Interleukin-6 Receptor Antibody Research Articles

Effects of Ex Vivo Perfusion and Il-6 Receptor Blockade on Ischemia Reperfusion Injury in Cardiac Transplantation

Purpose In cardiac transplantation, ischemia reperfusion injury (IRI) remains a major problem associated with poor short and long-term outcomes. Since pro-inflammatory cytokines and endothelial activation have been hallmarks of IRI for decades, they can be addressed by recent therapeutic advancements. Normothermic ex vivo heart perfusion using the Organ Care System, but also pre-emptive treatment strategies for highly immunized recipients using the IL-6 receptor antibody tocilizumab, are in current clinical use. Therefore, we retrospectively studied blood samples from our clinical cardiac transplantation cohort for parameters of IRI. Methods In a novel protocol for heart transplantation (HTx) recipients with preformed donor-specific antibodies (pfDSA), an intraoperative application of tocilizumab (10mg/kg) was given together with 5 sessions of plasmapheresis, followed by one infusion of IgGAM (2g/kg) and a single dose of anti-CD20 antibody (rituximab). This protocol was applied to 6 recipients of OCS-preserved hearts. 10 recipients of OCS-preserved hearts without pfDSA did not receive tocilizumab (group 2). 24 recipients of standard heart transplants preserved on ice represent group 3. Donor or recipient demographics did not differ among the groups. Plasma levels of cytokines and endothelial markers were compared before, immediately after transplant surgery (T0), 24h (T24) and 3 weeks after transplantation. Results IRI could be measured in standard heart recipients at T0 and T24 by significantly increased levels of IL-6, CXCL8/IL-8, IL-18, Ang-2 and IGFBP-1 (all p Conclusion Normothermic ex vivo preservation in the OCS reduces IRI at the cytokine and endothelial level in recipient blood immediately after transplantation. Application of tocilizumab during transplantation blocks binding of IL-6 to its receptor leading to higher plasma levels. These effects may have a clinically relevant impact on ischemia reperfusion injury post cardiac transplantation.

An IL-6 receptor antagonist attenuates postpartum anhedonia, but has no effect on anhedonia precipitated by subchronic stress in female rats.

Nearly 60-80% of women experience some form of sadness, anxiety, or anhedonia in the weeks following the birth of a child (Patel et al. 23(2):534-42, 2012; Degner 10: 359;j4692, 2017); however, the exact mechanisms that precipitate these changes in mood postpartum are still unknown. It is well-known that the function of the peripheral immune system is significantly altered during pregnancy in order to protect the developing fetus from being rejected by the maternal immune system (Fallon et al. 17(1):7-17, 2002), and we have recently found a dramatic change in the central immune system during and just after pregnancy in female rats (Sherer et al. 66:201-209, 2017). We observed anhedonia in Sprague-Dawley rat dams on the day of birth that is associated with an increase in interleukin (IL)-6 expression in the brain on the day of birth (Posillico and Schwarz 298(Pt B):218-28, 2016). The goal of the current experiments was to determine whether inhibiting the IL-6 receptor could prevent onset of this postpartum anhedonia, or anhedonia precipitated by subchronic stress in non-pregnant females. Treatment with an IL-6 receptor antibody attenuated postpartum anhedonia as characterized by a decrease in sucrose preference. In contrast, this antibody had no effect on the decrease in sucrose preference induced following a week of forced swim stress in non-pregnant female rats. The results of these studies suggest that the molecular mechanisms that underlie the onset of anhedonia following birth or mild stress in female rats may be distinct.

Abstract # 3173 An investigation into the impact of neuroimmune function after pregnancy or stress: Are there potential links to the onset of depression?

