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A man with a history of blind eye due to trauma 22 years earlier consulted at 53 years of age with a large conjunctival neoplastic lesion, compromising almost the entire temporal limbus, and reaching a size of approximately 16 mm on its larger diameter, in the conjunctiva. Management was started with topical and subconjunctival chemotherapy (interferon alpha-2b) in order to perform immunoreduction, but a dramatic response with total disappearance of the lesion was observed. In the follow-up time period of more than 7 years, there were no signs of recurrence.

Background: Hepatitis E viruses (HEV) are an underestimated global cause of enterically transmitted viral hepatitis, which may persist in immunocompromised hosts, posing a risk for progressive liver fibrosis with limited treatment options. We previously established liver-humanized mice as a model for chronic HEV infections, which can be cleared by a 2-week pegylated (peg)-Interferon(IFN)α treatment course. However, severe side effects may hamper the use of IFNα in immunocompromised transplant recipient patients. IFNλ may be a valuable alternative, as its receptor is less ubiquitously expressed. Aims: In this study, we assess the in vitro and in vivo potency of pegIFNλ to induce innate immune signalling in liver cells and to clear a persistent HEV infection in liver-humanized mice. Methods & Results: We found that human liver cells expressed the IFNλ receptor (IFNLR1) and are responsive to pegIFNλ. Treatment with pegIFNλ of liver-humanized mice persistently infected with HEV genotype 3 showed that pegIFNλ was well tolerated. Dose escalation studies showed that although HEV was not cleared at pegIFNλ doses up to 0.12 mg/kg for a maximum of 8 weeks, a dose of 0.3 mg/kg pegIFNλ treatment resulted in complete clearance of HEV antigen and HEV RNA from the liver in 8 out of 9 liver-humanized mice. Conclusions: PegIFNλ is well tolerated in mice and leads to clearance of a persistent HEV infection in liver-humanized mice.

As pegylated interferon alpha (PEG-IFN-α) is increasingly used in combination regimens of novel drugs, we aimed to characterize ALT flares and their relationship with serum HBsAg and HBV RNA kinetics in a large combined cohort of chronic hepatitis B (CHB) patients on PEG-IFN-α-based therapy. In this post hoc analysis of four international randomized trials, 269/130/124/128 patients on PEG-IFN-α monotherapy, PEG-IFN-α plus nucleos(t)ide analogue (NA) de novo combination, PEG-IFN-α add-on to NA or NA monotherapy were included, respectively. A flare was defined as an episode of ALT ≥5 × ULN. The association between flares and HBsAg and HBV RNA changes were examined. On-treatment flares occurred in 83/651 (13%) patients (median timing/magnitude: week 8 [IQR 4–12], 7.6 × ULN [IQR 6.2–10.5]). Flare patients were more often Caucasians with genotype A/D and had higher baseline ALT, HBV DNA, HBV RNA and HBsAg levels than the no-flare group. More flares were observed on PEG-IFN-α monotherapy (18%) and PEG-IFN+NA de novo combination (24%) vs. PEG-IFN-α add-on (2%) or NA monotherapy (1%) (p 10 at the final visit declines started shortly before the flare, progressing towards 24 weeks thereafter. On-treatment flares were seen in 16/22 (73%) patients who achieved HBsAg loss. In conclusion, ALT flares during PEG-IFN-α treatment are associated with subsequent HBsAg and HBV RNA decline and predict subsequent HBsAg loss. Flares rarely occurred during PEG-IFN-α add-on therapy and associated with low HBsAg loss rates. Combination regimens targeting the window of heightened response could be promising.

Purpose To study the effect of interferon-α2 auto-antibodies (IFN-α2 Abs) on clinical and virological outcomes in critically ill COVID-19 patients and the risk of IFN-α2 Abs transfer during convalescent plasma treatment. Methods Sera from healthy controls, cases of COVID-19, and other respiratory illness were tested for IFN-α2 Abs by ELISA and a pseudo virus–based neutralization assay. The effects of disease severity, sex, and age on the risk of having neutralizing IFN-α2 Abs were determined. Longitudinal analyses were performed to determine association between IFN-α2 Abs and survival and viral load and whether serum IFN-α2 Abs appeared after convalescent plasma transfusion. Results IFN-α2 neutralizing sera were found only in COVID-19 patients, with proportions increasing with disease severity and age. In the acute stage of COVID-19, all sera from patients with ELISA-detected IFN-α2 Abs (13/164, 7.9%) neutralized levels of IFN-α2 exceeding physiological concentrations found in human plasma and this was associated with delayed viral clearance. Convalescent plasma donors that were anti-IFN-α2 ELISA positive (3/118, 2.5%) did not neutralize the same levels of IFN-α2. Neutralizing serum IFN-α2 Abs were associated with delayed viral clearance from the respiratory tract. Conclusions IFN-α2 Abs were detected by ELISA and neutralization assay in COVID-19 patients, but not in ICU patients with other respiratory illnesses. The presence of neutralizing IFN-α2 Abs in critically ill COVID-19 is associated with delayed viral clearance. IFN-α2 Abs in COVID-19 convalescent plasma donors were not neutralizing in the conditions tested.

Janus kinase 2 (JAK2) gene mutations are the main drivers for polycythemia vera (PV) and essential thrombocythemia (ET). The mechanisms of single altered gene causing two different diseases are unclear. Additionally, novel treatments specifically targeting mutated JAK2 proteins are needed. In this study, the induced pluripotent stem cells (iPSCs) were virally transduced to express wild-type JAK2 (JAK2WT), JAK2p.V617F (JAK2V617F) or JAK2p.N542_E543del (JAK2exon12) under a doxycycline-inducible system. The modified iPSCs which were differentiated into megakaryocytes in the presence vs. absence of doxycycline were compared to ensure that the differences were solely from mutated JAK2 expressions. The JAK2V617-expressing iPSCs yielded significantly higher numbers of megakaryocytes consistent with the ET phenotype, while there was no enhancement by JAK2exon12 expression compatible with the pure erythrocytosis in humans. Capillary Western analyses revealed significantly greater JAK2 phosphorylation in iPSCs carrying JAK2V617F but not in JAK2WT and JAK2exon12 iPSCs. Activation of STAT3, STAT5 and AKT was increased by JAK2V617F, while they were decreased in JAK2exon12 iPSCs. Notably, interferon alpha and/or arsenic trioxide inhibited megakaryocytes proliferation and reduced JAK2, STAT3, STAT5 and AKT phosphorylation in mutant JAK2-expressing iPSCs compared with those without induction. In conclusion, JAK2V617F expression in iPSCs preferentially promoted megakaryocytes with a signaling profile distinctive from JAK2exon12 expression. Treatments with interferon alpha or arsenic trioxide preferentially suppressed the mutated over wild-type JAK2 signaling. This iPSC model is helpful in mechanistic studies and novel therapy screen for myeloproliferative neoplasm.

