Low Concentrations Of Interferon Research Articles

Sex-specific differences in myocardial injury incidence after COVID-19 mRNA-1273 booster vaccination.

To explore the incidence and potential mechanisms of oligosymptomatic myocardial injury following COVID-19 mRNA booster vaccination. Hospital employees scheduled to undergo mRNA-1273 booster vaccination were assessed for mRNA-1273 vaccination-associated myocardial injury, defined as acute dynamic increase in high-sensitivity cardiac troponin T (hs-cTnT) concentration above the sex-specific upper limit of normal on day 3 (48-96 h) after vaccination without evidence of an alternative cause. To explore possible mechanisms, antibodies against interleukin-1 receptor antagonist (IL-1RA), the SARS-CoV-2-nucleoprotein (NP) and -spike (S1) proteins and an array of 14 inflammatory cytokines were quantified. Among 777 participants (median age 37 years, 69.5% women), 40 participants (5.1%; 95% confidence interval [CI] 3.7-7.0%) had elevated hs-cTnT concentration on day 3 and mRNA-1273 vaccine-associated myocardial injury was adjudicated in 22 participants (2.8% [95% CI 1.7-4.3%]). Twenty cases occurred in women (3.7% [95% CI 2.3-5.7%]), two in men (0.8% [95% CI 0.1-3.0%]). Hs-cTnT elevations were mild and only temporary. No patient had electrocardiographic changes, and none developed major adverse cardiac events within 30 days (0% [95% CI 0-0.4%]). In the overall booster cohort, hs-cTnT concentrations (day 3; median 5, interquartile range [IQR] 4-6 ng/L) were significantly higher compared to matched controls (n = 777, median 3 [IQR 3-5] ng/L, p < 0.001). Cases had comparable systemic reactogenicity, concentrations of anti-IL-1RA, anti-NP, anti-S1, and markers quantifying systemic inflammation, but lower concentrations of interferon (IFN)-λ1 (IL-29) and granulocyte-macrophage colony-stimulating factor (GM-CSF) versus persons without vaccine-associated myocardial injury. mRNA-1273 vaccine-associated myocardial injury was more common than previously thought, being mild and transient, and more frequent in women versus men. The possible protective role of IFN-λ1 (IL-29) and GM-CSF warrant further studies.

Syphilis reinfection is associated with an attenuated immune profile in the same individual: a prospective observational cohort study

BackgroundAscertaining if the clinical and immunological response to repeat syphilis differs from that in initial syphilis may assist in designing optimal syphilis screening strategies and vaccine design.MethodsWe prospectively recruited 120 patients with a new diagnosis of (baseline) syphilis. During a 24-month follow-up period, 11 of these patients had a further diagnosis of (repeat) syphilis. We conducted a paired comparison of their plasma cyto-chemokines at baseline and repeat syphilis.ResultsComparing to their baseline infection, paired analyses of the 11 individuals with repeat infections during follow-up revealed that these reinfections had lower concentrations of Interferon (IFN)α (0.8 [Interquartile range (IQR) 0.8–0.8 vs. 12.2 [IQR 1.6–24.2], P = 0.004) and Chemokine (C-C motif) ligand (CCL) 4 (0.9 [IQR 0.9–12.2 vs. 17.5 [IQR 4.9–32.8], P = 0.022].ConclusionIn this small study of 11 individuals, repeat syphilis was found to present with an attenuated immune response. The relevance of these findings to the design of optimal syphilis screening programs is discussed.

Near eradication of clinically relevant concentrations of human tumor cells by interferon-activated monocytes in vitro.