The National Institute of Mental Health has identified postpartum depression as one of several types of depression that affects 10–15% of mothers. It has previously been hypothesized that postpartum depression may be caused by dramatic changes in hormone levels that occur throughout pregnancy and the immediate postpartum period (Harris et al., 1994); however, the exact underlying mechanisms are still unknown. Like the dramatic change in hormone levels, the peripheral immune system is also altered to protect the developing semi-allogenic fetus from being rejected by the maternal immune system (Fallon et al., 2002). Despite this well-known phenomenon, the literature on how the central immune system is altered during pregnancy is still very limited. Increased circulating cytokines have been associated with numerous types of depression as well as chronic stress (Dantzer, 2009). Recently, we have observed depressive-like behaviors on the day of birth and following sub-chronic stress, and increased IL-6 expression in the maternal brain on the day of birth (Posillico and Schwarz, 2016). Thus, we sought to determine whether blocking the function of this pro-inflammatory cytokine may prevent the anhedonia observed following birth or sub-chronic stress. Treatment with an IL-6 receptor antibody effectively attenuated depressive-like behavior immediately postpartum, but had no effect following sub-chronic stress. These results suggest that the molecular mechanisms that underlie the onset of anhedonia following birth and sub-chronic stress may be distinct.

IL-6: A hack to body fat and exercise?

The IL-6 receptor antibody tocilizumab abolished the ability of exercise to reduce visceral fat and cholesterol levels in obese individuals.

Exercise-Induced Changes in Visceral Adipose Tissue Mass Are Regulated by IL-6 Signaling: A Randomized Controlled Trial

Visceral adipose tissue is harmful to metabolic health. Exercise training reduces visceral adipose tissue mass, but the underlying mechanisms are not known. Interleukin-6 (IL-6) stimulates lipolysis and is released from skeletal muscle during exercise. We hypothesized that exercise-induced reductions in visceral adipose tissue mass are mediated by IL-6. In this randomized placebo-controlled trial, we assigned abdominally obese adults to tocilizumab (IL-6 receptor antibody) or placebo during a 12-week intervention with either bicycle exercise or no exercise. While exercise reduced visceral adipose tissue mass, this effect of exercise was abolished in the presence of IL-6 blockade. Changes in body weight and total adipose tissue mass showed similar tendencies, whereas lean body mass did not differ between groups. Also, IL-6 blockade increased cholesterol levels, an effect not reversed by exercise. Thus, IL-6 is required for exercise to reduce visceral adipose tissue mass and emphasizes a potentially important metabolic consequence of IL-6 blockade.

Personalized Therapy in Multicentric Castleman Disease Produces Excellent Outcomes in a Tertiary Referral Center