Vaginal epithelial abnormalities (VEA) are a common complication associated with pessary use. The objective of this study was to determine if there is a host pro-inflammatory response associated with pessary use and VEA. Patients wearing pessaries for at least two weeks for the management of pelvic organ prolapse and/or urinary incontinence were screened for eligibility. Vaginal swabs were collected from women with VEA (cases) and without VEA (controls). Cases were matched to controls in a 1:3 ratio. Cytokine analysis of the collected samples was performed using multiplex analysis to determine the concentrations of interleukin (IL)6, interferon alpha 2 (IFNα2), tumor necrosis factor alpha (TNFα) and IL1β. A cross-sectional analysis was performed, comparing vaginal cytokine concentrations in women with and without VEA. We enrolled 211 patients in this analysis: 50 cases and 161 controls. The median concentrations (pg/mL) of the four cytokines for cases and controls respectively were; IL6: 6.7 (IQR

Severe viral pneumonia caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by a hyperinflammatory state typified by elevated circulating pro-inflammatory cytokines, frequently leading to potentially lethal vascular complications including thromboembolism, disseminated intracellular coagulopathy and vasculitis. Though endothelial infection and subsequent endothelial damage have been described in patients with fatal COVID-19, the mechanism by which this occurs remains elusive, particularly given that, under naïve conditions, pulmonary endothelial cells demonstrate minimal cell surface expression of the SARS-CoV-2 binding receptor ACE2. Herein we describe SARS-CoV-2 infection of the pulmonary endothelium in postmortem lung samples from individuals who died of COVID-19, demonstrating both heterogeneous ACE2 expression and endothelial damage. In primary endothelial cell cultures, we show that SARS-CoV-2 infection is dependent on the induction of ACE2 protein expression and that this process is facilitated by type 1 interferon-alpha (IFNα) or -beta(β)—two of the main anti-viral cytokines induced in severe SARS-CoV-2 infection—but not significantly by other cytokines (including interleukin 6 and interferon γ/λ). Our findings suggest that the stereotypical anti-viral interferon response may paradoxically facilitate the propagation of COVID-19 from the respiratory epithelium to the vasculature, raising concerns regarding the use of exogenous IFNα/β in the treatment of patients with COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s10456-021-09823-4.

Background Interferons (IFNs) play a crucial role in antiviral immunity. Genetic defects in interferon receptors, IFNs, and auto-antibodies against IFNs can lead to the development of life-threatening forms of infectious diseases like a severe form of COVID-19. Case presentation A 13-year-old boy with a previously reported homozygous loss-of-function mutation in interferon alpha/beta receptor subunit 1 (IFNAR1) (c.674-2A > G) was diagnosed with severe COVID-19. He had cold symptoms and a high-grade fever at the time of admission. He was admitted to the pediatric intensive care unit after showing no response to favipiravir and being hypoxemic. High-resolution computed tomography (HRCT) scanning revealed lung involvement of 70% with extensive areas of consolidation in both lungs. Antibiotics, interferon gamma (IFN-γ), remdesivir, methylprednisolone pulse, and other medications were started in the patient. However, remdesivir and methylprednisolone pulse were discontinued because of their adverse side effects in the patient. His general condition improved, and a few days later was discharged from the hospital. Conclusion We reported a patient with severe COVID-19 who had a mutation in IFNAR1. Our finding suggests that patients with IFNAR1 deficiency are prone to severe forms of COVID-19. Besides, IFN-γ therapy may be a potential drug to treat patients with defects in IFN-α/β signaling pathways which needs further investigations.

По данным ВОЗ, каждый третий житель планеты ежегодно обращается за медицинской помощью по поводу острой респираторной инфекции. Результаты многих исследований показывают, что коррекция иммунных процессов в очаге воспаления дает больший эффект, чем влияние на иммунокомпетентные клетки кровеносного русла (при системном использовании препаратов). Поэтому логичным подходом к терапии респираторных вирусных инфекций, поражающих респираторный эпителий, является интраназальное применение препаратов интерферонов, которые обеспечивают противовирусное, иммуномодулирующее и противобактериальное действие в месте развития инфекционного процесса. В доступной литературе имеется достаточное количество клинических исследований, посвященных изучению эффективности назальных и аэрозольных форм интерферона альфа при острых респираторных вирусных инфекциях (ОРВИ). В них показано, что рекомбинантный интерферон альфа является эффективным препаратом для лечения и профилактики ОРВИ. Его применение сокращает сроки клинического выздоровления больных, уменьшает степень выраженности клинических симптомов заболевания, позволяет избежать манифестации заболевания. Также препараты интерферонов могут применяться как средство предотвращения ОРВИ и гриппа.

The long-term benefits of interferon-α (IFN-α) treatment in children with chronic hepatitis B (CHB) remain unclear. We conducted a retrospective and real-world study to evaluate the safety and long-term clearance rates of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in CHB children who received IFN-α mono-therapy for 72 weeks and were with 13-year follow-up visit. Participants treated with IFN-α (n = 316) were more likely to become HBeAg-negative (39.87% vs. 27.37%; P < 0.05) and HBsAg-negative (11.08% vs. 3.16%; P < 0.05) by the end of the treatment period than untreated participants (n = 95). Treated participants also had higher cumulative rates of HBeAg loss (74.13% vs. 59.27%; P < 0.05) and HBsAg loss (46.95 vs. 33.11%; P < 0.05) than untreated participants in parallel by the end of 13-year follow-up. In particular, the cumulative rate of HBsAg loss was higher in treated children aged 1-7 years than in those aged 8-17 years (71.40% vs. 39.0%; P < 0.01). Children who were HBeAg-negative at the end of IFN-α treatment or who had serum alanine aminotransferase levels of ≥ 80 IU/L at baseline were likely to have higher cumulative HBsAg loss rates. Accordingly, HBeAg loss at 72 weeks was positively associated with the cumulative HBsAg loss rate in untreated children. There were no serious adverse events of IFN-α therapy for the treated patients throughout the study period. Overall, IFN-α therapy was effective in obtaining higher long-term cumulative rates of HBeAg and HBsAg loss in children with HBeAg-positive immune-active CHB, especially among those aged 1-7 years.

