT04940299) investigating safety/efficacy of frontline tocilizumab (toci; IL-6R inhibitor) combined with ipi 3mg/kg + nivo 1mg/kg Q3 weeks (wks) for 12 wks in advanced melanoma. Initially, toci was given as 162 mg subcutaneously (SQ) bi-weekly for 6 doses (regular dosing regimen; RD). Then, we escalated to a dose dense (DD) regimen (162 mg SQ weekly for 6 wks then bi-weekly for 6 wks; 9 doses total). Primary objective was rate of G 3/4 irAEs. Secondary objectives were objective response rates (ORR) and disease control rate (DCR) per RECIST 1.1. Exploratory objectives involved immune analysis (gene expression, CyTOF, cytokine analysis) on longitudinal blood and tissue samples to identify drivers of auto- vs antitumor immunity. Results: As of Feb 2024, 35 pts were enrolled (25 pts to RD regimen; 10 pts to DD regimen). In RD group, median follow-up is 18 months (6 - 25 months). By 12 wks, 44% of pts developed G 3/4 irAEs including colitis (20%), hepatitis (16%), pancreatitis (12%), type I diabetes and serum sickness (4% each) and 20% of pts required hospitalization due to irAEs. Median time to G 3/4 irAEs onset was 7.4 wks. 16% of pts discontinued ICIs due to irAEs. ORR was 56% at 12 wks including 40% in pts with high LDH and DCR was 80%. Gene expression analysis showed a trend towards higher expression of IL-17 pathway genes in pts who developed G 3/4 irAEs, suggesting IL-6/Th17 pathway was not sufficiently inhibited. Thus, we enrolled 10 pts into the DD regimen aiming to achieve better inhibition of the IL-6/Th17 pathway. In DD group, median follow-up is 7 months (3 - 13 months). By 12 wks, 40% of pts developed G 3/4 irAEs, including colitis (10%), hepatitis (20%), and uveitis (10%) and 30% of pts required hospitalization due to irAEs. Median time to G 3/4 irAEs onset was 4.9 wks. 30% of pts discontinued ICIs due to irAEs. ORR was 70% at 12 wks including 75% in pts with high LDH and DCR was 80%. Conclusions: To our knowledge, this is the first study to investigate toci in combination with high dose ipi3/nivo1. Although our cohort is small, preliminary data suggests IL-6R blockade using the DD regimen could decrease the rate of G 3/4 irAEs while maintaining antitumor responses of ipi3/nivo1. A randomized phase ll trial investigating this strategy is underway. Ongoing immune analysis comparing treatment regimens aims to identify distinct pathways involved in auto- vs antitumor immunity and IL-6/Th17 independent pathways of toxicity. Clinical trial information: NCT04940299 .

Absence of IL-6 Receptor Blockade Effect on the Outcomes of Transplant Glomerulopathy in the Absence of Anti-HLA Donor-specific Antibodies.

Transplant glomerulopathy (TG) is the hallmark of chronic antibody-mediated rejection but often occurs without anti-HLA donor-specific antibodies (DSAs) in the assumption that other DSAs may be the effectors of the tissue injury. Recently, we reported a positive effect of interleukin-6 (IL-6) receptor blocker tocilizumab (TCZ) in TG/DSA+. In the present study, we investigate the effect of TCZ in a cohort of TG cases without detectable anti-HLA DSAs. Single-center retrospective analysis of TG cases without anti-HLA DSAs (TG/DSA) treated with TCZ for chronic antibody-mediated rejection as first-line therapy evaluated through clinical, protocol biopsies, and gene expression analyses was included. Differently from TG/DSA+, TG/DSA- showed a progressive reduction in the estimated glomerular filtration rate at 12 mo and after that with no significant modification in microvascular inflammation or C4d+. No upregulation in tight junction protein-1, aldo-keto reductase family 1 member C3, and calcium/calmodulin-dependent serine protein kinase, documented in TG/DSA+, was noted in post-TCZ biopsies. The reduction of microvascular inflammation was associated with natural killer-cell reduction in TG/DSA+, whereas TG/DSA- tends to maintain or increase periglomerular/interstitial infiltration. In the absence of anti-HLA DSAs, TG behavior seems not to be modified by IL-6 receptor blockade. These results are at variance with observational studies and previous trials with IL-6 inhibitors in TG associated with anti-HLA DSAs. These data may fuel the hypothesis of different mechanisms underlying TGs (including the potentially different roles of natural killer cells) and suggest carefully selecting patients with TG for clinical trials or off-label treatment based on their antidonor serologic status.

