Serum Levels Of Interferon Research Articles

Antiviral activity of biological response modifiers in a murine model of aids. requirement for augmentation of natural killer cell activity and synergy with oral AZT

We employed the Rauscher murine leukemia virus (RMuLV) as a murine retrovirus model of AIDS, to test biological response modifiers (BRM) and antiviral agents for potential therapeutic activity against the human immunodeficiency virus (HIV). We examined the relationship between the augmentation of natural killer (NK) cell activity and antiviral efficacy of a series of BRM, most of which are known inducers of interferon, in this model. Poly [I,C]-LC, MVE-2, and CL 246,738, but not Ampligen, soluble glucan, or 7-thia-8-oxoguanosine, consistently produced antiviral activity. In addition, the combination of suboptimal doses of oral 3'-azido-3'-deoxythymidine (AZT) (in drinking water) and poly [1,C]-LC produced a synergistic antiviral effect. With all the BRM tested, a consistent pattern emerged, namely that antiviral activity always correlated with the augmentation of splenic NK cell activity in infected animals. For instance, poly [I,C]-LC boosted NK activity much more in infected mice treated therapeutically (treatment initiated after infection) than prophylactically (treatment initiated before infection), and it had greater antiviral activity therapeutically than prophylactically. For the BRM tested, antiviral activity did not occur without augmentation of NK activity in infected mice. In contrast, augmentation of NK activity in uninfected mice bore no relationship to antiviral activity. Furthermore, elimination of NK cells by treating mice with anti-asialo GM 1 abolished the antiviral activity of poly [I,C]-LC. Although splenic NK activity was ablated by anti-asialo GM, serum interferon levels were not affected by this treatment. These results point to a causal connection between the augmentation of NK cell activity and the antiviral efficacy of these BRM in this murine AIDS model. NK cells thus appear to play a key role in resistance to this retrovirus, as has been suggested for HIV.

Serum levels of interferons and TNF-alpha are not correlated to psoriasis activity and therapy.

Sera from 52 patients with psoriasis and 106 controls were tested for IFN-tau, IFN-alpha 2 and TNF-alpha in ELISA and for total IFN activity using an infectivity inhibition micromethod. Psoriasis patients had lower serum levels of IFN-tau than had the controls: median 0.10 ng/ml vs. 0.16 ng/ml (p = 0.01). The highest median serum IFN-tau levels were in patients with peripherally spreading psoriasis, 0.10 ng/ml, and acute guttate psoriasis, 0.09 ng/ml. Patients with stable plaque psoriasis had lower serum IFN-tau levels (median 0.0) than those with other forms of psoriasis, or blood donors. The serum levels of IFN-alpha 2, total IFN activity and TNF-alpha did not differ between the psoriasis and control group. Treatment with cyclosporin, acitretin and the Goeckerman regimen increased the total IFN activity, but did not affect the levels of IFNs nor TNF-alpha.

Immunotoxicity of Mono-Nitrotoluenes in Female B6C3F1 Mice: II. Meta-Nitrotoluene

The nitrotoluenes are chemicals used in dyes, agricultural products, pharmaceuticals and explosives. In the present studies, the toxicology and immunotoxicity of meta-nitrotoluene (m-nitrotoluene) were evaluated. Mice, exposed to m-nitrotoluene at dose levels of 200, 400 and 600 mg/kg/body weight for 2 weeks by gastric gavage, gained body weight over the treatment period to a slightly greater extent than the control groups. Of the selected organs weighed, the liver and kidney of mice exposed to m-nitrotoluene were increased in weight while the thymus weight was decreased. The liver of mice exposed to m-nitrotoluene, but not ortho-nitrotoluene, showed slight to moderate swelling of the hepatocytes adjacent to the central veins. The hepatocyte swelling appeared to be reversible and there was no evidence of necrosis. The hematology and serum chemistries examined were unaffected by m-nitrotoluene exposure although there were modest decreases in the percentage of polymorphonuclear leukocytes and eosinophils in differential blood counts. Bone marrow cellularity and the number of CFU/M and CFU/GM were unaffected by m-nitrotoluene exposure. m-Nitrotoluene suppressed the IgM response to sRBC and the DHR response to KLH. There was a slight (8%) decrease in the percentage of B lymphocytes in the spleen. The response to the T cell mitogens was suppressed by as much as 39%. Fc-mediated adherence and phagocytosis of chicken erythrocytes and NK cell activity were increased dose dependently in mice exposed to m-nitrotoluene. Several immune parameters were unaffected by exposure to m-nitrotoluene, including the IgG response to sRBC, responses to the B cell mitogen LPS and to allogeneic cells, and serum interferon levels. Resistance to Streptococcus pneumoniae and Plasmodium yoelii were unaffected also. Resistance to the tumor model PYB6 was increased. Exposure of mice to m-nitrotoluene decreased resistance to Listeria monocytogenes. The decreased resistance to L. monocytogenes may be related to an effect on T cells, evidenced by a decrease in T cell numbers and in the DHR.