Introduction. Recommendations cover the current state of diagnosis and treatment of mastocytosis.Aim — а consolidation of the Russian experts’ opinion on treatment for adult mastocytosis.Main findings. The recommendations have been developed taking into account foreign literature, national experience and world clinical evidence on therapy for systemic and cutaneous mastocytoses, mast cell leukaemia and other mastocytosis forms. The significance of bone marrow and peripheral blood molecular genetic testing for the presence of KITD816V gene variants is demonstrated. The treatment regimens described are based on midostaurin, imatinib, cladribine, hydroxycarbamide, interferon alfa and haematopoietic stem cell transplantation. Prognosis in different forms of mastocytosis is provided.

Background Cytokine treatment with Interferon-alpha (IFN-α) represents a clinical model of immune associated depression, but it remains unclear if it is of the same entity as major depressive disorder (MDD). The study focuses on possible gender differences in IFN-α induced depression and effects of a pre-emptive antidepressant treatment. Methods Data from 181 patients with chronic hepatitis C infection (cHC) without history of mental illnesses undergoing treatment with IFN-α 2a and ribavirin were re-analyzed for gender effects. Patients with a pre-emptive antidepressant therapy with Escitalopram (n = 90, verum group) to prevent IFN-induced depression were compared to patients who received placebo (n = 91). Depressive symptoms before and during HCV-treatment were assessed using the Montgomery–Asberg Depression Rating Scale (MADRS), Beck's Depression Inventory (BDI) and the Hamilton Anxiety Rating Scale. Results We found significant differences regarding the incidence and severity of depressive symptoms between men and women for patients without antidepressant pre-treatment (placebo group). Significantly more women without pre-emptive antidepressant therapy suffered from clinically relevant depression (MADRS values ≥ 13, p = 0.041) and self-rated depressive symptoms (BDI ≥ 17, p = 0.024). Antidepressant pre-treatment showed comparable effects regarding the reduction of incidence and severity of depression in both women and men. Conclusions Compared to MDD, IFN-alpha-induced depression in patients with cHC is also characterized by gender differences with an increased risk for women but no gender difference regarding the effects of an antidepressant pre-treatment is found. Our data strengthens the hypothesis that Interferon-induced depression serves as a clinical model for immune related depressive disorders.

Overexpression of interferon induced transmembrane protein-1 (IFITM1) enhances tumor progression in multiple cancers, but its role in triple-negative breast cancer (TNBC) is unknown. Here, we explore the functional significance and regulation of IFITM1 in TNBC and strategies to target its expression. Immunohistochemistry staining of a tissue microarray demonstrates that IFITM1 is overexpressed in TNBC samples which is confirmed by TCGA analysis. Targeting IFITM1 by siRNA or CRISPR/Cas9 in TNBC cell lines significantly inhibits proliferation, colony formation, and wound healing in vitro. Orthotopic mammary fat pad and mammary intraductal studies reveal that loss of IFITM1 reduces TNBC tumor growth and invasion in vivo. RNA-seq analysis of IFITM1/KO cells reveals significant downregulation of several genes involved in proliferation, migration, and invasion and functional studies identified NF-κB as an important downstream target of IFITM1. Notably, siRNA knockdown of p65 reduces IFITM1 expression and a drug-repurposing screen of FDA approved compounds identified parthenolide, an NFκB inhibitor, as a cytotoxic agent for TNBC and an inhibitor of IFITM1 in vitro and in vivo. Overall, our findings suggest that targeting IFITM1 by suppressing interferon-alpha/NFκB signaling represents a novel therapeutic strategy for TNBC treatment.

Esophageal adenocarcinoma (EAC) has increased in incidence in Western countries, and its poor prognosis necessitates the development of novel therapeutics. We previously reported the potential of conditionally replicative adenoviruses (CRAd) as a novel therapeutic treatment for this disease. To further augment the therapeutic effectiveness of our cyclooxygenase-2 (Cox2) controlled CRAd in EAC, we inserted an interferon alpha (IFN) transgene into the viral genome that is expressed upon viral replication. In this manuscript, we analyze the cytotoxic and oncolytic effects of an IFN-expressing oncolytic adenovirus in EAC and the role of the Cox2 promoter in providing for selective replication in human tissues. An infectivity-enhanced IFN-expressing CRAd (5/3 Cox2 CRAd ΔE3 ADP IFN) and other control viruses were first tested in vitro with cell lines. For the in vivo study, EAC xenografts in nude mice were treated with a single intratumoral dose of virus. An ex vivo analysis with live tissue slices was conducted using surgically resected EAC patient specimens. Expression of IFN significantly enhanced the cytotoxic and oncolytic effect of a Cox2-promoter controlled CRAd. This virus showed significant tumor growth suppression in a xenograft model. Furthermore, in human EAC samples, the promoter-controlled virus demonstrated selective replication in cancerous tissues, leaving normal esophageal tissue unaffected. An IFN-expressing CRAd driven by the Cox2 promoter has strong oncolytic effects as well as cancer-specific replication. Our novel vector possesses critical characteristics that make it a potential candidate for clinical translation to treat EAC.

The maximum incidence of pertussis in young children confirms the importance of their timely immunization.The goal is – to study the timeliness of vaccination against whooping cough, causes of violation of the vaccination schedule in young children, the effect of recombinant interferon-a on the post-vaccination period.Materials and methods: the vaccination history and data on the course of the post-vaccination period after immunization with DPT and DaPT vaccines of 469 children at the age of 3–24 months were studied.Results. The analysis showed that 14,9% of the observed children were not vaccinated against whooping cough in a timely manner. Of these: 34,3% had a written refusal to vaccinate (5.1% of the total number of observed children), in 32,8% of cases, the vaccination schedule was violated due to late arrival of parents, 32,9% of children by the start of immunization had medical challenges, and only half of them had justified contraindications. Non-serious side effects associated with immunization were observed in 11.3% of cases, statistically more often with DTP (22,0%) compared with DaPT (5.,5%). General and local reactions, in general, were recorded on DPT (6,9% and 15,1%, respectively) and less often developed with the use of DaPT (1,0% and 4,5%, respectively). Within 1 month after immunization, 16,2% of the observed children had an acute respiratory viral infection of varying severity. Those who did not receive antiviral therapy more often carried the disease in a moderate and severe form, which in all cases led to the postponement of the administration of the second and third doses of the vaccine.Conclusion. To increase the timeliness of vaccination of children against whooping cough, medical professionals should persistently remind parents about the timing of turnout for the next vaccination, when making medical withdrawals, be guided by modern methodological documents and instructions for vaccines. The use of antiviral and immunomodulatory effects of IFN-alpha drugs allows us to comply with the recommended schedule for vaccination of children with a high risk of SARS in the post-vaccination period.

