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Key Points The type I interferon (IFN) system involves a single form of IFNβ, several variants of IFNα and other less well-characterized IFNs, all of which signal via a heterodimeric IFNα/β receptor 1 (IFNAR1)–IFNAR2 receptor to transactivate IFN-stimulated genes (ISGs). IFNβ also promotes the transactivation of ISGs through homodimeric IFNAR1. The secretion of type I IFNs is stimulated by viral constituents, as well as by danger signals emitted by dying cells, including nuclear and mitochondrial nucleic acids found at ectopic locations. The production of type I IFNs has marked antiviral and immunostimulatory effects. Beyond their role in curtailing viral infection, type I IFNs play an essential part in natural cancer immunosurveillance, functioning both at the level of malignant cell precursors and through effects on the immune system. Thus, the knockout of Ifnar1 in mouse epithelial cells predisposes them to malignant transformation, as does the knockout of Ifnar1 in leukocytes, especially dendritic cells. Type I IFN signalling is also essential for the full-blown efficacy of various anticancer agents, including chemotherapeutics (such as anthracyclines), antibodies that target growth factor receptors (such as human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR)), the injection of adjuvants and oncolytic virotherapy. The expression levels of ISGs constitute a positive prognostic or predictive biomarker in patients affected by several cancers including melanoma and breast carcinoma. Recombinant type I IFNs have been successfully used for the treatment of various human neoplasms, particularly ulcerative melanoma, renal cell carcinoma and hepatitis B virus (HBV)-induced hepatocellular carcinoma. Preclinical data identify four distinct approaches to improve the targeted delivery of type I IFNs to malignant lesions: first, fusing or linking recombinant type I IFNs to antibodies specific for tumour-associated surface antigens; second, engineering leukocytes or mesenchymal stem cells to express type I IFNs once they have infiltrated neoplastic lesions; third, injecting type I IFN-encoding vectors into the tumour mass; and fourth, supplying artificial ligands of type I IFN-stimulating pattern recognition receptors (PRRs). Type I interferons (IFNs) are best known for their role in antiviral immunity. As discussed in this Review, recent evidence indicates that these cytokines also have an integral role in natural and therapy-induced anticancer immunity. Harnessing the antineoplastic properties of type I IFNs may lead to the development of ever-more effective anticancer therapies. Type I interferons (IFNs) are known for their key role in antiviral immune responses. In this Review, we discuss accumulating evidence indicating that type I IFNs produced by malignant cells or tumour-infiltrating dendritic cells also control the autocrine or paracrine circuits that underlie cancer immunosurveillance. Many conventional chemotherapeutics, targeted anticancer agents, immunological adjuvants and oncolytic viruses are only fully efficient in the presence of intact type I IFN signalling. Moreover, the intratumoural expression levels of type I IFNs or of IFN-stimulated genes correlate with favourable disease outcome in several cohorts of patients with cancer. Finally, new anticancer immunotherapies are being developed that are based on recombinant type I IFNs, type I IFN-encoding vectors and type I IFN-expressing cells.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic. An unbalanced immune response, characterized by a weak production of type I interferons (IFN-Is) and an exacerbated release of proinflammatory cytokines, contributes to the severe forms of the disease. SARS-CoV-2 is genetically related to SARS-CoV and Middle East respiratory syndrome-related coronavirus (MERS-CoV), which caused outbreaks in 2003 and 2013, respectively. Although IFN treatment gave some encouraging results against SARS-CoV and MERS-CoV in animal models, its potential as a therapeutic against COVID-19 awaits validation. Here, we describe our current knowledge of the complex interplay between SARS-CoV-2 infection and the IFN system, highlighting some of the gaps that need to be filled for a better understanding of the underlying molecular mechanisms. In addition to the conserved IFN evasion strategies that are likely shared with SARS-CoV and MERS-CoV, novel counteraction mechanisms are being discovered in SARS-CoV-2-infected cells. Since the last coronavirus epidemic, we have made considerable progress in understanding the IFN-I response, including its spatiotemporal regulation and the prominent role of plasmacytoid dendritic cells (pDCs), which are the main IFN-I-producing cells. While awaiting the results of the many clinical trials that are evaluating the efficacy of IFN-I alone or in combination with antiviral molecules, we discuss the potential benefits of a well-timed IFN-I treatment and propose strategies to boost pDC-mediated IFN responses during the early stages of viral infection.

