Endogenous Interferon Production Research Articles

Identification of genetic fingerprint of type I interferon therapy in visceral metastases of melanoma

Malignant melanoma is a difficult-to-treat skin cancer with increasing incidence worldwide. Although type-I interferon (IFN) is no longer part of guidelines, several melanoma patients are treated with type-I interferon (IFN) at some point of the disease, potentially affecting its genetic progression. We run genome-wide copy number variation (CNV) analysis on previously type-I IFN-treated (n = 17) and control (n = 11) visceral metastases of melanoma patients. Results were completed with data from the TCGA and MM500 databases. We identified metastasis- and brain metastasis-specific gene signatures mostly affected by CN gains. Some cases were genetically resistant to IFN showing characteristic gene alterations (e.g. ABCA4 or ZEB2 gain and alterations of DNA repair genes). Analysis of a previously identified type-I IFN resistance gene set indicates that only a proportion of these genes was exclusive for the IFN-treated metastases reflecting a possible selective genomic pressure of endogenous IFNs during progression. Our data suggest that previous type-I IFN treatment and/or endogenous IFN production by immune response affect genomic progression of melanoma which may have clinical relevance, potentially influence immune checkpoint regulation in the tumor microenvironment.

Combined artificial tear medications in the treatment of patients with dry eye syndrome

In the treatment of patients with dry eye syndrome, the main measure is tear replacement therapy, the most accessible for practicing physicians. It is understandably based on the instillations of artificial tear medications, whose number is steadily growing. In Russia, there are 47 registered medications of this type. Considering the set of requirements for artificial tear medications (which are expected to moisturize the ocular surface, stop the hyperosmolarity of the tear film, ensure osmo-protection and reduce inflammation in the tissues of the ocular surface, as well as activate their reparative regeneration), the most promising medications are those containing two or more active ingredients. One such medication is Oftolik ® medium-viscosity tear substitute that contains a combination of 1.4 % polyvinyl alcohol and 0.6 % polyvinylpyrrolidone. The moisturizing effect of these polymers is complemented by reparative regeneration stimulation (polyvinyl alcohol) and the production of endogenous interferon (polyvinylpyrrolidone). Multiple studies confirmed high clinical efficacy of the medication for the treatment of patients with the main pathogenetic types of dry eye syndrome, as well as its syndromal and secondary symptomatic forms (computer visual syndrome) and revealed. As these effects are achieved with no significant side effects, we can recommend Oftolik® and its preservative-free form Oftolik BK ® for wide clinical use.

Inhaled interferons beta and SARS-COV2 infection: a preliminary therapeutic perspective

ABSTRACT Introduction SARS-COV2 infection represents a therapeutic challenge due to the limited number of effective therapies available and due to the fact that it is not clear which host response in terms of inflammation pattern is the most predictive for an optimal (and rapid) recovery. Interferon β pathway is impaired in SARS-COV2 infection and this is associated with a bigger disease burden. Exogenous inhaled interferon might be beneficial in this setting. Areas covered Nebulized interferon-β is currently investigated as a potential therapy for SARS-COV2 because the available data from a phase II study demonstrate that this medication is able to accelerate the recovery from disease. Expert opinion Further clinical studies are needed in order to better document the efficacy of this therapy especially in severe forms of COVID-19, the optimal duration of therapy and if such a medication is appropriate for domiciliary use. Also combined regimens with antivirals or with compounds which are able to enhance the endogenous production of interferon might be of promise.

Strategies to Circumvent Host Innate Immune Response by Hepatitis C Virus.

Innate immune responses generate interferons, proinflammatory cytokines, complement activation, and natural killer (NK) cell response. Ultimately, this leads to the induction of a robust virus-specific adaptive immunity. Although the host innate immune system senses and responds to eliminate virus infection, hepatitis C virus (HCV) evades immune attack and establishes persistent infection within the liver. Spontaneous clearance of HCV infection is associated with a prompt induction of innate immunity generated in an infected host. In this review, we have highlighted the current knowledge of our understanding of host–HCV interactions, especially for endogenous interferon production, proinflammatory response, NK cell response, and complement activation, which may impair the generation of a strong adaptive immune response for establishment of chronicity. The information may provide novel strategies in augmenting therapeutic intervention against HCV.