Introduction. Multicentric Castleman Disease (MCD) is an inflammatory disorder characterized by lymphadenopathy. The clinical course of MCD is variable; some patients have mild symptoms while others develop hypercytokinemia progressing to organ failure. Severely ill patients often have the TAFRO-variety of MCD characterized by Thrombocytopenia, Anasarca, Fever, Reticulin marrow fibrosis, and Organomegaly. We report on 76 MCD patients: the largest series from a single institution.Methods. Data was collected from our institution and outside records via systematic chart review and standardized survey for self-reported symptoms. Laboratory data represent each patient's most severe episode. TAFRO- and non-TAFRO or “classical” iMCD subtypes were grouped (iMCD) for some analyses. Patients were classified as POEMS-associated MCD when they had MCD with full POEMS syndrome or clear features of POEMS.Results. Forty-nine patients had classical iMCD and 12 TAFRO-iMCD. Fifteen patients had POEMS-associated MCD, of which 8 had coexistent POEMS syndrome. iMCD and POEMS-associated MCD had similar age and sex, but the hyaline vascular variant was more common in iMCD (44.3 vs 6.7%, p=0.006) (Table 1). iMCD patients were more symptomatic in terms of night sweats (61.0 vs 33.3%, p=0.001) and fever (50.8 vs 20%, p=0.031) compared to POEMS-associated MCD, but had similar laboratory characteristics and disease activity (CHAP) scores. TAFRO-iMCD patients were mostly male and had more fever (91.6 vs 42.9%, p=0.002), anasarca (100 vs 24.5%, p<0.0001), higher creatinine (2.6 vs 0.9 mg/dL, p=0.001), poorer CHAP scores (5.5 vs 2.0, p=0.01), and a trend to lower hemoglobin. Interleukin-6 (IL6) levels were not different among groups, but vascular endothelial growth factor (VEGF) was higher in TAFRO-iMCD (328.5 vs 79.5 pg/mL, p=0.034), accounting for anasarca.Commonly-used treatment regimens for iMCD were the anti-IL6/IL6 receptor antibodies siltuximab and tocilizumab (n=41), rituximab ± steroids (n=23), steroids alone (n=13), and chemotherapy (n=7). There was a high rate of response to anti-IL6 therapy (97%) with a treatment failure (TF) rate of 5%. Two further relapses occurred in patients who discontinued therapy. Steroid monotherapy or rituximab + steroids yielded response rates of 46 and 82%, but were marred by high TF rates (85 and 43%). Chemotherapy responses were noted in 7 instances, but TF occurred twice. There were no significant differences in response to therapy comparing the classical and TAFRO-iMCD groups, but both patients failing anti-IL6 therapy had TAFRO-iMCD. Six TAFRO-iMCD patients received chemotherapy and 2 relapsed. Six patients with POEMS and CD underwent autologous stem cell transplant with major improvement in polyneuropathy and MCD; 2 experienced relapse of their MCD and one died of late myelodysplastic syndrome. One improved post irradiation of a plasmacytoma and 1 died of progressive disease. Most MCD patients with POEMS features received rituximab-based therapies; 6/7 were alive and 1 died of sepsis. There was no difference in overall survival (OS) among the three groups (p=0.35) with a median OS of 5.65 years (4 - 9.2, 95% CI) in the iMCD group, 7.9 years (4.5 - 11.8, 95% CI) in POEMS-associated MCD, and 5.85 years (3.2 - 8.7, 95% CI) in the TAFRO group. The 5-year OS was 91%, 94% and 100% for the iMCD, POEMS-associated MCD and TAFRO groups, respectively.Conclusions. In a tertiary referral setting, excellent outcomes were achieved in all subgroups, likely attributed to highly selective therapeutic choices. Anti-IL6 therapy for iMCD was reserved for patients with active disease and laboratory evidence of inflammatory syndrome. Some TAFRO-iMCD patients achieved complete responses with anti-IL6 therapy, while others fared well with chemotherapy. Rituximab-based therapy was given to those with more indolent iMCD and those with POEMS-associated MCD. The polyneuropathy of POEMS benefitted most from transplant. Significant differences were noted in VEGF levels both in POEMS-associated MCD and TAFRO-iMCD compared to classical iMCD cases, with each cohort presenting a distinct clinical picture suggesting differing underlying etiologies and cytokine profiles. IL6 levels were not different among groups, though this may be confounded by effects of prior therapy. A better understanding of the pathobiology of the MCD continuum is essential to developing more targeted therapies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

IL-6 Receptor Antibody Preferentially Affects Tumors in the Repopulation Phase of Growth

IL-6 increases tumorigenic potential of primary human cancer stem cells. The goal of our study was to determine if an IL-6 receptor antibody (Tocilizumab) has an impact on tumor growth. IACUC approval was obtained before starting the experiments. The HNSCC cell line UT-SCC-14 was used for all experiments. A MTT assay was used to establish any effect of tocilizumab on cell growth. The effect of tocilizumab on clonogenic survival was also assessed. In the first set of experiments, a four armed study looked at tumor volume of flank tumors treated with a sham antibody (sham), tocilizumab (TOC), radiation (RT), and tocilizumab + radiation (TOC + RT). In the second set of experiments, a three arm study looked at flow cytometry stained for aldehyde dehydrogenase (ALDH) and CD44 at day 22, 30, and 43 with TOC, RT, TOC + RT for ex-vivo flank tumors. There was no significant difference in clonogenic survival in TOC versus the control. There was also no correlation with increasing concentration of TOC. In experiment 1, the TOC + RT had significantly smaller tumor volumes compared to the RT alone group at days 25 and 37 while trended for smaller tumor volumes at days 29 and 32. In experiment 2, the TOC + RT had significantly smaller tumor volumes compared to the RT alone group at days 31 and 35. On flow cytometry, ALDH(+) CD44(-) population significantly increased during day 30 in the TOC + RT group compared to both the TOC alone and RT alone. IL-6 receptor antibody has no effect on in vitro cell survival but does impact in vivo repopulation with an increase in non-cancer stem cells. Further studies are necessary to validate improvement with chemotherapy.