The influence of antiviral therapy with ingaron on the dynamics of production of interferons α and γ and clinical effects in patients with chronic viral Epstein – Barr infection was studied. The study involved 51 patients (33 women and 17 men aged 35,27 ± 1,28 years) suffering from chronic infection caused by the Epstein – Barr virus. The duration of the disease from the appearance of the first complaints to laboratory confirmation of the Epstein – Barr virus infection and diagnosis was 2,23 ± 0,21 years. Determined the serum, spontaneous and induced production of cytokines interferons α and γ in serum and in the culture of lymphocytes. Three months after the end of antiviral therapy, in patients with an initially low level of induced interferon-γ, the production of interferon-γ increased. The absence of an increase in the production of induced interferon-γ in patients one and three months after the end of therapy with ingaron indicates the absence of the effect of the drug on the level of endogenous interferon-γ. It has been established that the initially low level of induced interferon-γ can be a marker of the positive effect of the therapy with ingaron. Correlation analysis revealed the effect of baseline interferon-γ induced on the clinical picture of the disease. Thus, initially a high level of induced interferon-γ (2706 ± 1058.94 pg/ml) inversely affects the development of sweating in patients ( r = –0.506, p = 0,023; τ = –0.419, р = 0.021), and initially low level of the induced IFN-γ (287.2 ± 64.65 pg/ml) — on development of weakness ( r = –0.405, р = 0.045; τ = –0.419, р = 0.037). In general, ingarone can be used in the therapy of patients with chronic Epstein virus — Bar infection at a dose of 500,000 IU every other day, at least 10 injections.

This study aims to explore the effect of the ITI (interferon alpha-1b, thalidomide, and interleukin-2) regimen on the AML1-ETO fusion gene in patients with t(8;21) acute myeloid leukemia (AML) who were in hematologic remission but positive for the AML1-ETO fusion gene. From September 2014 to November 2020; 20 patients with AML (15 from The Affiliated Cancer Hospital of Zhengzhou University, 4 from The First Affiliated Hospital; and College of Clinical Medicine of Henan University of Science and Technology, and 1 from Anyang District Hospital) with hematological remission but AML1-ETO fusion gene positivity were treated with different doses of the ITI regimen to monitor changes in AML1-ETO fusion gene levels. Twenty patients were treated with a routine dose of the ITI regimen, including 13 males and 7 females. The median patient age was 38 (14–70 years). The fusion gene was negative in 10 patients after 1 (0.5 ~ 8.6) month, significantly decreased in 4 patients after 2.8 (1 ~ 6) months, increased in 4 patients, and unchanged in 2 patients. The 4 patients with elevated levels of the fusion gene were treated with an increased dose of the ITI regimen, and all four patients became negative, for a total effective rate of 90%. The ITI regimen reduces AML1-ETO fusion gene levels in patients with AML who are in hematologic remission but are fusion gene–positive. Improvement was observed in patients’ response to a higher dose administration, and patients tolerated the treatment well.

We have read with great interest the article entitled “Identification of an immune-related signature indicating the dedifferentiation of thyroid cells” by Wang et al. Their data reinforce our own previous results, here compiled. Anaplastic thyroid carcinoma had higher stromal scores, immune scores and enrichment of most immune cells than the control groups, suggesting that the immune microenvironment may correlate with differentiation status in thyroid cancer. We previously demonstrated that the differentiation status expressed by the pattern of protein expression may be related to the profile of immune cell infiltration of differentiated thyroid carcinoma. Wang et al. also explored the differences between the high-risk and low-risk score groups of samples. Among the distinct signaling pathways enriched in the high-risk score group, the epithelial to mesenchymal transition, TNFα signaling, and some common immune-related signaling pathways, including the IL-6/JAK/STAT3 pathway, interferon alpha response, interferon gamma response and inflammatory response were observed with high normalized enrichment score. We also investigated the IL-6 protein immune-histochemical expression in a retrospective study of 114 patients with papillary thyroid carcinoma and 39 patients with follicular thyroid carcinoma. We also obtained samples of 14 normal thyroid tissues from autopsies, 50 goiters and 43 follicular adenoma. We found IL-6 more frequently positive among malignant tumors than non-malignant samples. We demonstrated that IL-6 positivity was associated with infiltration of CD3 + cells, CD16 + cells and CD68 + macrophages. In addition, IL-6 expression was associated with infiltration of activated lymphocytes such as Granzyme B + cells and CD69 + cells. IL-6 positivity was not associated with infiltration of CD4+, CD8+, CD20+, FOXP3+, CD25 + cells but IL-6 was associated with tumor expression of PD-L1, FOXP3, IL-17, COX2, IL-1β, IL-10, CD134, IL-23. In summary, Wang et al. beautiful data reinforce the seminal idea that the immune landscape is closely related to the differentiation status of the tumor. This concept may help select individuals who deserve more careful attention, an essential point in the management of patients with mostly indolent tumors such as those of the thyroid. In fact, our results, here compiled, were obtained with immune-histochemistry, a routine laboratory technique that offers the possibility of simpler and practical execution.

Objectives The aim of this study was to evaluate the role of antiviral drugs in reducing the risk of developing severe illness in patients with moderate COVID-19 pneumonia. Methods This retrospective cohort study included 403 adult patients with moderate COVID-19 pneumonia who were admitted to Shenzhen Third People’s Hospital, China. The antiviral drugs arbidol, interferon alpha-1b, lopinavir–ritonavir and ribavirin were distributed to the patients for treatment. The primary endpoint of this study was the time to develop severe illness. Results Of the 462 patients admitted, 403 had moderate COVID-19 symptoms at hospital admission and were included in this study. 90 of the 403 (22.3%) patients progressed to severe illness. The use of arbidol was associated with a lower severity rate 3.5% compared to control group 30.5%, p-value p = 0.033). The use of interferon alpha-1b was associated with a lower severity rate 15.5% compared to control group 29.3%, with p-value p = 0.0005). The use of lopinavir–itonavir and ribavirin did not show significant differences in adjusted regression models. Early use of arbidol within 7 days of symptom onset was significantly associated with a reduced recovery time of − 5.2 days (IQR − 3.0 to − 7.5, p = 4e−06) compared with the control group. Conclusion Treatment with arbidol and interferon alpha-1b contributes to reducing the severity of illness in patients with moderate COVID-19 pneumonia. Early use of arbidol may reduce patients’ recovery time.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as Coronavirus disease-2019 (COVID-19), has caused the sixth world’s public health emergency. Healthcare staff, as the frontline population fighting the pandemic, are exposed to a high risk of infection. Therefore, developing a protective intervention for medical staff is of significant importance. Objective: The aim of the study was to explore the effectiveness and safety of recombinant human interferon alpha (rhIFN-α) nasal drops for the prevention of coronavirus disease 2019 (COVID-19) through administering it to medical staff. Methods: This was a prospective open-label clinical trial with parallel intervention assignment conducted on 2944 medical staff including both doctors and nurses from Taihe Hospital, Shiyan City, Hubei Province, China from January 21, 2020 to July 30, 2020. The participants were bifurcated into two groups of low risk and high risk groups according to the level of direct exposure to COVID-19 patients. The individuals of the low-risk group received rhIFN-α nasal drops for one month in addition to first level protection, and the high-risk group received a combination of rhIFN-α nasal drops coupled with thymosin-α1 with either second or third-level protection protocol. Moreover, the new-outset of COVID-19 pneumonia diagnosed by chest computed tomography (CT), after thirty days, was the primary outcome. The adverse reactions were recorded in all participants. Results: 2415 of 2944 individuals belonged to the low-risk group, while 529 to the high-risk group. There was no COVID-19 pneumonia in either of the group after thirty days. The pulmonary CT scans were negative for COVID-19 pneumonia in both the groups with no new clinical symptoms. No serious adverse event was observed during the course of the intervention. Conclusion: The rhIFN-α nasal drops along with augmented safeguards based on standard physical isolation could effectively protect medical staff against COVID-19 pneumonia.