Identification of Feline Interferon Regulatory Factor 1 as an Efficient Antiviral Factor against the Replication of Feline Calicivirus and Other Feline Viruses.

Interferons (IFNs) can inhibit most, if not all, viral infections by eliciting the transcription of hundreds of interferon-stimulated genes (ISGs). Feline calicivirus (FCV) is a highly contagious pathogen of cats and a surrogate for Norwalk virus. Interferon efficiently inhibits the replication of FCV, but the mechanism of the antiviral activity is poorly understood. Here, we evaluated the anti-FCV activity of ten ISGs, whose antiviral activities were previously reported. The results showed that interferon regulatory factor 1 (IRF1) can significantly inhibit the replication of FCV, whereas the other ISGs tested in this study failed. Further, we found that IRF1 was localized in the nucleus and efficiently activated IFN-β and the ISRE promoter. IRF1 can trigger the production of endogenous interferon and the expression of ISGs, suggesting that IRF1 can positively regulate IFN signalling. Importantly, the mRNA and protein levels of IRF1 were reduced upon FCV infection, which may be a new strategy for FCV to evade the innate immune system. Finally, the antiviral activity of IRF1 against feline panleukopenia virus, feline herpesvirus, and feline infectious peritonitis virus was demonstrated. These data indicate that feline IRF1 plays an important role in regulating the host type I IFN response and inhibiting feline viral infections.

HIV infection in humanized mice: role of type I interferon on disease progression (VIR9P.1139)

Abstract HIV and SIV disease progression is associated with chronic expression of type I IFN and IFN-stimulated genes. A recent study showed that a high-dose injection of IFN-1 early during primary SIV infection in the rhesus macaque model was protective, while neutralization of endogenous IFN-1 was deleterious. In contrast, in the same animal model, prolonged IFN-1 administration accelerated disease development in the chronic stage of the infection. To better understand the role of IFN-1 during HIV infection, we used humanized-PBL mouse model for this study. The advantage of this model is that there is no endogenous interferon production upon HIV infection, allowing analysis of IFN-1 therapy. Since continuous presence of IFN-1 is detrimental in the SIV model, we hypothesized that intermittent treatment with IFN-1 may be protective against HIV infection. To test this hypothesis, we carried out intermittent pegasys (peg-interferon alpha) treatment after HIV infection in human PBL infused NOD-scid IL2rγcnull (hu-PBL) mice. This treatment with pegasys diminished HIV replication and delayed CD4 depletion compared to control mice. To further test the role of IFN, we are currently using humanized BLT mouse model of HIV infection. HIV infection in BLT mice leads to continuous production of high levels of type-I IFNs; and thus, we are studying the effects of continuous or intermittent IFN blockade using type I IFN antagonist. The results will be discussed.

Interactions Between Hepatitis C Virus and Mitochondria: Impact on Pathogenesis and Innate Immunity

Hepatitis C virus (HCV) causes a persistent chronic infection of hepatocytes resulting in progressive fibrosis and carcinogenesis. Abnormalities in mitochondria are prominent features of clinical disease where ultrastructural changes, alterations in electron transport, and excess reactive oxygen species (ROS) production occur. These mitochondrial abnormalities correlate with disease severity and resolve with viral eradication. Multiple viral proteins, particularly core and NS3/4a bind to mitochondria. The core and NS5a proteins primarily cause ER stress, ER Ca2+ release and enhance direct transfer of Ca2+ from ER to mitochondria. This results in electron transport changes, increased ROS production and sensitivity to mitochondrial permeability transition and cell death. The viral protease, NS3/4a, binds to mitochondria as well where it cleaves an important signaling adapter, MAVS, thus preventing viral clearance by endogenous interferon production. This review discusses the mechanisms by which HCV causes mitochondrial changes and consequences of these for disease.