Recovery of respiratory function in mdx mice co-treated with neutralizing interleukin-6 receptor antibodies and urocortin-2.

Impaired ventilatory capacity and diaphragm muscle weakness are prominent features of Duchenne muscular dystrophy, with strong evidence of attendant systemic and muscle inflammation. We performed a 2-week intervention in young wild-type and mdx mice, consisting of either injection of saline or co-administration of a neutralizing interleukin-6 receptor antibody (xIL-6R) and urocortin-2 (Ucn2), a corticotrophin releasing factor receptor 2 agonist. We examined breathing and diaphragm muscle form and function. Breathing and diaphragm muscle functional deficits are improved following xIL-6R and Ucn2 co-treatment in mdx mice. The functional improvements were associated with a preservation of mdx diaphragm muscle myosin heavy chain IIx fibre complement. The concentration of the pro-inflammatory cytokine interleukin-1β was reduced and the concentration of the anti-inflammatory cytokine interleukin-10 was increased in mdx diaphragm following drug co-treatment. Our novel findings may have implications for the development of pharmacotherapies for the dystrophinopathies with relevance for respiratory muscle performance and breathing. The mdx mouse model of Duchenne muscular dystrophy shows evidence of hypoventilation and pronounced diaphragm dysfunction. Six-week-old male mdx (n= 32) and wild-type (WT; n= 32) mice received either saline (0.9% w/v) or a co-administration of neutralizing interleukin-6 receptor antibodies (xIL-6R; 0.2mgkg-1 ) and corticotrophin-releasing factor receptor 2 agonist (urocortin-2; 30μgkg-1 ) subcutaneously over 2weeks. Breathing and diaphragm muscle contractile function (ex vivo) were examined. Diaphragm structure was assessed using histology and immunofluorescence. Muscle cytokine concentration was determined using a multiplex assay. Minute ventilation and diaphragm muscle peak force at 100Hz were significantly depressed in mdx compared with WT. Drug treatment completely restored ventilation in mdx mice during normoxia and significantly increased mdx diaphragm force- and power-generating capacity. The number of centrally nucleated muscle fibres and the areal density of infiltrates and collagen content were significantly increased in mdx diaphragm; all indices were unaffected by drug co-treatment. The abundance of myosin heavy chain (MyHC) typeIIx fibres was significantly decreased in mdx diaphragm; drug co-treatment preserved MyHC typeIIx complement in mdx muscle. Drug co-treatment increased the cross-sectional area of MyHC typeI and IIx fibres in mdx diaphragm. The cytokines IL-1β, IL-6, KC/GRO and TNF-α were significantly increased in mdx diaphragm compared with WT. Drug co-treatment significantly decreased IL-1β and increased IL-10 in mdx diaphragm. Drug co-treatment had no significant effect on WT diaphragm muscle structure, cytokine concentrations or function. Recovery of breathing and diaphragm force in mdx mice was impressive in our studies, with implication for human dystrophinopathies.

Tocilizumab in patients with adult-onset still’s disease refractory to glucocorticoid treatment: a randomised, double-blind, placebo-controlled phase III trial

ObjectiveTo evaluate the efficacy and safety of tocilizumab, an interleukin-6 receptor antibody, in patients with adult-onset Still’s disease.MethodsIn this double-blind, randomised, placebo-controlled phase III trial, 27 patients with adult-onset Still’s...

Doxorubicin resistance induces IL6 activation in the colon cancer cell line LS180.