Immunotoxicity of Mono-Nitrotoluenes in Female B6C3F1 Mice: I. Para-Nitrotoluene

para-Nitrotoluene (p-nitrotoluene) is used primarily as an intermediate in the production of various dyes, explosives, pharmaceuticals, and in the production of rubber and agricultural products. Previous investigations indicated that p-nitrotoluene was mutagenic in the Ames Test and that other mono-substituted nitrotoluenes bound covalently to hepatic macromolecules. The objective of these studies was to evaluate the potential immunotoxicity of p-nitrotoluene in mice exposed by the oral route. Mice exposed to p-nitrotoluene (200-600 mg/kg) daily for 14 days showed modest dose-dependent increases in liver and spleen weights. The livers of mice exposed subchronically to 400 and 600 mg/kg showed a mild to moderate swelling of the hepatocytes adjacent to the central veins; this swelling appeared to be reversible and there was no evidence of necrosis. The proportion of monocytes in blood was decreased in mice treated with p-nitrotoluene or toluene. Serum chemistries, bone marrow cellularity and the number of CFU-M and CFU-GM were unaffected. Immunologic investigations showed p-nitrotoluene suppressed the IgM response to sRBC and the DHR response to KLH. There was a 24% decrease in the percentage of CD4+ T lymphocytes in the spleen. There was no dose-dependent alteration of peritoneal macrophage numbers or differential count, unstimulated natural killer cell activity, response to B cell mitogen LPS, C3 activity or interferon levels. Exposure of mice to p-nitrotoluene decreased resistance to Listeria monocytogenes but not to Streptococcus pneumoniae, Plasmodium yoelii or the B16F10 melanoma, and increased resistance to the PYB6 tumor. These studies indicated that the immune system is an important target for toxicity of p-nitrotoluene. The decreased host resistance to L. monocytogenes can be attributed to the decrease in T lymphocytes and to a decreased delayed hypersensitivity response to KLH.

Protective Effect of Carrageenan against Murine Cytomegalovirus Infection in Mice

The protective effect of iota-carrageenan (CAR) was evaluated against murine cytomegalovirus (MCMV) infection in mice. Female ICR mice were challenged intraperitoneally (i.p.) with 3 LD50 of salivary gland-passaged MCMV. More than 0.5 mg of CAR showed a protective effect on mice only when CAR was administered i.p. and then MCMV was inoculated i.p. The protective effect of CAR was evidenced by an increase in plaque-forming unit per LD50 and a decrease in the titre of infectious viruses in the target organs. Neither a virucidal nor a virustatic effect on MCMV was evidenced for CAR. The protective effect of CAR seemed to be host-mediated. Pretreatment of mice with CAR augmented natural killer (NK) activity of the spleen cells without elevating the serum interferon level. However, administration of anti-asialo GM1 antibody did not nullify the inhibitory effect of CAR on virus replication in the target organs. MCMV infection induced leukopenia including neutropenia and lymphopenia in saline-treated mice. Pretreatment with CAR protected mice from those signs, except for slight lymphopenia. Administration of cyclophosphamide induced severe leukopenia including neutropenia and lymphopenia even in CAR-treated mice. Under such conditions, the protective effect of CAR against MCMV infection was abrogated by cyclophosphamide. Thus, the protective effect of CAR seems to be non-NK-mediated.

Inotropic responses of human myocardium in ischemic heart disease

It was shown that human recombinant gamma IFN given to volunteers intramuscularly (90 x 10(3) IU) and by inhalation (120 x 10(3) IU) induced 5-10-fold increase circulating IFN (up to 40-60 IU/ml); the activities of 2,5-oligoadenylate synthetase increased 1.5-2 fold and protein kinase of lymphocytes--3-5-fold. The repeated doses of gamma IFN at 12-15-hour intervals maintained a relatively stable IFN status, the inhalatory route of application being more effective. Convalescents after influenza different from healthy donors by a higher level of serum interferon and activity of 2.5-oligoadenylate synthetase but the activity of protein kinase was lowered in lymphocytes and plasma. The side effects induced by IFN administration were more marked only after intramuscular injections of 90 10 IU and were absent after inhalation of IFN (120,000 IU).

Immunological Abnormalities in Adults Treated with hGH in Childhood; Responses to One Month Trial of hGH

Twelve adult patients with growth hormone deficiency (GHD) were studied in regard to serum levels of immunoglobulins, immunoglobulin G (IgG) subclasses, natural killer (NK) activities, interferon (IFN) augmented NK activities and lymphokine activated killer (LAK) activities before and after one month of human growth hormone (hGH) treatment. They were compared with 114 age-matched controls. All the patients were diagnosed as having GHD in childhood and had been treated with hGH for more than 5 years. The present study was performed 1 to 7 years after the cessation of hGH treatment.Serum immunoglobulin G1 (IgG1) levels and IFN augmented NK activities in the patients were significantly lower than in the controls, although NK and LAK activities of the patients were normal. Therefore it was concluded that NK and LAK activities were maintained at normal levels without hGH in adults who had been treated with hGH, although IFN augmented NK activities were reduced without it. It seems that longer treatment with hGH is needed to produce normal levels of serum IgG1 and IFN augmented NK activities.