Effect of IL-6R blockade on plasma lipids and clinical outcomes among hospitalized patients with COVID-19 infection

Plasma lipid levels are modulated by systemic infection and inflammation; it is unknown whether these changes reflect inflammatory responses or caused directly by pathogen presence. We explored the hypothesis that anti-inflammatory intervention via interleukin 6 receptor (IL-6R) blockade would influence plasma lipid levels during severe infection and evaluated the association of plasma lipid changes with clinical outcomes. Sarilumab (monoclonal antibody blocking IL-6R) efficacy was previously assessed in patients with coronavirus disease 2019 (COVID-19) (NCT04315298). This analysis determined whether strong inflammatory reduction by sarilumab in patients with COVID-19 pneumonia of increasing severity (severe, critical, multisystem organ dysfunction) affected plasma lipid changes between day 1 and day 7 of study therapy. Baseline lipid levels reflected the presence of acute systemic infection, characterized by very low HDL-C, low LDL-C, and moderately elevated triglycerides (TGs). Disease severity was associated with progressively more abnormal lipid levels. At day 7, median lipid levels increased more in the sarilumab versus placebo group (HDL-C +10.3%, LDL-C +54.7%, TG +32% vs. HDL-C +1.7%, LDL-C +15.4%, TG +8.8%, respectively). No significant association between lipid changes and clinical outcomes was observed. In conclusion, severe-to-critical COVID-19 pneumonia causes profound HDL-C depression that is only modestly responsive to strong anti-IL-6R inflammatory intervention. Conversely, LDL-C depression is strongly responsive to IL-6R blockade, with LDL-C levels likely returning to the predisease set point. These results advance our understanding of the complex relationship between serum lipids and infection/inflammation and suggest that HDL-C depression during acute contagious disease is driven by infection and not IL-6–mediated inflammation.

IL-6 receptor antibody treatment improves muscle weakness in experimental autoimmune myasthenia gravis mouse model.

Myasthenia gravis (MG) is a chronic autoimmune disease characterized by muscle weakness and fatigue. It is caused by pathological autoantibodies against components expressed at neuromuscular junctions, such as acetylcholine receptor (AChR). Interleukin-6 (IL-6) has been suggested to play a role in the pathogenesis of MG, and IL-6 receptor (IL-6R) antibody treatment may provide a novel therapeutic option. In this study, we investigated the effects of IL-6R antibody treatment in an experimental autoimmune MG (EAMG) mouse model. We demonstrated that IL-6R antibody treatment improved muscle weakness, reduced IgG deposition at neuromuscular junctions, and the levels of AChR autoantibodies in serum. In addition, follicular helper T cells and Th17, plasma cells in lymph nodes were lower in IL-6R antibody treated mice. Our findings suggest that IL-6R blockade may be a novel and effective therapeutic strategy for the treatment of MG.

IL-6 receptor blockade prevents polarization of pro-fibrotic macrophages in myeloid-rich RA synovial tissue

IL-6 receptor blockade prevents polarization of pro-fibrotic macrophages in myeloid-rich RA synovial tissue

(91) - IL-6 Receptor Blockade Induces Tolerance of Heart Allografts in NHPs in a Simultaneous but Not Delayed Mixed-Chimerism Protocol

(91) - IL-6 Receptor Blockade Induces Tolerance of Heart Allografts in NHPs in a Simultaneous but Not Delayed Mixed-Chimerism Protocol

Effects of interleukin-6 signal inhibition on Treg subpopulations and association of Tregs with clinical outcomes in rheumatoid arthritis.