Despite improvements in the development of drugs for the treatment of cancer, drug resistance remains a major obstacle. In colon cancer, following an initially promising response, patients develop drug resistance, which impacts the efficacy and halts the response of cancerous cells towards drugs. In the present study, a phosphatase and tensin homolog (PTEN) knockdown model of LS180 cells, doxorubicin-resistant models of LS180 cells as well as doxorubicin-resistant LS180 (PTEN) knockdown model were established. The present study demonstrated that doxorubicin resistance led to the activation of interleukin (IL)6 signalling pathway which was enhanced by knockdown of PTEN. There was also an increase in the levels of IL8 and IL2 which were further enchanced by knockdown of PTEN. Doxorubicin resistance also led to an increase in the population of cancer stem cells in LS180 and shPTEN-treated LS180 cells. Notably, doxorubicin resistance also induced epithelial to mesenchymal transition and increased the formation of mammospheres. Furthermore, the present study also reported that IL6 receptor antibody not only decreased IL6 levels but also led to a significant decreased number of cancer stem cell like population and mammosphere formation. In conclusion, in the present study it was demonstrated that doxorubicin resistance led to activation of IL6 signalling pathway which was further elevated by the knockdown of PTEN in the colon cancer cell line LS180. Thus, inhibiting the IL6 loop may provide an alternative pathway to tackle doxorubicin resistance.

Suppression of SOCS3 enhances TRAIL-induced cell growth inhibition through the upregulation of DR4 expression in renal cell carcinoma cells.

BackgroundTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a tumor-selective apoptosis inducer that is expressed in natural killer cells, whose cytotoxicity is activated by interferon (IFN). We investigated the effect of suppressor of cytokine signaling (SOCS) 3 on the expression of TRAIL receptors (DR4) and on TRAIL sensitivity in renal cell carcinoma (RCC) cells.MethodsVector expression, RNA interference and IL-6 receptor antibody tocilizumab were used to investigate the functional role of SOCS3 in DR4 expression. Immunoprecipitation was employed to detect the biochemical interaction between SOCS3 and DR4. The expression of DR4 induced by combination with IFN-α and tocilizumab was also examined by immunohistochemical staining using mice xenograft model.ResultsDR4 expression was up-regulated by IFN stimulation in RCC cells. 786-O cells were resistant to TRAIL and showed higher SOCS3 expression. ACHN cells showed higher DR4 expression and lower SOCS3 expression. Suppression of SOCS3 up-regulated DR4 expression and enhanced the TRAIL sensitivity in 786-O cells. In ACHN cells, DR4 expression was down-regulated by transfection with pCI-SOCS3, and the cells became resistant to TRAIL. Immunoprecipitation revealed the biochemical interaction between SOCS3 and DR4. A marked increase in IFN-induced DR4 protein expression after tocilizumab treatment was observed by immunohistochemical staining in the tumor from the mice xenograft model.ConclusionsOur results indicate that IFN and SOCS3 regulate DR4 expression in RCC cells. Combination therapy with IFN-α, tocilizumab and an anti-DR4 agonistic ligand appears to effectively inhibit advanced RCC cell growth.

SOCS3 Suppression Promoted the Recruitment of CD11b+Gr-1-F4/80-MHCII- Early-Stage Myeloid-Derived Suppressor Cells and Accelerated Interleukin-6-Related Tumor Invasion via Affecting Myeloid Differentiation in Breast Cancer.

Interleukin-6 (IL-6) is an important trigger for the expansion and recruitment of myeloid-derived suppressor cells (MDSCs), which are regarded to be major coordinators of the immunosuppressive tumor microenvironment. In this study, we constructed IL-6-knockdown breast cancer mice models to explore the molecular events involved in the IL-6-mediated effects on MDSC development. We defined a subset of early-stage MDSCs (e-MDSCs) with the phenotype of CD11b+Gr-1−F4/80−MHCII− in IL-6 high-expressing 4T1 mice mammary carcinoma models, which were the precursors of CD11b+Gr-1+ conventional MDSCs. Furthermore, sustained suppression of SOCS3 and aberrant hyperactivation of the JAK/STAT signaling pathway was exclusively detected in wide-type 4T1 tumor-bearing mice, which promoted the accumulation of e-MDSCs in situ and their immunosuppressive capability in vitro. After blocking the IL-6/STAT3 signaling pathway with the IL-6 receptor antibody or STAT3 antagonist JSI-124 in tumor-bearing mice, significant shrinkage of primary tumors and decrease in lung metastatic nodules were observed in vivo, accompanied by the dramatic decrease of e-MDSC recruitment and recovery of anti-tumor T cell immunity. Thus, SOCS3 suppression accelerated the IL-6-mediated growth and metastasis of mammary carcinoma via affecting myeloid differentiation in breast cancer. Moreover, the IL-6/STAT3 signaling pathway might be a promising candidate target in developing novel therapeutic strategies to eliminate e-MDSCs and improve breast cancer prognosis.