Effective antitumor immunity in mice requires activation of the type I interferon (IFN) response pathway. IFNα and IFNβ therapies have proven promising in humans, but suffer from limited efficacy and high toxicity. Intratumoral IFN retention ameliorates systemic toxicity, but given the complexity of IFN signaling, it was unclear whether long-term intratumoral retention of type I IFNs would promote or inhibit antitumor responses. To this end, we compared the efficacy of IFNα and IFNβ that exhibit either brief or sustained retention after intratumoral injection in syngeneic mouse tumor models. Significant enhancement in tumor retention, mediated by anchoring these IFNs to coinjected aluminum-hydroxide (alum) particles, greatly improved both their tolerability and efficacy. The improved efficacy of alum-anchored IFNs could be attributed to sustained pleiotropic effects on tumor cells, immune cells, and nonhematopoietic cells. Alum-anchored IFNs achieved high cure rates of B16F10 tumors upon combination with either anti-PD-1 antibody or interleukin-2. Interestingly however, these alternative combination immunotherapies yielded disparate T cell phenotypes and differential resistance to tumor rechallenge, highlighting important distinctions in adaptive memory formation for combinations of type I IFNs with other immunotherapies.

Natural Killer (NK) cells are innate immune responders critical for viral clearance and immunomodulation. Despite their vital role in viral infection, the contribution of NK cells in fighting SARS-CoV-2 has not yet been directly investigated. Insights into pathophysiology and therapeutic opportunities can therefore be inferred from studies assessing NK cell phenotype and function during SARS, MERS, and COVID-19. These studies suggest a reduction in circulating NK cell numbers and/or an exhausted phenotype following infection and hint toward the dampening of NK cell responses by coronaviruses. Reduced circulating NK cell levels and exhaustion may be directly responsible for the progression and severity of COVID-19. Conversely, in light of data linking inflammation with coronavirus disease severity, it is necessary to examine NK cell potential in mediating immunopathology. A common feature of coronavirus infections is that significant morbidity and mortality is associated with lung injury and acute respiratory distress syndrome resulting from an exaggerated immune response, of which NK cells are an important component. In this review, we summarize the current understanding of how NK cells respond in both early and late coronavirus infections, and the implication for ongoing COVID-19 clinical trials. Using this immunological lens, we outline recommendations for therapeutic strategies against COVID-19 in clearing the virus while preventing the harm of immunopathological responses.

To analyze the susceptibility of SARS-CoV-2 in pregnancy and the drugs that can be used to treat pregnancy with COVID-19, so as to provide evidence for drug selection in clinic. By reviewing the existing literature, this paper analyzes the susceptibility of pregnant women to virus, especially to SARS-CoV-2, from the aspects of anatomical, reproductive endocrine and immune changes during pregnancy and screens effective and fetal-safe treatments from the existing drugs. The anatomical structure of the respiratory system is changed during pregnancy, and the virus transmitted by droplets and aerosols is more easily inhaled by pregnant women and is difficult to remove. Furthermore, the prognosis is worse after infection when compared with non-pregnancy women. And changes in reproductive hormones and immune systems during pregnancy collectively make them more susceptible to certain infections. More importantly, angiotensin-converting enzyme (ACE)-2, the SARS-CoV-2 receptor, has been proven highly increased during pregnancy, which may contribute to the susceptibility to SARS-CoV-2. When it comes to treatment, specific drugs for COVID-19 have not been found at present, and taking old drugs for new use in treating COVID-19 has become an emergency method for the pandemic. Particularly, drugs that show superior maternal and fetal safety are worthy of consideration for pregnant women with COVID-19, such as chloroquine, metformin, statins, lobinavir/ritonavir, glycyrrhizic acid, and nanoparticle-mediated drug delivery (NMDD), etc. Pregnant women are susceptible to COVID-19, and special attention should be paid to the selection of drugs that are both effective for maternal diseases and friendly to the fetus. However, there are still many deficiencies in the study of drug safety during pregnancy, and broad-spectrum, effective and fetal-safe drugs for pregnant women need to be developed so as to cope with more infectious diseases in the future.