We have previously reported that low concentrations of interferon (IFN)-activated monocytes exert near-eradicative cytocidal activity against low concentrations of several human tumor cells in vitro. In the present study, we examined 7 human tumor cell lines and 3 diploid lines in the presence or absence of 10 ng/mL IFNα2a and monocytes. The results confirmed strong cytocidal activity against 4 of 7 tumor lines but none against 3 diploid lines. To model larger in vivo tumors, we increased the target cell concentration and determined the concentration of IFNα2a and monocytes, required for cell death. We found that increasing the tumor cell concentration from 10- to 100-fold (10(5) cells/well) required an increase in the concentration of IFNs by over 100-fold and monocytes by 10-fold. High concentrations of monocytes could sometimes kill tumor or diploid cells in the absence of IFN. We may conclude that killing of high concentrations of tumor or diploid cells required high concentrations of monocytes that could sometimes kill in the absence of IFN. Thus, high concentrations of tumor cells required high concentrations of IFN and monocytes to cause near eradication of tumor cells. These findings may have clinical implications.

Immunotoxicity and Environment: Immunodysregulation and Systemic Inflammation in Children

Environmental pollutants, chemicals, and drugs have an impact on children's immune system development. Mexico City (MC) children exposed to significant concentrations of air pollutants exhibit chronic respiratory inflammation, systemic inflammation, neuroinflammation, and cognitive deficits. We tested the hypothesis that exposure to severe air pollution plays a role in the immune responses of asymptomatic, apparently healthy children. Blood measurements for markers of immune function, inflammatory mediators, and molecules interacting with the lipopolysaccharide recognition complex were obtained from two cohorts of matched children (aged 9.7 +/- 1.2 years) from southwest Mexico City (SWMC) (n = 66) and from a control city (n = 93) with criteria pollutant levels below current standards. MC children exhibited significant decreases in the numbers of natural killer cells (p = .003) and increased numbers of mCD14+ monocytes (p < .001) and CD8+ cells (p = .02). Lower concentrations of interferon gamma (p = .009) and granulocyte-macrophage colony-stimulating factor (p < .001), an endotoxin tolerance-like state, systemic inflammation, and an anti-inflammatory response were also present in the highly exposed children. C-reactive protein and the prostaglandin E metabolite levels were positively correlated with twenty-four- and forty-eight-hour cumulative concentrations of PM(2.5). Exposure to urban air pollution is associated with immunodysregulation and systemic inflammation in children and is a major health threat.

Cytokine profiles in immunocompetent persons infected with Mycobacterium avium complex.

To evaluate the immunologic factors that contribute to protection against Mycobacterium avium complex (MAC), cytokine production by peripheral blood mononuclear cells (PBMC) from human immunodeficiency virus-negative persons with pulmonary MAC (MAC patients) and healthy control subjects with a delayed hypersensitivity skin test response to M. avium sensitin (MAS-positive control subjects) was measured. In MAC patients, mycobacterium-stimulated PBMC produced higher concentrations of interleukin (IL)-10 but lower concentrations of interferon (IFN)-gamma, IL-12, and tumor necrosis factor (TNF)-alpha, compared with PBMC from MAS-positive control subjects. Immunolabeling for intracellular IL-10 revealed that this cytokine was produced by both monocytes and T cells. Alveolar macrophages produced TNF-alpha and IL-10 in response to MAC, which suggests that these cytokines are produced in the lungs of patients with pulmonary disease caused by this pathogen. Our findings suggest that IFN-gamma, TNF-alpha, and IL-12 contribute to protection against MAC, whereas IL-10 is immunosuppressive.

The virion of mengovirus contains anti-interferon activity.

Many viruses are resistant to the antiviral state induced by interferon (IFN) in certain cell lines because they produce factors having anti-IFN activity (AIA). We show here that is+, a mengovirus strain resistant to low concentrations of IFN, also produces an AIA, but that an IFN-sensitive mutant (is-1) does not. This activity was detected when is+ rescued is-1 from the antiviral state induced in mouse L cells by mouse IFN. The mengovirus AIA was found in cell lysates prepared from cells infected with is+, and in the virions of purified, inactivated is+ but not in lysates prepared from is-1-infected cells or in the is-1 virion. Also the pentameric subunits that make up the viral capsid contained AIA, whereas the individual monomeric subunits that constitute the pentamers did not. We also describe an assay system for detecting and quantitating the mengovirus AIA.