Anti-IL-6 receptor antibodies are clinically efficacious in the management of RA with an associated increase in Tregs; however, the role of functional Treg subsets has yet to be clarified. This study aimed to evaluate how functional Treg subsets are altered by IL-6 receptor blockade and to analyse the relationship between these Treg subsets and the clinical outcome of RA. We collected frozen peripheral blood mononuclear cells (PBMCs) from 40 patients with RA who started tocilizumab (TCZ) with or without MTX and 11 healthy controls (HCs). We fractionated Tregs with flow cytometry based on markers of phenotype and function and measured the proportions of detailed Treg subsets sequentially from baseline to week 52. The proportions of resting Tregs (rTregs) and rTregs+activated Tregs (aTregs) were significantly lower in RA patients at baseline than in HCs. The proportions of all those CD127low Tregs, rTregs, aTregs and rTregs+aTregs were significantly increased with TCZ treatment. In patients treated with TCZ without MTX, rTreg were increased. Patients with an increase in the proportion of rTregs at week 12 had significantly less arthritis flares during the observation period. Blocking the IL-6 receptor with TCZ increased the proportion of rTregs, a functional Treg subpopulation. Patients with an early increase in rTregs showed a favourable treatment course and this increase in rTregs may reflect molecular remission induced by IL-6 signal inhibition.

Fungal microbiota sustains lasting immune activation of neutrophils and their progenitors in severe COVID-19.

Gastrointestinal fungal dysbiosis is a hallmark of several diseases marked by systemic immune activation. Whether persistent pathobiont colonization during immune alterations and impaired gut barrier function has a durable impact on host immunity is unknown. We found that elevated levels of Candida albicans immunoglobulin G (IgG) antibodies marked patients with severe COVID-19 (sCOVID-19) who had intestinal Candida overgrowth, mycobiota dysbiosis and systemic neutrophilia. Analysis of hematopoietic stem cell progenitors in sCOVID-19 revealed transcriptional changes in antifungal immunity pathways and reprogramming of granulocyte myeloid progenitors (GMPs) for up to a year. Mice colonized with C. albicans patient isolates experienced increased lung neutrophilia and pulmonary NETosis during severe acute respiratory syndrome coronavirus-2 infection, which were partially resolved with antifungal treatment or by interleukin-6 receptor blockade. sCOVID-19 patients treated with tocilizumab experienced sustained reductions in C. albicans IgG antibodies titers and GMP transcriptional changes. These findings suggest that gut fungal pathobionts may contribute to immune activation during inflammatory diseases, offering potential mycobiota-immune therapeutic strategies for sCOVID-19 with prolonged symptoms.