LACTOBACILLUS AND BIFIDOBACTERIUM INFLUENCE ON THE INDICES OF IMMUNE RESPONSE OF THE ORGANISM SHOWED ON THE EXPERIMENTAL MODEL

It was studied the influence of Lactobacillus and Bifidobacterium on interferonogenesis and functional activity of murine phagocytosis system cells in vivo. It was established that Bifidobacterium Bifidobacterium, Bifidobacterium longum, Lactobacillus acidophilus, Lactobacillus casei and Lactobacillus bulgaricus in vivo had activated the endogenous interferon production proved to be true by essential increase of interferon concentration in murine blood plasma. Lactobacillus acidofillus and Bifidobacterium longum have appeared the most effective inducing agent of both “early” and “late” interferon. These preparation also extended spontaneous and ridostin-induced production of interferon by spleen cells. The probiotic strains of Lactobacillus and Bifidobacterium introduction was accompanied by stimulation of oxygen-depending bactericide and absorbing activity of peritoneal macrophages. Received data testify the obtained composition on the basis of Bifidobacterium longum and Lactobacillus acidophilus is the most perspective for immune correction.

Effect of human recombinant interferon alpha 2b (Viferon) in treatment of severe bacterial infections in neonates. (B32)

Abstract Neonates have decreased cytotoxic mechanisms and low levels of endogenous interferon production. Aim: Clinical efficacy and mechanisms of adjunctive immunotherapy with human recombinant interferon alpha 2b (Viferon) were studied in neonates suffering from severe bacterial infections. Design. 48 neonates with bacterial pneumonia were observed in NICU. 23 infants (group 1) were treated with Viferon-1, 150,000 IU per suppositorium q8h per rectum during 7 days in addition to combined antibacterial and supportive therapy. 25 babies (group 2) received the same basic therapy plus placebo instead of Viferon in similar way. Results. Clinical course of pneumonia was more favourable in neonates treated with Viferon. The duration of central venous line usage and total parenteral nutrition were significantly less in group 1 than in group 2. Inflammatory signs in blood analyses were significantly decreased after the treatment with Viferon in comparison with placebo-group. Infants treated with Viferon had significantly higher levels of CD3+, CD4+ and CD25+-lymphocytes, higher serum levels of IFN, elevation of mitogen-induced IFN-gamma production after Viferon than infants from group 2. Conclusion. Immunotherapy with Viferon improves the clinical course of severe bacterial infections and restores the balance in immune system of infected newborn infants.

Interferons and interferon inhibitory activity in disease and therapy.

Interferon (IFN) resistance is an important factor in the pathophysiology of neoplastic disorders, certain viral infections (e.g., AIDS), and autoimmune diseases (e.g., lupus erythematosus and Wegner's granulomatosis). In addition, in some of these disorders, there is also decreased ability to produce IFNs. The capacity of viruses and neoplastic processes to interfere with the IFN system are thought to represent a "virus-against-host" or "cancer-against-host" defense mechanism. Four resistance factors have been identified: 1) release of free IFN-alpha/beta type 1 receptors into the circulation that, at appropriate concentrations, capture and inactivate IFNs; 2) a new IFN inhibitory protein has been isolated and its chemical structure is under study; 3) prostaglandin E2, which is produced by certain tumor cells, inhibits IFN production; and 4) high levels of cAMP phosphodiesterases present, for example in certain tumor cells, reduces cAMP, an important second messenger in IFN synthesis. Studies are under way to reverse these inhibitory effects and to increase endogenous interferon production.