Effects of Interferons β or γ on Neopterin Biosynthesis and Tryptophan Degradation by Human Alveolar Macrophages In Vitro: Synergy with Lipopolysaccharide

Interferons can induce neopterin biosynthesis and tryptophan degradation in monocytic cells. Indoleamine 2,3-dioxygenase (IDO), an inducible cellular enzyme, metabolizes tryptophan to N-formyl-L-kynurenine. Tryptophan degradation has been linked to interferon-mediated inhibition of replication by intracellular pathogens and inhibition of cancer cell proliferation. We evaluated the ability of the recombinant human interferons beta ser and gamma to stimulate neopterin production and tryptophan degradation in vitro by alveolar macrophages (AM) obtained from normal volunteers by bronchoalveolar lavage. Additionally, because other biologic response modifiers such as lipopolysaccharide (LPS) can also stimulate monocytic cells to produce increased amounts of neopterin and degrade tryptophan, we evaluated the effects of LPS on interferon-induced neopterin production and tryptophan degradation by AM. Both interferon-gamma (IFN-gamma) and interferon-beta (IFN-beta) induced neopterin production and tryptophan degradation by AM with corresponding inhibition of intracellular replication by Chlamydia psittaci in AM, but IFN-gamma was a more potent inducer of these responses than IFN-beta. LPS enhanced neopterin production and tryptophan degradation by interferon-exposed cells. This effect was particularly evident at lower concentrations of interferon, and LPS synergy was more pronounced with IFN-beta than IFN-gamma. Concentrations of LPS that alone had no stimulatory effect on tryptophan degradation synergistically enhanced the induction of IDO activity by lower concentrations of interferon. These studies suggest that IFN-gamma stimulates human AM to produce neopterin and degrade tryptophan more potently than IFN-beta, and that low concentrations of LPS can synergistically enhance such effects of interferons on tissue macrophage metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Tryptophan reversal of recombinant human gamma-interferon inhibition ofChlamydia trachomatis growth

Recombinant human gamma-interferon was shown to inhibit the growth ofChlamydia trachomatis (L2/434/Bu) in HEp-2 cells. This inhibition could be reversed by the addition of tryptophan. The effect of tryptophan was dose dependent and determined by the interferon concentration. At low concentrations of interferon, the addition of tryptophan completely restoredC. trachomatis infectivity, whereas at high concentrations (100–1000 IU/ml) the effect of interferon could not be totally reversed. The reversal effect of tryptophan could be achieved even when the addition was 48 h after infection. The probability that tryptophan degradation induced by gamma-interferon might be the mechanism involved in its antichlamydial activity is discussed.

Combined effects of interferon and mutagens on survival of mouse L929 cells

We studied the effect of mouse interferon (IFN) alpha/beta on the sensitivity of L929 cells to cytotoxic activity of ultraviolet (UV) irradiation or ethyl methanesulfonate (EMS) administration. Exposure of L929 cells to IFN for 48 h before mutagen treatment markedly enhanced their sensitivity to UV, but only slightly to EMS. Incubation of L929 cells after UV-irradiation for 24 h in the presence of low concentrations of IFN (15 units/ml) increased the cellular recovery, while with graded concentrations of IFN the protective activity was inhibited (60 units/ml) and after 250 units/ml the ability of IFN treated cells to recover was found to decrease. Incubation of cells after EMS treatment for 24 h with low (15 units/ml) or moderate (60 units/ml) IFN concentrations markedly reduced the cellular recovery. It has been shown that the extent and the direction of IFN activity on cellular sensitivity to mutagens was influenced by the type of mutagen, IFN-concentration and length of its action on the cell and upon application of IFN before or after mutagen treatment.