IL6/STAT3 axis mediates resistance to BRAF inhibitors in thyroid carcinoma cells

Thyroid carcinomas (TCs) bearing BRAF mutations represent approximately 26–53% of human thyroid malignancies and, differently from melanomas, are poorly sensitive to BRAF inhibitors (BRAFi), and develop acquired resistance through activation of alternative signaling pathways. A whole-genome gene expression analysis of TC BRAF V600E cells exposed to PLX4032 identified JAK/STAT among the most significantly modulated signaling pathways. Interestingly, both transient exposure and chronic adaptation to PLX4032 resulted in upregulation of IL6/STAT3 axis and this impaired the cytostatic activity of PLX4032. Mechanistically, exposure to PLX4032 enhanced IL6 secretion and this, in turn, was responsible for STAT3 upregulation, activation of ERK signaling and poor sensitivity to BRAF inhibition. Consistently, the dual blockade of STAT3 (by siRNA or pharmacological inhibition) or IL6 signaling (by the humanized anti-human IL6 receptor antibody, tocilizumab) and BRAF (by PLX4032) improved the inhibition of cell cycle progression compared to PLX4032 single agent. These data support the role of IL6/STAT3 signaling pathway in modulating TC cell response to PLX4032 and candidate IL6 targeting as a strategy to improve the activity of PLX4032 in BRAF V600E TC cells.

Abstract 925: In silico models accurately predict in vivo response for IL-6 blockade in head and neck cancer

Abstract The purpose of this study is to create and validate a mathematical model describing the effect of interleukin-6 (IL-6) on head and neck cancer growth and cancer stem cell fraction. Head and Neck Squamous Cell Carcinoma (HNSCC) is the seventh most-common solid tumor with about 55,000 new cases diagnosed every year. Malignant features of HNSCC cells are derived from a shift towards more stem-like features, as postulated by the cancer stem cell (CSC) hypothesis. CSCs encompass a unique cellular subpopulation characterized by multipotency, uniquely high tumorigenic potential, and self-renewal. These cells function as putative drivers of tumor initiation, therapeutic evasion, metastasis, and recurrence. Though they are an appealing conceptual target, CSC directed cancer therapies remain scarce. High levels of both serum IL-6 and tumor IL-6 receptor (IL-6R) expression are strongly correlated with poor patient survival. Endothelial cell-secreted IL-6 enhances the tumorigenic potential and self-renewal of head and neck CSCs. Furthermore, interruption of the IL-6 pathway results in a decreased fraction of HNSCC CSCs. Efficacy and optimal administration of the FDA approved rheumatoid arthritis IL-6R antibody Tocilizumab in HNSCC is not known. Here we used a multi-scale mathematical model that operates at the intracellular, molecular, and tissue level to investigate the impacts of endothelial cell-secreted IL-6 signaling on the crosstalk between tumor cells and ECs during tumor growth. This endothelial cell - tumor cell (EC-TC) model was used to study the effect of tocilizumab treatment on HNSCC, and particularly the CSC fraction. Our ordinary differential equation model is the first of its kind to include full occupancy dynamics between endothelial-cell produced IL-6, IL-6R, and the competitive IL-6R inhibitor Tocilizumab. In order to biologically validate the utility of our mathematical model, we performed a series of in-vivo experiments using HNSCC cell lines and human endothelial cells co-embedded in a porous scaffold and implanted in SCID mice flank. Tumor volumes were measured serially. CSC fraction was determined in HNSCC cell lines using flow cytometry for aldehyde dehydrogenase (ALDH) high/CD44 high proportion. Without artificial tuning to the laboratory data, our model provided superb predictive agreement to the decrease in tumor volumes observed in TCZ treated mice (r = 0.947, p &amp;lt; 0.0001), as well as a decrease in CSC fraction. This predictive in-silico framework can serve to rapidly evaluate dosing strategies for IL-6 pathway modulation, as well as providing the basis for proposing combination treatments with IL-6 blockade and cytotoxic or other targeted therapies. Citation Format: Fereshteh Nazari, Alexandra E. Oklejas, Jacques E. Nör, Alexander T. Pearson, Trachette L. Jackson. In silico models accurately predict in vivo response for IL-6 blockade in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 925.