Haiyu Hong,1– 3,&ast; Kai Sen Tan,3– 6,&ast; Yan Yan,3,7,8,&ast; Fenghong Chen,2,&ast; Hsiao Hui Ong,3,5 Yukei Oo,4 Jing Liu,3,5 Yew Kwang Ong,3,9 Mark Thong,3,9 Richard Sugrue,10 Vincent T Chow,4,5 De Yun Wang3,5 1Allergy Center, Department of Otolaryngology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 2Otorhinolaryngology Hospital, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 3Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; 4Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; 5NUHS Infectious Diseases Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 6Biosafety level 3 Core Facility, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore; 7Guangdong Provincial Key Laboratory of Biomedical and Guangdong Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 8Central Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 9Department of Otolaryngology Head & Neck Surgery, National University Hospital, National University Health System, Singapore; 10School of Biological Sciences, Nanyang Technological University, Singapore&ast;These authors contributed equally to this workCorrespondence: Vincent T ChowDepartment of Microbiology and Immunology, National University of Singapore, 5 Science Drive 2, Singapore, 117545, SingaporeEmail micctk@nus.edu.sgDe Yun WangDepartment of Otolaryngology, National University of Singapore, National University Health System, 1E Kent Ridge Road, Singapore, 119228, SingaporeEmail entwdy@nus.edu.sgBackground: Epithelial cytokines including IL-25, IL-33 and thymic stromal lymphopoietin (TLSP) are recently established as drivers of type 2 chronic inflammatory diseases such as chronic rhinosinusitis with nasal polyps (CRSwNP). Here, we further confirmed the increased expression of IL-25 in CRSwNP and investigated potential contributors of IL-25 in CRSwNP epithelium.Methods: Sixty CRSwNP, 25 CRSsNP and 15 healthy control tissues were examined for IL-25 expression and for the accompanying type 2 inflammatory cytokines. We then tested different respiratory virus infections on human nasal epithelial cells (hNECs) for their ability to trigger IL-25 expression. In addition, we subjected hNECs generated from CRSwNP tissues to pretreatment with recombinant interferon-alpha (IFN-α) prior to viral infection to evaluate IFN effects on IL-25 induction.Results: We confirmed that significantly enhanced levels of IL-25 were observed in CRSwNP tissues, and that IL-25 expression correlated with type 2 inflammatory cytokine expression. In vitro, we observed significantly elevated IL-25 in hNECs infected with influenza A virus as early as 24 hours post-infection (hpi), regardless of tissue origin, and IL-25 correlated positively with viral load. While other respiratory viruses exhibited increasing trends of IL-25, these were not significant at the time-points tested. IFN-α treatment of CRSwNP epithelium was found to exert bimodal effects, ie IFN-α treatment alone induced moderate IL-25 expression, whereas IFN-α pretreatment of hNECs before influenza infection significantly diminished IL-25 induction by active influenza virus infection.Conclusion: We have authenticated the observation of elevated IL-25 in CRSwNP, which is correlated with type 2 inflammatory cytokines. Notably, we identified influenza virus infection as a potential contributor of IL-25 in both control and CRSwNP epithelium during active infection. This IL-25 induction can be abated by IFN-α pretreatment which ameliorated active influenza infection.Trial Registration: Chictr.org.cn ChiCTR-BON-16010179, Registered 18 December 2016, http://www.chictr.org.cn/showproj.aspx?proj=17331. The authors agree on the sharing of deidentified participant data where it pertains to request directly related to the data in this article when contacted (Haiyu Hong; honghy@mail.sysu.edu.cn).Keywords: chronic rhinosinusitis with nasal polyps, interferon-alpha, interleukin 25, respiratory viruses, influenza virus, type 2 inflammation

A descriptive cross-sectional study was conducted on 300 patients selected by random sampling who were reported with Hepatitis-C at GIMHS. Questions were asked from patients regarding symptoms and adverse drug reactions (ADR’S). Results were analyzed by using SPSS-22. Out of total patients (n=300) the frequency of male gender was (n=192) as compared to females (n=108). Among 300 patients some patients were on sofosbuvir (n=150), patients on interferon (n=150). Rate of ADR’S observed with interferon as fever (n=28), anemia (n=27), hair loss (n=21), headache (n=19), insomnia (n= 11), nausea (n=13), depression (n=14, 09), malaise (n=25), vomiting (n=06), ulcer (n=13), pain and redness at site of injection (n=17). While rate of ADR’S in patients who were on sofosbuvir, fever (n=33), chill (n=17), nausea (n=28), anemia (n=06), headache (n=14), insomnia (n=13), loss of appetite (n=5), diarrhea (n=1). This study concluded that as compared to Interferon, rate of ADR’S were less with Sofosbuvir.