Immune effects of α-interferon in chronic liver disease

The effect of prolonged alpha-interferon therapy on immune function was studied in patients with chronic type B hepatitis. These patients with chronic type B hepatitis have been shown to have a defect in their in vitro response to human recombinant alpha-interferon. This defect consists of a failure to augment pokeweed mitogen-stimulated immunoglobulin production at low concentrations of interferon and an increased susceptibility to the suppressive effects of interferon. After 2 weeks therapy with interferon, immunoglobulin production was further suppressed. However, after 4 months of therapy with interferon, pokeweed mitogen-stimulated immunoglobulin production partially returned towards the pretreatment values. Antibody to hepatitis B core antigen was less affected by interferon therapy. This altered response to interferon was not specific as it was seen in some patients with other forms of liver disease. The suppression of B cell differentiation appears to be separate from its antiviral and antiproliferative effects.

Synergism of Antiviral Activity in Cell Cultures Treated with Low Concentrations of Interferon and Interferon-Treated Lymphocytes

Human T cells treated with low levels of interferon (IFN) (1-10 units/ml), and washed to remove the IFN, transferred the same level of antiviral activity to recipient WISH cells as an equivalent IFN treatment alone could induce in WISH cells. Further, when T cells pretreated with IFN (1-10 units/ml) were cocultivated with WISH cells in the presence of IFN (1-10 units/ml), a 2.5- to 5-fold greater level of protection developed than could be expected from the additive effect of each. Antibody to leukocyte, fibroblast, or immune IFN blocked the antiviral effect of the respective IFN types but had no effect on the transfer of antiviral activity initiated by leukocyte, fibroblast, or immune IFN. Also, treatment of T cells with actinomycin D blocked the transfer of antiviral activity of IFN-treated T cells. Taken together, the data suggest that the increased antiviral activity is not merely an additive effect of the IFN, but represents a synergistic amplification of protection most likely due to the combination of the separate effects of IFN and IFN-induced transfer. Such interactions would be expected to play a major role in early protection against virus infections in vivo when low levels of interferon are present and lymphocytes are migrating into the area.

Unexpectedly rapid action of human interferon in physiological conditions.

THE progression of many viral infections can be affected by the administration of exogenous interferon or the production of endogenous interferon1,2, the concentration of which is greatest at the site of infection3,4. Therapy with interferon generally requires large amounts5,6 presumably to allow for diffusion to the site. Model studies of this phenomenon in vitro have usually been carried out in the non-physiological conditions of relatively low concentrations of interferon and room temperature7–9. To understand better the factors that govern the local protective action of interferon, we have done model experiments in tissue culture to define the time and concentration variables under strict simulation of body temperature by carrying out all manipulations in a 37 °C water bath.

Viral Ribonucleic Acid Synthesis by Newcastle Disease Virus Mutants Isolated from Persistently Infected L Cells: Effect of Interferon

The synthesis of different viral ribonucleic acid (RNA) species was studied in chick embryo (CE) and mouse L-cell cultures infected with the Herts strain of Newcastle disease virus (NDV(o)) and a mutant isolated from persistently infected L cells (NDV(pi)). In CE cell cultures, both viruses synthesized significant amounts of 54, 36, and 18S RNA. However, in L cells, synthesis of 54S virion RNA was markedly reduced. From these results, it seems likely that the low yield of infective virus in L cells is due to a deficient synthesis of 54S RNA in this host. On this basis, however, it is apparent that the "covert" replication of NDV(o) in L cells is due to factors other than viral RNA synthesis. When low concentrations of interferon were used to pretreat CE cells, a differential effect on the synthesis of various RNA species was observed. The 18S RNA of NDV(o) was more sensitive to interferon action than the 36 and the 54S RNA species. In contrast, the 18S RNA of NDV(pi) was less sensitive than the 36S and the 54S RNA. The inhibition of 54S RNA synthesis correlated with the reduction of viral yield and explained the greater sensitivity of NDV(pi) to interferon.

Interaction of interferon with cells: induction of antiviral activity.

A study of interferon–cell interaction has shown that interferon becomes associated with cells (uptake) and that this association is partly reversible. It was further found that "uptake" of interferon was induced by low concentrations of interferon and that this process required host cell messenger ribonucleic acid (mRNA) and protein synthesis. The results of this study are interpreted as indicating that interferon itself is the viral inhibitory substance and the protein induced by interferon is associated with interferon transport.