Cutting edge: Inhibition of IL-6 trans-signaling protects from malaria-induced lethality in mice.

Circulating IL-6 levels correlate with the severity of blood-stage malaria in humans and mouse models, but the impact of IL-6 classic signaling through membrane IL-6Rα, as well as IL-6 trans-signaling through soluble IL-6Rα, on the outcome of malaria has remained unknown. In this study, we created IL-6Rα-deficient mice that exhibit a 50% survival of otherwise lethal blood-stage malaria of the genus Plasmodium chabaudi. Inducing IL-6 trans-signaling by injection of mouse recombinant soluble IL-6Rα in IL-6Rα-deficient mice restores the lethal outcome to malaria infection. In contrast, inhibition of IL-6 trans-signaling via injection of recombinant sGP130Fc protein in control mice results in a 40% survival rate. Our data demonstrate that IL-6 trans-signaling, rather than classic IL-6 signaling, contributes to malaria-induced lethality in mice, preceded by an increased inflammatory response. Therefore, inhibition of IL-6 trans-signaling may serve as a novel promising therapeutic basis to combat malaria.

Update of sarilumb to treat rheumatoid arthritis based on randomized clinical trials: a systematic review.

INTRODUCTION: Sarilumab is a human monoclonal antibody against Interleukin 6 α (IL-6α) receptor. Compared to tocilizumab, another IL-6 α receptor antibody, sarilumab has a different structure and higher affinity. Areas covered: In a systematic literature review, we examined all sarilumab randomized clinical trials (RCTs) in rheumatoid arthritis. The 6 reviewed RCTs included patients who were inadequate MTX, DMARD and/or TNFi responders. Sarilumab 150-200 mg every 2 weeks improved RA signs, symptoms, function and decreased radiological progression up to 52 weeks. The most common adverse events were infections and neutropenia, the latter of which will require careful observation in future trials. Examination of the effect of sero-positivity, disease duration, presence of erosions, use of previous biologic and comparisons to other biologics etc are still needed to complete understanding of this drug's profile. Long term studies, too, will be needed to assess long term tolerability Expert commentary: Results support the use of sarilumab to treat RA patients with inadequate response to MTX, other DMARDs and TNFis, although further studies are needed to fully assess its toxicity and understand the specific place of sarilumab in the RA armamentarium.

An affibody-adalimumab hybrid blocks combined IL-6 and TNF-triggered serum amyloid A secretion in vivo.

In inflammatory disease conditions, the regulation of the cytokine system is impaired, leading to tissue damages. Here, we used protein engineering to develop biologicals suitable for blocking a combination of inflammation driving cytokines by a single construct. From a set of interleukin (IL)-6-binding affibody molecules selected by phage display, five variants with a capability of blocking the interaction between complexes of soluble IL-6 receptor α (sIL-6Rα) and IL-6 and the co-receptor gp130 were identified. In cell assays designed to analyze any blocking capacity of the classical or the alternative (trans) signaling IL-6 pathways, one variant, ZIL-6_13 with an affinity (KD) for IL-6 of ∼500 pM, showed the best performance. To construct fusion proteins ("AffiMabs") with dual cytokine specificities, ZIL-6_13 was fused to either the N- or C-terminus of both the heavy and light chains of the anti-tumor necrosis factor (TNF) monoclonal antibody adalimumab (Humira®). One AffiMab construct with ZIL-6_13 positioned at the N-terminus of the heavy chain, denoted ZIL-6_13-HCAda, was determined to be the most optimal, and it was subsequently evaluated in an acute Serum Amyloid A (SAA) model in mice. Administration of the AffiMab or adalimumab prior to challenge with a mix of IL-6 and TNF reduced the levels of serum SAA in a dose-dependent manner. Interestingly, the highest dose (70 mg/kg body weight) of adalimumab only resulted in a 50% reduction of SAA-levels, whereas the corresponding dose of the ZIL-6_13-HCAda AffiMab with combined IL-6/TNF specificity, resulted in SAA levels below the detection limit.

Tumor dormancy resulting from subcutaneous injection to SCID mice with cultured nasopharyngeal carcinoma cells is mediated via IFN-γ induction of a highly differentiated phenotype.