Les différents interférons : Pharmacologie, mécanismes d'action, tolérance et effets secondaires

Background. -Interferons are a recombinant form of endogenous interferon. By inducing the release of intracellular enzymes such as 2′5′ oligoadenylate synthetase and double stranded RNA dependent protein kinase, the drug causes degradation of viral messenger RNA and inhibits protein synthesis. Main points. -Interferons are cytokines efficient in the treatment of infections diseases. Three main types are described as alpha, beta and gamma depending on their antigenic specificity. They have antiviral activity, antiproliferative and immunomodulation properties in response to a viral infection or other enzyme inducers. Furthermore, they increase expression of major histo-compatible complex antigens, increase natural killer and cytotoxic T cell activity, cytokine induction and production of endogenous interferon. Adverse effects frequently occur but are generally wild and reversible at current dosages. The pharmacokinetics of interferons have been fairly well described. The decline in serum concentrations is rapid after intravenous administration. The volume of distribution approximates 20–60% of bodyweight. Terminal elimination half lives range from 4–16 hrs, 1–2 hrs and 25–35 min for alpha, beta, gamma respectively. Intra-muscular and subcutaneous administration of interferons alpha and beta results in protracted but fairly good absorption > 80% for interferon alpha to 70% for interferon gamma. Pegylated interferon safety and pharmacodynamic profiles were comparable. Pegylated interferon demonstrated delayed clearance compared with non-pegylated interferon, consistent with once-weekly administration. The severity of adverse effects is dose dependent. Most patients treated have an influenza like syndrome within 2–8 hrs of drug administration. Other effects such as fatigue, lethargy, anorexia are usually dose limiting. Neuropsychiatric reactions may also become dose limiting. Interferon induced the formation of serum neutralizing antibodies in approximately 10–20% of treated patients. Perspectives. -The development of pegylated forms, a greater understanding of action mechanisms, and the combination with othertherapies should reinforce the place of interferons in the therapeutic arsenal.

Effects of oral administration of Echinacea purpurea (American herb) on incidence of spontaneous leukemia caused by recombinant leukemia viruses in AKR/J mice.

Four-week-old female AKR/J mice were given oral doses of powdered leaves from Echinacea purpurea three times weekly for 8 weeks (7.5 mg/mouse/week): controls received phosphate-buffered saline. Mean survival age of experimental AKR/J mice treated with the E. purpurea preparation was significantly prolonged and enlargement of thymic lymphoma in experimental mice was significantly suppressed compared with controls. In normal 3-week-old female AKR/J mice, mortality from thymic lymphoma was delayed markedly after injection into the thymus of cell-free extract of thymus from the experimental 28-week-old female AKR/J mice that received the oral E. purpurea preparation was injected directly into the thymus. Proliferation of endogenous recombinant murine leukemia viruses (MuLV) in the thymus was markedly inhibited after the first oral administration of the E. purpurea preparation as compared with untreated controls (final age, 28 weeks). Production of endogenous interferon (IFN)-gamma in AKR/J mice was also effectively augmented by the oral treatment with the E. purpurea preparation, however, the production of other cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-12 was minimal. These results suggest that this suppressive effects on spontaneously occurring leukemia caused by endogenous recombinant MuLV in female AKR/J mice may depend on enhancement of nonspecific immune or cellular immune systems (or of both) by the E. purpurea preparation.

Biological basis for the clinical use of interferon.

Interferons are proteins produced by certain cells in response to stimuli such as foreign cells (including tumour cells), bacteria, and viral antigens. They interact both with the interferon producing cells and other cells through production of effector proteins. There are three main types of interferons, known as alpha, beta, and gamma, which have direct antiviral and immunomodulatory effects. Antiviral effects may include inhibition of viral replication, protein synthesis, maturation, or release from infected cells. Immunomodulating effects may include enhancement of macrophage, cytotoxic T cell, and natural killer cell activity. In chronic viral hepatitis, the precise mechanisms of action of alpha interferon are not yet certain. Patients with chronic hepatitis B, however, have been shown to lack endogenous interferon production; those who respond to alpha interferon treatment show a characteristic peak in serum amino-transferase activity before resolution of the infection, indicating an immune reaction. In chronic hepatitis C, the antiviral effect may be more important; patients who respond to alpha interferon tend to have higher values of 2'5' oligo adenylate synthetase, an enzyme induced by interferons that breaks down viral RNA. The clinical relevance of anti-interferon neutralising antibodies produced by some patients during interferon treatment has yet to be firmly established.