My burning issues in aggressive Non Hodgkin’s Lymphoma

Combined-modality treatment with chemo-immunotherapy and radiotherapy produces excellent outcomes in early-stage, non-bulky diffuse large B‑cell lymphoma, and reducing toxicity of therapy is a major concern, especially in elderly patients. In a recent trial, elderly patients with non-bulky (<7.5 cm) in complete metabolic remission after four courses of therapy (rituximab, cyclophosphamide, doxorubicine, vincristine, prednisone [R‑CHOP-14] based) were spared additional chemotherapy and went on to receive four cycles of rituximab only, while all other patients continued on chemo-immunotherapy. The 2‑year overall survival was 98%, which matches historical controls. In another analysis from the same trial, elderly patients with bulky disease in positrone emission tomography (PET) based CR (complete remission) after six cycles of chemo-immunotherapy were spared radiotherapy, while PET-positive patients were irradiated. This approach resulted in a significant reduction (42%) of radiotherapy compared to historical controls without compromising efficacy. Radiotherapy could also be omitted in patients of any age with limited stage, non-bulky disease in another trial, with a 5-year event-free survival of 89% and an overall survival of 92%. Another burning issue is enhancing efficacy in relapsed and refractory diffuse large B‑cell lymphoma. Arguably the most exciting approach in this area is chimeric-antigen-receptor T‑cell therapy. Recent trials have shown nearly 10-fold increases in complete responses compared to historical controls, and most importantly, a high percentage (40%) of durable remissions after one year of follow-up. As in other advances in immunotherapy, toxicity is a major concern. Cytokine release syndrome occurs frequently (1–18% grade 3–4) and management is complex, sometimes requiring admission to intensive care and often including the interleukin-6 receptor antibody tocilizumab.

IL-6 knockout mice are protected from cocaine-induced kindling behaviors; possible involvement of JAK2/STAT3 and PACAP signalings

IL-6 has been recognized as an anticonvulsant against certain neuroexcitotoxicities. We aimed to investigate on the interactive role between IL-6 and PACAP in cocaine-induced kindling behaviors. Although we found that cocaine (45 mg/kg, i.p./day x 5) significantly increased IL-6 and TNF-α expression, it resulted in a decrease in IFN-γ expression. We observed that the cocaine-induced increase in IL-6 expression was more pronounced than that in TNF-α expression. Genetic depletion of IL-6 significantly activated cocaine kindling behaviors. This phenomenon was also consistently observed in WT mice that received a neutralizing IL-6 receptor antibody. Cocaine-treated IL-6 knockout mice exhibited significantly decreased PACAP and PACAP receptor (PAC1R) mRNA levels and significantly increased TNF-α gene expression. TNF-α knockout mice were protected from cocaine kindling via an up-regulation of IL-6, phospho-JAK2/STAT3, PACAP, and PAC1R levels, which produced anti-apoptotic effects. Recombinant IL-6 protein (rIL-6, 2 μg, i.v./mouse/day x 5) also up-regulated phospho-JAK2/STAT3, PACAP, and PAC1R mRNA levels, leading to anti-apoptotic effects in IL-6 knockout mice. Consistently, AG490, a JAK2/STAT3 inhibitor, and PACAP 6–38, a PAC1 receptor antagonist, counteracted rIL-6-mediated protection. Combined, our results suggest that IL-6 gene requires up-regulation of phospho-JAK2/STAT3, PACAP, and PAC1R and down-regulation of the TNF-α gene to modulate its anticonvulsive/neuroprotective potential.