Purpose: To study the combined effects of tenofovir and interferon α1b on viral load and peripheral blood regulatory T cell concentrations of chronic hepatitis B (CHB) subjects. Methods: Patients with chronic hepatitis B (86 cases) were randomly assigned to two groups: control group and study group. In control subjects, tenofovir was given orally (300 mg/kg bwt/day). In addition to tenofovir, the study group received interferon α1b injection intramuscularly at a dose of 50 μg/kg thrice a week. Liver function, serum hepatitis B viral (HBV) load, and serum levels of peripheral blood regulatory T-lymphocytes were determined. Clinical effectiveness and adverse reactions in both groups were also assessed. Results: After treatment, total effectiveness was higher in the study group (86.04 %) than in control patients (62.79 %) (p < 0.05). Serum aspartate transaminase (AST), alanine aminotransferase (ALT) and total bilirubin (TBIL) significantly decreased in the study group, relative to control, but HBV DNAnegative, HbeAg-negative and HbsAg-negative cells were markedly higher in patients in the study group (p < 0.05). Moreover, there were higher CD4+ T and CD8+ T counts, and CD4+ T/CD8+ T ratio in study subjects than in control subjects (p < 0.05). Conclusion: The combination of tenofovir with interferon α1b effectively improves liver functions in patients with CHB, reduces viral load, and exerts anti-HBV effect by regulating the levels of peripheral blood T-lymphocytes.

Aim of the study: to determine the level of Toll-like receptor type 9 expression on peripheral blood mononuclears in patients with measles infection of varying severity, both with and without complications.Materials and methods. The study included 65 patients with a diagnosis of measles who were on inpatient treatment in the Kharkiv region infectious hospital in the period from 2017 to 2019 years. Depending on the severity of the disease and the presence of complications the patients were divided into 4 groups. The control group consisted of 20 voluntary donors who did not have the exclusion criteria at the time of blood sampling.All patients on the day of admission to the hospital underwent assessment of the level of Tolllike receptors type 9 expression in the white blood cell suspension, the concentration in the blood serum of pro- and anti-inflammatory cytokines (IL-1, IL-6, IL-4, IL-10) and interferons alpha and gamma, as well as the determination in the blood serum of the level of virusspecific immunoglobulins of M, A and G classes with the determination of the level of avidity of the latter. Based on the obtained data a correlation analysis between the indicators of the level of Toll-like receptors type 9 expression and the levels of production of mentioned indices was performed.Results. The study revealed three types of cytokine response among patients with measles – normoreactive, dissociative, and hyporeactive, each of which is characterized by a different nature of the cytokine network response to measles infection and has a direct relationship with the severity of the disease and the risk of complications. It was found that measles infection in the adult population develops against the background of low titers of specific antibodies and their low avidity, and the severe course of the disease is to some extent caused by the reaction of the immune system according to the primary type, which is confirmed by high levels of specific IgM at the beginning of the disease.Analysis of the data obtained when studying the level of Toll-like receptors type 9 showed that in patients of groups 1 and 2, who had a normoreactive type of cytokine response and significantly higher levels of IgA and IgG, the level of TLR9 expression on peripheral blood mononuclears was higher than in the control group. In patients of group 3, who had a dissociative type of immune response and a more significant decrease in IgA and IgG levels compared to patients of groups 1 and 2, the level of TLR9 expression was 1.33 times lower than in the control group. In group 4 patients who had a hyporeactive cytokine response and a statistically significant decrease in IgA and IgG levels, the level of TLR9 expression was the lowest; in patients of this group, the TLR9 expression index was 1.35 times lower than in the control group.Pearson’s correlation analysis of the indices on the day of admission to the hospital showed a direct correlation between the level of TLR9 expression and the level of interferon alpha and gamma in the blood serum, as well as level of proinflammatory cytokines (IL-1, IL-6). An inverse correlation was established with respect to antiinflammatory cytokines-IL-4 and IL-10.Conclusions. The severity of measles infection is associated with the level of Toll-like receptors type 9 expression. The level of TLR9 expression is directly correlated with the activity of proinflammatory cytokines, interferons alpha and gamma production and can be considered as a factor affecting the state of the immune response to measles infection. A decrease in the activity of TLR9 expression on mononuclears can be considered as a factor of the severity of the course of measles infection and its complications, and the risk of bacterial pneumonia.Studies of violations of TLR9 expression activity on immunocompetent peripheral blood cells can be used to better understand the immune system disorders in patients with viral diseases as a predictor and possible factor of severe disease and the development of complications.

Background Alopecia areata (AA) is an autoimmune skin disease characterized by abnormal levels of several cytokines, such as interferon alpha (IFN-α) and tumor necrosis factor-alpha (TNF-α), which are T-helper type 1 cytokines that have important roles in the pathogenesis of AA. The aim of our study was to correlate circulating IFN-α and TNF-α levels with disease severity, activity, and clinical type in patients with AA and to evaluate the relationship between the two cytokines. Methods We investigated serum IFN-α and TNF-α levels in 72 patients with AA (35 children and 35 adults) and 75 healthy control individuals (34 children and 41 adults) using the enzyme-linked immunosorbent assay (ELISA) technique. We evaluated AA severity using the Severity of Alopecia Tool (SALT) and determined the activity based on dermoscopic criteria of disease activity. Results Serum IFN-α and TNF-α concentrations were significantly higher in the patients than in the controls. There was a significant positive correlation between serum IFN-α and TNF-α levels in all patients with alopecia areata, as well as between serum TNF-α levels and disease severity in all patients and in children. Conclusions Our results support the association between IFN-α and TNF-α levels and AA and suggest that TNF-α might be related to disease severity.

Background Immune cells play a major role in the pathogenesis of COPD. Changes in the distribution and cellular functions of major immune cells, such as alveolar macrophages (AMs) and neutrophils are well known; however, their transcriptional reprogramming and contribution to the pathophysiology of COPD are still not fully understood. Method To determine changes in transcriptional reprogramming and lipid metabolism in the major immune cell type within bronchoalveolar lavage fluid, we analysed whole transcriptomes and lipidomes of sorted CD45+Lin−HLA-DR+CD66b−Autofluorescencehi AMs from controls and COPD patients. Results We observed global transcriptional reprogramming featuring a spectrum of activation states, including pro- and anti-inflammatory signatures. We further detected significant changes between COPD patients and controls in genes involved in lipid metabolism, such as fatty acid biosynthesis in GOLD2 patients. Based on these findings, assessment of a total of 202 lipid species in sorted AMs revealed changes of cholesteryl esters, monoacylglycerols and phospholipids in a disease grade-dependent manner. Conclusions Transcriptome and lipidome profiling of COPD AMs revealed GOLD grade-dependent changes, such as in cholesterol metabolism and interferon-α and γ responses., AMs from COPD patients undergo GOLD grade-specific transcriptional reprogramming and acquire a complex activation profile. Among the observed changes are gene programmes involved in lipid metabolism that translate into alterations in the AM lipidome. https://bit.ly/3sYAqgd

Introduction Recombinant bovine interferon alpha (rBoIFN-α) has been demonstrated to have antiviral activity. However, no conduct of acute or chronic toxicity tests has been reported. Material and Methods Specific pathogen-free Sprague Dawley rats were administered doses at different concentrations through intraperitoneal or intravenous injection. After the administration (single for an acute toxicity test over 14 days or daily for a sub-chronic toxicity test over 30 days), the rats’ behaviour and other indicators and the degree of toxic reaction were continuously monitored. Blood was collected for haematological and serum biochemical examinations. At the end of the experiments, the rats were sacrificed for necropsy and histopathological tissue analysis. Results The external performance, behaviour characteristics, and changes in body temperature and body weight of the rats in each subgroup were comparable to the normal control subgroup. Except for a few cases, there were no lesions in the viscera’s pathological structures, and the blood parameters and biochemical indicators were not noticeably different from those of the control subgroup. Conclusion This study suggests that rBoIFN-α seems to be safe for rats, and its use may foster the development of the cattle industry in China by protecting livestock health.