Superinduction of Cytotoxic Interferon-β in Glioma Cells

The possibility for new interferon therapy was investigated using the effect of endogenous human interferon-beta (HuIFN-beta) on various culture cell lines. Cell lines were exposed to superinduction agents (poly I: poly C, cycloheximide, and actinomycin D) and the production of endogenous interferon analyzed. Quantitative determination of HuIFN-beta and messenger ribonucleic acid (mRNA) showed HuIFN-beta was induced in all of five glioma cell lines, one of two melanoma cell lines, and all of three lung carcinoma cell lines as well as fibroblasts. Northern blot analysis showed HuIFN-beta mRNA induced in glioma cells was identical to that from fibroblasts. Endogenous HuIFN-beta induced from glioma cells had a cytostatic or cytocidal effect against various human glioma cell lines, even those resistant to fibroblast-derived HuIFN-beta. These results show it may be possible to use the induction of excess endogenous cytotoxic HuIFN-beta in human glioma tissue itself.

Evidence endogenous interferon production contributed to the lack of ocular virulence of an HSV intertypic recombinant.

An intertypic recombinant isolated from rabbit kidney cells following co-transfection of HSV-1(17) and HSV-2(186) DNA failed to induce overt ocular pathology when inoculated onto the murine sacrificed cornea at concentrations as high as 10(7) PFU per eye. In contrast, both parents induced corneal disease at a 1000-fold lower dose. The reason(s) for the failure of the intertypic recombinant, designated RO25X, to induce corneal pathology was investigated. It was found that the recombinant was 100-fold more sensitive to the inhibitory effects of interferon (IFN) alpha/beta than the parent strains in corneal button growth studies in vitro. R025X readily grew in cultured mouse corneal fibroblasts at a low multiplicity of infection. However, the peak titer was approximately 8-fold lower than that of strain 17. Addition of rabbit anti-IFN alpha/beta to the culture medium resulted in a 4 to 5-fold increase in infectious titer compared to its growth in the absence of antiserum. Most significantly, when mice were pre-treated in vivo with anti-IFN alpha/beta 24 hours prior to virus corneal infection, 67% of the recipients developed moderate to severe stromal keratitis, whereas none of the controls developed corneal pathology. Blepharitis was also significantly increased in incidence and severity in the antiserum treated hosts. We conclude that the inability of R025X to induce ocular disease was due, at least in part, to the inhibitory effects of interferon produced in response to infection.

Induction of erythrocyte HLA expression during interferon treatment and HIV infection

Although HLA antigens are present on the surface membrane of most cells, erythrocytes express little or no HLA. Occasionally red cells from normal individuals or patients with certain diseases express elevated levels of these molecules. The reasons for such variations are currently not understood. We report here that the expression of very high levels of HLA on erythrocytes occurs in response to interferon α given as a therapeutic agent for viral hepatitis. Increased expression became apparent after the second or third week of treatment, peaked at 3–4 months, and decreased at the end of the treatment period. This chronology suggests that elevated HLA expression is originated during erythropoiesis and persists throughout the lifetime of the erythrocyte. Furthermore, erythrocyte HLA expression did not correlate with changes of plasma HLA or β 2-microglobulin concentrations and was not affected by in vitro chloroquine treatment, ruling out the possibility that HLA was adsorbed from plasma. Increased expression of HLA on erythrocytes was also demonstrated in patients infected with the human immunodeficiency virus, a disease in which increased production of endogenous interferon has been previously documented. We conclude that high HLA expression in red cells occurs in response to persistent interferon stimulation. Further studies will determine if this effect can also be produced by interferon τ or other factors.