Psoriasis is an immune-mediated disease, with the interleukin (IL)-23/IL-17 axis currently considered its main pathogenic pathway. Tyrosine kinase 2 (TYK2) is responsible for mediating immune signalling of IL-12, IL-23 and type I interferons, without interfering with other critical systemic functions as other JAK proteins do. This article aims to review the current knowledge on deucravacitinib, a new oral drug that selectively inhibits TYK2, granting it a low risk of off-target effects. After good efficacy and safety results in a phase II, placebo-controlled trial, two phase III, 52-week trials evaluated deucravacitinib 6 mg against placebo and apremilast-an active comparator. POETYK PSO-1 and PSO-2 involved 1688 patients with moderate-to-severe psoriasis. After 16 weeks, in both studies, over 50% of patients treated with deucravacitinib reached PASI75, which was significantly superior to placebo and apremilast. In POETYK PSO-1, these results improved until week 24 and were maintained through week 52, with over 65% of patients achieving PASI75 at this point. A reduction in signs and symptoms was also reported by patients, with greater impact on itch. Deucravacitinib was well tolerated and safe. There were no reports of serious infections, thromboembolic events, or laboratory abnormalities, which are a concern among other JAK inhibitors. Persistent efficacy and consistent safety profiles were reported for up to 2 years. Despite advances in the treatment of psoriasis, namely among biologic agents, an oral, effective and safe new drug can bring several advantages to prescribers and patients. Further investigation is required to understand where to place deucravacitinib among current psoriasis treatment options.

Type I interferons (IFN-I) were first discovered over 60 years ago in a classical experiment by Isaacs and Lindenman, who showed that IFN-Is possess antiviral activity. Later, it became one of the first approved protein drugs using heterologous protein expression systems, which allowed its large-scale production. It has been approved, and widely used in a pleiotropy of diseases, including multiple-sclerosis, hepatitis B and C, and some forms of cancer. Preliminary clinical data has supported its effectiveness against potential pandemic pathogens such as Ebola and SARS. Still, more efficient and specific drugs have taken its place in treating such diseases. The COVID-19 global pandemic has again lifted the status of IFN-Is to become one of the more promising drug candidates, with initial clinical trials showing promising results in reducing the severity and duration of the disease. Although SARS-CoV-2 inhibits the production of IFNβ and thus obstructs the innate immune response to this virus, it is sensitive to the antiviral activity of externally administrated IFN-Is. In this review I discuss the diverse modes of biological actions of IFN-Is and how these are related to biophysical parameters of IFN-I-receptor interaction and cell-type specificity in light of the large variety of binding affinities of the different IFN-I subtypes towards the common interferon receptor. Furthermore, I discuss how these may guide the optimized use IFN-Is in combatting COVID-19.