The coronavirus disease (COVID-19) caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide. Given that this contagious viral outbreak is still unfolding, it is urgent to understand the pathogenesis of SARS-CoV-2 infection and explore effective treatments to protect patients from developing a severe illness related to COVID-19. Recently, IFN-α has been considered a potential therapeutic strategy to treat COVID-19 disease, mainly because the innate immune system rapidly produces IFN-α as the first line of defense to combat viral infections. However, IFN-α can also play a role in immunoregulatory effects, causing pathogenic damage and uncontrolled inflammatory responses. There are 13 human IFN-α subtypes that bind to the same receptor and induce different interferon-stimulated gene (ISG) expression, regulating various antiviral and immunoregulatory effects. The varying degrees of inflammatory regulations may raise concerns about the possible side effects to enlarge the inflammatory responses, exacerbating the severity of infection. Thus, the analysis of various IFN-α subtype induction during SARS-CoV-2 infection is necessary in exploring the mechanism of COVID-19 pathogenesis. This review summarizes the current understanding of IFN-α in the pathogenesis of respiratory virus diseases and IFN-α based clinical intervention used in SARS-CoV-2 infection and other respiratory virus diseases. Besides, new ideas in selecting suitable IFN-α subtypes or combinations as drug candidates for viral infection treatment will also be discussed.Key Points• IFN-α plays an important role in anti-viral and immunoregulatory effects in COVID-19 patients caused by SARS-CoV-2.• The uncontrolled inflammation and disease severity correlated to the diversity of IFN-α subtype induction.• Selecting suitable IFN-α subtypes or combinations as drug candidates will be beneficial for the treatment of patients with COVID-19.Graphical abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by a complex immune dysregulation leading to diverse clinical phenotypes. The preclinical lupus phase (preclinical SLE) is...

Therapeutic strategies to treat pancreatic ductal adenocarcinoma (PDAC) remain unsatisfying and limited. Therefore, it is imperative to fully determine the mechanisms underlying PDAC progression. In the present study, we report a novel role of regulator of calcineurin 1, isoform 4 (RCAN1.4) in regulating PDAC progression. We demonstrated that RCAN1.4 expression was decreased significantly in PDAC tissues compared with that in para-cancerous tissues, and correlated with poor prognosis of patients with pancreatic cancer. In vitro, stable high expression of RCAN1.4 could suppress the metastasis and proliferation and angiogenesis of pancreatic tumor cells. In addition, interferon alpha inducible protein 27 (IFI27) was identified as having a functional role in RCAN1.4-mediated PDAC migration and invasion, while VEGFA play a vital role in RCAN1.4-mediated PDAC angiogenesis. Analysis of mice with subcutaneously/orthotopic implanted xenograft tumors and liver metastasis model confirmed that RCAN1.4 could modulate the growth, metastasis, and angiogenesis of tumors via IFI27/VEGFA in vivo. In conclusion, our results suggested that RCAN1.4 suppresses the growth, metastasis, and angiogenesis of PDAC, functioning partly via IFI27 and VEGFA. Importantly, our results provided possible diagnostic criteria and therapeutic targets for PDAC.

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell malignancies. Chronic inflammation and a dysregulated immune system are central to the pathogenesis and progression of MPNs. Interferon alpha (IFNα) was first used for the treatment of MPNs approximately 40 years ago. It has significant antiviral effects and plays a role in anti-proliferative, pro-apoptotic, and immunomodulatory responses. IFNα is an effective drug that can simultaneously induce significant rates of clinical, hematological, molecular, and histopathological responses, suggesting that the disease may be cured in some patients. However, its frequent dosage and toxicity profile are major barriers to its widespread use. Pegylated IFNα (peg-IFNα), and more recently, ropeginterferon alpha-2b (ropeg-IFNα-2b), are expected to overcome these drawbacks. The objective of this article is to discuss the clinical role of IFNα in Philadelphia-negative MPNs through a review of recent studies. In particular, it is expected that new IFNs, such as peg-IFNα and ropeg-IFNα-2b, with lower rates of discontinuation due to fewer adverse effects, will play important clinical roles.

Aicardi-Goutieres Syndrome (AGS) is a monogenic leukodystrophy with pediatric onset, clinically characterized by a variable degree of neurologic impairment. It belongs to a group of condition called type I interferonopathies that are characterized by abnormal overproduction of interferon alpha, an inflammatory cytokine which action is mediated by the activation of two of the four human Janus Kinases. Thanks to an ever-increasing knowledge of the molecular basis and pathogenetic mechanisms of the disease, Janus Kinase inhibitors (JAKIs) have been proposed as a treatment option for selected interferonopathies. Here we reported the 24 months follow-up of the fifth AGS patient treated with ruxolitinib described so far in literature. The treatment was globally well tolerated; clinical examinations and radiological images demonstrated a progressively improving course. It is however to note that patients presenting with mild and spontaneously improving course have been reported. Large natural history studies on AGS spectrum are strongly required in order to get a better understanding of the results emerging from ongoing therapeutic trials on such rare disease.