Anti-interleukin-6 receptor antibody prevents loss of bone structure and bone strength in collagen-induced arthritis mice

Objective: Rheumatoid arthritis (RA) is a disease that typically induces secondary osteoporosis, which increases the risk of bone fractures. Anti-interleukin-6 (IL-6) receptor antibody is used to treat RA; however, its effect on bone strength is not clear. Therefore, we investigated the influence of MR16-1, an anti-mouse IL-6 receptor antibody, on bone structure and femoral strength in a collagen-induced arthritis (CIA) mouse model.Method: DBA/1J mice were immunized by intradermal injection of bovine type II collagen. MR16-1 was administered intraperitoneally at the same time as immunization. Thirty-five days after the first immunization, bone structure and bone strength were measured by micro-computed tomography and the three-point bending test.Results: In the CIA group, most bone mineral density and bone structure parameters in the foot, femur, and lumbar spine were significantly lower than in the normal group. Moreover, the maximum load of the femoral shaft in the CIA group was significantly lower than in the normal group. MR16-1 treatment significantly prevented the CIA-induced deterioration of bone structure and loss of bone strength.Conclusion: These results suggest that CIA systemically induces a deterioration of bone structure and loss of bone strength, and that IL-6 signalling plays an important role in these processes.

Efficacy and safety of monotherapy with sirukumab compared with adalimumab monotherapy in biologic-naïve patients with active rheumatoid arthritis (SIRROUND-H): a randomised, double-blind, parallel-group, multinational, 52-week, phase 3 study

ObjectiveThis randomised, double-blind, parallel-group, phase 3 study compared monotherapy with sirukumab, an anti–interleukin-6 cytokine monoclonal antibody, with adalimumab monotherapy in patients with rheumatoid arthritis (RA).MethodsBiologic-naïve patients with active RA who...

Inhibition of interleukin-6 decreases atrogene expression and ameliorates tail suspension-induced skeletal muscle atrophy.

BackgroundInterleukin-6 (IL-6) is an inflammatory cytokine. Whether systemic IL-6 affects atrogene expression and disuse-induced skeletal muscle atrophy is unclear.MethodsTail-suspended mice were used as a disuse-induced muscle atrophy model. We administered anti-mouse IL-6 receptor antibody, beta-hydroxy-beta-methylbutyrate (HMB) and vitamin D to the mice and examined the effects on atrogene expression and muscle atrophy.ResultsSerum IL-6 levels were elevated in the mice. Inhibition of IL-6 receptor suppressed muscle RING finger 1 (MuRF1) expression and prevented muscle atrophy. HMB and vitamin D inhibited the serum IL-6 surge, downregulated the expression of MuRF1 and atrogin-1 in the soleus muscle, and ameliorated atrophy in the mice.ConclusionSystemic IL-6 affects MuRF1 expression and disuse-induced muscle atrophy.

IL-6 receptor blockade ameliorates diabetic nephropathy via inhibiting inflammasome in mice

Background and ObjectiveInterleukin 6 (IL-6) has been identified as a key mediator in inflammation, immune responses and glucose metabolism. In this study, we assessed the effects of an IL-6 receptor antibody on diabetic nephropathy in a mouse model of type 2 diabetes mellitus. MethodsTwelve week old male db/db mice were treated with Tocilizumab (an IL-6 receptor antibody), normal IgG1 control antibody, insulin or normal saline for 12 weeks. Renal injury, inflammation and insulin resistance were assessed. ResultsDb/db mice treated with Tocilizumab exhibited reduced proteinuria and glomerular mesangial matrix accumulation compared to db/db + IgG controls. Additionally, Tocilizumab suppressed inflammatory response, oxidative stress and the IL-6 signaling pathway in the diabetic kidneys. It is noteworthy that blockade of IL-6 receptor blunted the activation of NLRP3 inflammasome partly through inhibition of IL-17A. Furthermore, insulin resistance assessed by glucose tolerance test, was ameliorated by Tocilizumab treatment. ConclusionsThe protective effects of an IL-6 receptor blockade against diabetic renal injury may be due to decreased insulin resistance and inhibition of the inflammasome.