There is increasing recognition of the important role that B cells play in the pathogenesis of multiple sclerosis (MS). Recently it was reported that the B cell chemokine CXCL13 is elevated in MS serum and cerebrospinal fluid. Here we study whether serum levels of CXCL13 are associated with active MS. We measured serum levels of CXCL13 by enzyme-linked immunosorbent assay in 74 patients with relapsing MS randomized to interferon beta 1b or glatiramer acetate and examined with monthly 3 T brain MRI scans optimized for detection of gadolinium-enhancement for up to 2 years. The median (range) serum levels of CXCL13 pre-treatment were 40 (3—171) pg/ml. Serum levels of CXCL13 were significantly higher at times of active brain MRI scans (p < 0.01). Furthermore, serum levels were higher in patients who never reached MRI remission compared with those in complete (p < 0.01) or partial (p = 0.01) remission. There was a significant positive correlation between the pattern of serum levels of CXCL13 and MRI activity during the first (r = 0.33, p < 0.05) and the full 2 years (r = 0.35, p < 0.01) of the study. Treatment with interferon beta 1b or glatiramer acetate did not affect serum CXCL13. We conclude that the serum levels of the B cell chemokine CXCL13 are associated with active MS.

Purpose To describe the psychometric properties and identify the minimally important difference (MID) of the hepatitis C virus patient-reported outcomes (HCV-PRO) instrument. Chronic HCV infection and associated treatments negatively affect PROs of function and well-being. Methods In a phase 2 trial, HCV-infected patients received direct-acting antivirals (DAAs) for 12 weeks with peg-interferon/ribavirin (peg-IFN/RBV) for 48 weeks, or placebo plus peg-IFN/RBV. The HCV-PRO total score, SF-36 PCS and MCS scores, EQ-5D-3L, and EQ VAS were measured at baseline, week 8, end of DAA treatment (EODT), end of peg-IFN/RBV treatment (EOT), and posttreatment week 24 (SVR24). Convergent validity of the HCV-PRO was assessed by Pearson's correlation coefficients. Discriminant validity was assessed by analyzing mean HCV-PRO total scores by EQ-5D anxiety/depression and pain/discomfort domain scores (none vs. some) and presence/absence of depression or fatigue adverse events. MID was identified through effect size (ES) and receiver-operating characteristic (ROC) curve analyses (HCV-PRO response vs. SF-36 PCS/MCS and EQ VAS MID thresholds). Results In 74 patients (22 % female; 81 % White; 51 % ≥50 years), correlations (0.64–0.96) between HCV-PRO total scores, SF-36 PCS/MCS scores, and EQ VAS scores at all time points supported convergent validity. HCV-PRO total scores were reduced to 10–30 points in patients impaired by depression, pain, or fatigue symptoms. Impact of peg-IFN/RBV regimen on HCV-PRO ES increased over time (EODT −0.76; EOT −0.93). ES and ROC curve analyses indicated an MID of −10 points. Conclusion The HCV-PRO was valid and responsive in the population studied. An MID of −10 points represented a threshold of clinical significance for the HCV-PRO.

Coronavirus disease 2019 (COVID-19) is a respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Droplets and contacts serve as the main route of transmission of SARS-CoV-2. The characteristic of the disease is rather heterogeneous, ranging from no symptoms to critical illness. The factors associated with the outcome of COVID-19 have not been completely characterized to date. Inspired by previous studies on the relevance of infectious diseases, viral and host factors related to clinical outcomes have been identified. The severity of COVID-19 is mainly related to host factors, especially cellular immune responses in patients. Patients with mild COVID-19 and improved patients with severe COVID-19 exhibit a normal immune response to effectively eliminate the virus. The immune response in patients with fatal severe COVID-19 includes three stages: normal or hypofunction, hyperactivation, and anergy. Eventually, the patients were unable to resist viral infection and died. Based on our understanding of the kinetics of immune responses during COVID-19, we suggest that type I interferon (IFN) could be administered to patients with severe COVID-19 in the hypofunctional stage, intravenous immunoglobulin (IVIG) and glucocorticoid therapy could be administered in the immune hyperactivation stage. In addition, low molecular weight heparin (LMWH) anticoagulation therapy and anti-infective therapy with antibiotics are recommended in the hyperactivation stage.