An increasing number of Bacillus strains have been developed for use as animal feed additives. The aim of the current work was to evaluate the impacts of Bacillus pumilus fsznc-09 in growth performance, organs development, blood constituents, genes expression of growth and immune in spleen and microbial communities in jejunum of weanling mice. The results showed that the body weight of mice in BP1 group increased significantly (p < 0.05) after feeding Bacillus pumilus fsznc-09. Compared with control group, the feed conversion ratio of BP1 and BP2 groups showed 13.57% (p < 0.05) and 9.64% improvements, respectively. The lengths of large intestine, small intestine in BP1 group were significantly increased (p < 0.05). While compared with control group, the organ indexes in BP1 and BP2 group did not differ significantly. Compared with control group, the activities of serum total superoxide dismutase (T-SOD), alkaline phosphatase (AKP), lysozyme (LZM) in BP1 group and T-SOD, AKP in BP2 group were significantly increased (p < 0.05). Compared with control group, the expressions of ghrelin-2 (Ghrl-2) and insulin-like growth factor 1 (Igf1) in BP1 group were significantly increased (p < 0.05). Compared with control group, the expressions of interleukin-6 (IL-6), nitric oxide synthase (INOS), tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) in BP1 group and the expressions of IL-6, INOS, TNF-α, IL-1β and interferon alpha 11 (Ifna11) in BP2 group were slightly decreased. Moreover, compared with control group, the diversity of intestinal flora and relative abundance of potentially probiotics (e.g., Bifidobacterium, Bacillus) in BP1 and BP2 groups were increased. While compared with control group, the relative abundance of the potentially pathogenic bacterium (e.g., Staphylococcus) was reduced. The relative abundances of dominant species in BP1 (Lactobacillus johnsonii) and BP2 (Lactobacillus reuteri) groups were also higher than control group (Lactobacillus intestinalis). In conclusion, Bacillus pumilus fsznc-09 might improve the growth performance and immunity of mice.

A 46-year-old woman with uveitis was referred to our respiratory diseases department in July 2018. Her medical history included transient bilateral hilar mediastinal lymphadenopathy (BHL) and multiple pulmonary nodules in May 2013 during pegylated interferon-alpha and ribavirin treatment for chronic hepatitis C infection. Five years post-treatment, chest X-ray revealed BHL and nodular recurrence. A biopsy of the subcutaneous buttock nodules revealed scattered non-caseating epithelioid granulomas with positive PAB immunohistochemical staining. This seem to be the first report of Propionibacterium acnes-associated sarcoidosis possibly initially triggered by interferon-alpha therapy. Understanding the mechanisms underlying interferon-triggered P. acnes-associated sarcoidosis may clarify the sarcoidosis immunopathogenesis.

Objectives The randomized, double-blind, phase 2 b MUSE study evaluated the efficacy and safety of the type I IFN receptor antibody anifrolumab (300 mg or 1000 mg every 4 weeks) compared with placebo for 52 weeks in patients with chronic, moderate to severe SLE. Characterizing the exposure–response relationship of anifrolumab in MUSE will enable selection of its optimal dosage regimen in two phase 3 studies in patients with SLE. Methods The exposure–response relationship, pharmacokinetics (PK) and SLE Responder Index (SRI(4)) efficacy data were analysed using a population approach. A dropout hazard function was also incorporated into the SRI(4) model to describe the voluntary patient withdrawals during the 1-year treatment period. Results The population PK model found that type I IFNGS–high patients, and patients with a higher body weight, had significantly greater clearance of anifrolumab. Stochastic clinical simulations demonstrated that doses Conclusions Based on PK, efficacy and safety considerations, anifrolumab 300 mg every 4 weeks was recommended as the optimal dosage for pivotal phase 3 studies in patients with SLE.

Plasmacytoid dendritic cells (pDCs) are the most potent type I interferon-producing cells and play an important role in antiviral immunity. Tumor-infiltrating pDCs were shown to be predominantly pro-tumorigenic, with reduced ability to produce interferon alpha (IFNα) and confirmed capacity to prime regulatory T cells (Tregs) by the ICOS/ICOS-L pathway. Because a significant number of HNSCCs are induced by human papillomaviruses and show markedly different immune profiles than non-virally induced tumors, we compared the phenotype and functional capacity of HNSCC-infiltrating pDCs to the HPV status of the tumor. We observed a reduced capacity of pDCs to produce IFNα upon toll-like receptor activation in HPV-negative samples and a rather uncompromised functionality in HPV-associated tumors. Additionally, supernatants from non-virally induced but not HPV-associated tumor cell suspensions significantly inhibited IFNα production by peripheral blood-derived pDCs. We identified IL-10 and TNFα as the soluble pDC-suppressive factors with the highest variability between HPV-negative and HPV-positive tumor-derived supernatants. Additionally, we observed a positive correlation of tumor-infiltrating pDCs with Tregs in HPV-negative samples but not in virally induced tumors. Overall, our study indicates that the immunosuppressive cytokine milieu rich in IL-10 and TNFα in HPV-negative but not in HPV-positive HNSCC significantly affects the functional capacity of tumor-infiltrating pDCs, and such dysfunctional pDCs may further support the immunosuppressive tumor microenvironment by promoting the expansion of Tregs in the tumor tissue.

Cancer immunotherapy plays an important role in the treatment of patients with advanced stage melanoma. Recombinant cytokines were the first tested and approved treatments; however, due to disappointing response rates and severe toxicities, their use has significantly decreased. More recently, adoptive cell transfer therapies have shown to be a promising new treatment strategy able to induce complete and durable remissions in patients with melanoma progressive on first-line treatment. This review provides an overview of the cellular therapies (tumor-infiltrating lymphocytes, T-cell receptor T cells, chimeric antigen receptor T cells) and cytokine treatments (interleukin-2 [IL-2], IL-15, IL-7, IL-10, IL-21, interferon alpha, granulocyte-macrophage colony-stimulating factor) for melanoma.

Background: Ischemia-reperfusion injury of organ transplantation activates several mediators which may link the innate to the adaptive immune response. Down the cascade of TLRs, we selected to study the expression of Interferon Regulatory Factors (IRF)-3 and -7 inside human Kidney Transplanted (KTx) organs and the synthesis of IFNα, the main growth factor induced by them, in KTx aspiration biopsy cultures. Simultaneously, we tested their robustness in diagnosing Acute Rejection (AR). Methods: Fine-needle aspiration biopsies (F-nab) were performed either on day 7 or 14 post-KTx among stable patients or on the day of AR diagnosis. On Fnab cytopreparations, we studied IRF3 and IRF7 by the enzymatic avidin-biotin complex staining, and in a different group of cases we quantified IFNα by ELISA in 48 hours Fnab culture supernatants. Results: AR group showed a significantly up-regulated expression for IRF3 and IRF7, reaching Positive Predictive Values (PPV) of 0.824 and 0.8, respectively, as well as Negative Predictive Values (NPV) above 0.9 for both; IFNα presented a PPV = 1.0 and a NPV = 0.9. A variation in the results was noticed according to different immunosuppressive therapies. Conclusions: Our findings suggest that IRF3 and IRF7, and IFNα which they promote, may be very important players in the early days post-KTx, linking the innate with an adaptive response and triggering acute rejection. These differences were very clear-cut, lending consistency to our speculation. It would be important to scrutinize for other potential effects derived from these IRFs up-regulation which could be of clinical relevance.