The mechanisms underlying tumor dormancy in human primary lesions and bone marrow metastases of nasopharyngeal carcinoma (NPC) are still not completely understood. The aim of this study was to determine differences in the fates of cultured primary NPC (P-NPC) cells, interferon-γ-transduced primary NPC (IFN-γ-P-NPC) cells, bone marrow metastatic NPC (BM-NPC), and IFN-γ-transduced BM-NPC (IFN-γ-BM-NPC) cells following xenotransplantation into these four groups of SCID mice through subcutaneous injection of 5×10(6) cells/site/animal (4 animals/group). The injected mice were monitored for tumor development at the sites of injection. In only the group injected with IFN-γ-P-NPC cells, the resulting nodules remained small throughout the 60-day observation period after injection, but gradually became palpably prickly. Histopathological examination revealed that these lesions invariably consisted of mostly structures of horny pearls and keratin bridges with occasional apoptotic and degenerative cells. In contrast, animals injected with nontransduced-P-NPC cells developed tumors progressively with occasional central necroses. In the two groups injected with IFN-γ-NPC-BM and NPC-BM cells, progressive growths of tumors were noted, with the latter being at slightly faster rates, whereas the xenografts of both groups showed a poorly differentiated phenotype with abundant vascularity. The study results highlight the high susceptibility of P-NPC but not BM-NPC following IFN-γ gene transfer to the induction of tumor dormancy, which is mediated via induced cell differentiation. Thus, induced cell differentiation could provide a new mechanism by which tumor dormancy is induced.

Interleukin-6: from identification of the cytokine to development of targeted treatments.

Interleukin-6 (IL-6) was identified based on extensive research conducted simultaneously on a variety of topics ranging from hepatocyte production of acute-phase proteins to plasmacytoma growth. IL-6 is a cytokine produced by a broad array of cell types and can exert its effects on virtually all cells. IL-6 can induce cell signaling not only via the classic pathway involving the transmembrane receptor IL-6Rα (restricted cellular expression) associated with gp130 (ubiquitous and responsible for signal transmission), but also via the soluble receptor IL-6Rα, which binds to IL-6 and induces a signal mediated by the ubiquitous gp130 molecule (transsignaling). IL-6 is deregulated in many inflammatory and autoimmune diseases, including rheumatoid arthritis (RA). By virtue of its multiple effects, IL-6 is involved in the various phases of RA development, including the acute phase, immuno-inflammatory phase, and destructive phase. IL-6 has an impact on the many pathogenic factors identified in RA and, consequently, holds promise for targeted treatments. However, anti-IL-6 monoclonal antibodies evaluated as IL-6 antagonists, instead, increased the half-life of the cytokine. In contrast, monoclonal antibody (tocilizumab) to transmembrane and soluble IL-6Rα has been found effective in patients with RA. Tocilizumab is now indicated for the treatment of adults with RA who have failed at least one synthetic disease-modifying antirheumatic drug or TNFα antagonist.

Chemokine-guided CD4+ T cell help enhances generation of IL-6RalphahighIL-7Ralpha high prememory CD8+ T cells.

CD4(+) T cells promote effective CD8(+) T cell-mediated immunity, but the timing and mechanistic details of such help remain controversial. Furthermore, the extent to which innate stimuli act independently of help in enhancing CD8(+) T cell responses is also unresolved. Using a noninfectious vaccine model in immunocompetent mice, we show that even in the presence of innate stimuli, CD4(+) T cell help early after priming is required for generating an optimal pool of functional memory CD8(+) T cells. CD4(+) T cell help increased the size of a previously unreported population of IL-6Ralpha(high)IL-7Ralpha(high) prememory CD8(+) T cells shortly after priming that showed a survival advantage in vivo and contributed to the majority of functional memory CD8(+) T cells after the contraction phase. In accord with our recent demonstration of chemokine-guided recruitment of naive CD8(+) T cells to sites of CD4(+) T cell-dendritic cell interactions, the generation of IL-6Ralpha(high)IL-7Ralpha(high) prememory as well as functional memory CD8(+) T cells depended on the early postvaccination action of the inflammatory chemokines CCL3 and CCL4. Together, these findings support a model of CD8(+) T cell memory cell differentiation involving the delivery of key signals early in the priming process based on chemokine-guided attraction of naive CD8(+) T cells to sites of Ag-driven interactions between TLR-activated dendritic cells and CD4(+) T cells. They also reveal that elevated IL-6Ralpha expression by a subset of CD8(+) T cells represents an early imprint of CD4(+) T cell helper function that actively contributes to the survival of activated CD8(+) T cells.