Long-term Effects of IL-6 Receptor Blockade Therapy on Regulatory Lymphocytes and Neutrophils in Neuromyelitis Optica Spectrum Disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a disabling autoimmune neurologic disease. Anti-IL-6 receptor (IL-6R) therapy prevents relapses in patients with anti-aquaporin 4 (AQP4)-IgG-positive NMOSD; however, it remains unclear how cellular immune components are altered by anti-IL-6R therapy. In this study, we examined the long-term effects of the anti-IL-6R monoclonal antibody tocilizumab (TCZ) on immune cell profiles in patients with NMOSD. Monthly IV injections of TCZ (8 mg/kg) were administered as an add-on therapy to 19 anti-AQP4-IgG-positive patients, who had been refractory to corticosteroids and immunosuppressive drugs. Peripheral blood was collected before infusion of TCZ for flow cytometry analysis of lymphocyte subsets. Seven patients provided whole blood samples for gene expression profiles. Patients with NMOSD had reduced numbers of lymphocyte subsets with regulatory functions, including transitional B cells, CD56high NK cells, and CD45RA-FoxP3high regulatory T cells. However, after initiating TCZ therapy, the numbers increased to normal levels within 1 year. Gene expression analysis revealed that neutrophil granule-related genes, predominated by those related to azurophil granules, were significantly upregulated in patients with NMOSD. Such alterations suggestive of accelerated myeloid turnover were not observed 1 year after TCZ therapy, and the effects of TCZ on some neutrophil genes were observed as early as 5 days after starting TCZ. In vitro analysis demonstrated that naïve T-cell division was impaired in the enrolled patients, which was fully recovered after 18 months of therapy. In patients with active NMOSD not treated with molecular targeting drugs, we observed reduction or deficiency in lymphocytes with regulatory potentials and activation of neutrophils. However, introduction of anti-IL-6R therapy accompanied by tapering concomitant drugs corrected such abnormalities, which might contribute to persistent relapse prevention. The recovery in the naïve T-cell division after starting TCZ may underlie the relatively low risk of infection in patients under anti-IL-6R therapy. University Hospital Medical Information Network Clinical Trials Registry: UMIN000005889 (July 8, 2011) and UMIN000007866 (May 1, 2012) (umin.ac.jp/ctr/index.htm). The first participant was enrolled on November 2, 2011.

Therapeutic potential of single-nucleotide polymorphism-mediated interleukin-6 receptor blockade in cancer treatment: A Mendelian randomization study

BackgroundInterleukin-6 (IL-6) is a crucial member of the cytokine network and plays a pivotal role in the pathogenesis of various diseases, including cancer. IL-6 receptor (IL-6R) blockade is widely employed as a therapeutic strategy; however, its efficacy in anticancer therapy remains ambiguous. MethodsAn inverse variance-weighted Mendelian randomization (MR) analysis was conducted to assess the causal effects exerted by IL-6R blockade in remediating cancer. Drug-targeted single-nucleotide polymorphisms (SNPs) were introduced within 300 kb of the IL-6R gene. An instrumental variable comprising 26 SNPs represented IL-6 signaling downregulation and C-reactive protein level reduction. Datasets pertaining to the 33 types of cancer investigated in this study were acquired from the FinnGen genome-wide association study. ResultsThe selected instrumental variable lowered fibrinogen levels, confirming its ability to mimic IL-6R blockade. IL-6R blockade exhibited therapeutic effects on five different cancer types documented in the FinnGen database (N = 334,364, including 76,781 cancer patients): bladder (odds ratios (OR) = 0.563), laryngeal (OR = 0.293), eye (OR = 0.098), gallbladder (OR = 0.059), and myeloid leukemia (OR = 0.442); however, it simultaneously elevated the risk of developing basal cell carcinoma (OR = 1.312) and melanoma (OR = 1.311). Sensitivity analyses did not alter the primary results. ConclusionTherefore, this study aimed to evaluate the potential and efficacy of SNP-based IL-6R blockade in treating cancer.

Feasibility of Interleukin-6 Receptor Blockade in Cardiac Antibody-mediated Rejection.

Antibody-mediated rejection (AMR) remains a significant cause of heart transplant mortality with few effective therapies. This study aimed to describe initial experience of using interleukin-6 receptor blockade with tocilizumab in the treatment of acute cardiac AMR at Barnes-Jewish Hospital/Washington University Transplant Center from July 2017 to May 2021 (n = 7). Clinical, echocardiographic, and serum alloantibody data were analyzed before and after treatment. All participants demonstrated marked improvement in functional status. Echocardiographic data following 4-6 mo of tocilizumab revealed significant improvements in biventricular systolic function for all participants. Consistent reductions in donor-specific HLA or angiotensin type I receptor antibodies were not observed, suggesting that tocilizumab may act downstream of antibody production. No patient experienced drug-related complications that necessitated discontinuation of therapy. These findings provide initial insights into the safety and efficacy of interleukin-6 receptor blockade in the treatment of cardiac AMR and support the design of larger prospective studies.