Interferon induced inhibition of queuine uptake in cultured human fibroblasts

Interferon inhibits uptake of the radiolabeled queuine analog, rQT 3, into cultured human fibroblasts. Simultaneous exposure to 10 nM phorbol-12, 13-didecanoate (PDD) potentiates interferon-induced inhibition of rQT 3 into cultured fibroblasts. All three major classes of human interferon tested affected uptake similarly, with fibroblasts derived beta-interferon being more effective in dose response than gamma or alpha interferons. This suggests that endogenous production of interferon by cultured cells, such as that observed during a low grade viral infection, inhibits queuine uptake and may subsequently lead to a decreased level of queuine modified transfer RNA. Queuine-hypomodified transfer RNA has been implicated in growth control, differentiation and neoplastic transformation.

Cytokines in the Control of Beta-2 Microglobulin Release. II. In vivo Studies with Recombinant Interferons and Antigens

The influence of in vivo application of recombinant interferon-alpha 2c (IFN-α 2c) and recombinant interferon-gamma (IFN-γ) on beta-2 microglobulin levels was studied in eight patients with chronic myelogenous leukaemia or advanced renal cell carcinoma. Data indicated enhanced beta-2 microglobulin biosynthesis in close temporary association with injection of both types of interferons. The influence of in vivo stimulation by allogenic leukocytes and the influence of renal allografts or cytomegalovirus infection on serum beta-2 microglobulin and IFN-γ levels were also studied. Increased beta-2 microglobulin concentrations were observed again in each of these clinical situations and were closely associated with enhanced endogenous interferon production. From these in vivo data and the in vitro data presented in the preceding publication, (1) we conclude that endogenous interferon levels are crucial for the regulation of beta-2 microglobulin release in vivo.

Effect of antibody to interferon on genital herpesvirus infection in mice

The effect of anti-mouse interferon (IFN) antibody on the course of genital herpes infection was studied in C57BI/6J mice. As we have previously described, intravaginal inoculation of C57 mice with herpes simplex virus type 2 (HSV-2) results in the development of genital lesions, subsequent encephalitis and death, with the mortality rate dependent on virus dose. In the present study, we found that intravaginal application of 1 × 10 5 units of anti-mouse ( α β ) IFN antibody did not significantly affect the course of infection. However, intraperitoneal or intravenous injection (the latter to a lesser extent) of anti-IFN antibody resulted in increased morbidity and mortality. In addition, intraperitoneal injection of anti-IFN antibody decreased the level of detectable endogenous IFN in peripheral blood and at the site of infection. The clear effect of anti-IFN antibody during early stages of infection points to the possible significance of early endogenous IFN production in ameliorating HSV-2 genital infection.

Effect of bovine alpha 1 interferon on bovine herpesvirus type 1-induced respiratory disease.

Treatment of calves with bovine recombinant alpha 1 interferon prior to challenge with bovine herpesvirus type 1 increased the animals' ability to withstand a subsequent Pasteurella haemolytica challenge. The reduction in viral-bacterial synergy observed following interferon treatment did not appear to be due to a direct effect of the interferon on virus replication in the upper respiratory tract. Thus, even though interferon-treated animals shed slightly less virus from their nasal passages than did untreated animals, this reduction was not statistically significant. Furthermore, there was no difference in the level of intranasal interferon secreted by control or interferon-treated animals. These results suggest that interferon treatment does not affect the production of endogenous interferon. In contrast, a significant difference was observed between the number of days that control animals were sick, the levels of serum fibrinogen and the functional activity of polymorphonuclear neutrophilic granulocytes obtained from infected calves. These results suggest that bovine recombinant alpha 1 interferon may have a greater immunomodulatory effect than a direct antiviral effect in this model. This is further supported by the observation that bovine herpesvirus type 1 is relatively resistant to the direct antiviral effect of bovine recombinant alpha 1 interferon in vitro.