Pharmacokinetic properties of recombinant feline interferon and its stimulatory effect on 2',5'-oligoadenylate synthetase activity in the cat.

The pharmacokinetic behavior of recombinant feline interferon produced in silkworm infected with recombinant baculovirus harboring cDNA coding for feline interferon was studied in vivo in cats. The decreasing profile of the serum interferon level after intravenous administration was fitted to a two-compartment model. The half-times of the first phase (distribution phase) and second phase (metabolic phase) were 5.0 +/- 0.5 min and 31 +/- 5 min, respectively. In the whole body autoradiogram, at 15 min after the administration, the highest radioactivity was observed in urine in the bladder, and predominant radioactivity in the kidneys, liver, thyroid gland and spleen. Almost no radioactivity was detected in the brain or fat. Three hr after administration, the highest radioactivity was recorded in the thyroid gland, urine in the bladder, intestinal contents, and gastric mucous membrane. The data obtained in this study suggest that recombinant feline interferon has similar pharmacokinetic properties to human interferons and that it is distributed primarily in the liver and kidneys, is catabolized rapidly mainly in the kidneys, and is excreted in the urine without residual accumulation in the body. It was confirmed that 2',5'-oligoadenylate synthetase activity was increased by the interferon in vivo for 3 days after an intravenous bolus injection in cats.

Interferon production in severe hemophiliacs with and without HIV antibodies.

The interferon (IFN) system, both serum IFN levels and the in vitro IFN production, was investigated in 38 clinically asymptomatic multitransfused hemophiliacs, half positive and half negative for HIV antibodies. In most patients, no circulating IFN was detected; similar levels of IFN-alpha were obtained after peripheral blood mononuclear cell (PBMC) stimulation with Sendai virus both in hemophiliacs and controls, while production of IFN-gamma following stimulation with phytohemagglutin (PHA) was diminished in a large number of patients irrespective of their HIV serology. These data indicate that the deficiency in IFN-gamma generation is not only related to HIV contamination but may be a direct consequence of the chronic antigenic stimulation through Factor VIII concentrates.

Protective value of elevated levels of gamma interferon in serum against exoerythrocytic stages of Plasmodium falciparum

In vitro experiments suggested that gamma interferon, CD8+ T cells, and anticircumsporozoite antibodies inhibited the exoerythrocytic stages of malaria parasites. To assess the role played in vivo by these factors, we conducted a prospective study in Madagascar. Forty individuals with a negative blood smear were followed for 8 weeks to detect the appearance of parasites in blood. Nineteen subjects remained negative for malaria, whereas 21 individuals became positive during follow-up. Among these, seven presented with blood parasites within the first 2 weeks and were excluded, as they probably were infected by sporozoites at enrollment. When measured at enrollment, antibodies to the synthetic peptide (NANP)5, lymphocyte proliferation with (NANP)5, and various lymphocytes subsets were similar among individuals that later presented with a Plasmodium falciparum blood infection or were not infected. Conversely, the level of gamma interferon in serum was higher in individuals that did not present with a P. falciparum infection during follow-up. These data suggest that gamma interferon may inhibit the malaria exoerythrocytic stages of development under in vivo conditions, as it does in vitro.

Inhibition of induction of natural killer activity in mice by general anesthesia (Avertin): Role of interferon

We have previously reported that general anesthesia (Avertin) inhibits the induction of natural killer (NK) cell activity following administration of Poly I:C in vivo. Since Poly I:C has been shown to increase NK activity through the induction of interferon (IFN), the current study examines the role of IFN in this inhibition. The data suggest that (i) anesthesia does not effect the ability of Poly I:C to induce endogenous IFN synthesis (serum IFN levels are unaltered by anesthesia) and (ii) anesthesia is capable of inhibiting stimulation of NK activity induced directly by treatment with IFN either in vivo or in vitro. The duration of the former effect was at least 10 days, with complete recovery by Day 14 after anesthesia. Interestingly, NK activity stimulated by IFN prior to anesthesia was not significantly altered. In view of the increasingly evident role of NK cells in anti-tumor and anti-infectious host defenses, their inertness to stimulation in the postanesthesia period may be a significant contributing factor to the clinically observed postoperative morbidity. Thus, preanesthesia stimulation of NK activity with IFN may be of therapeutic value.

Dissociation between antiinflammatory action of tilorone and its interferon inducing activity

A relation between antiinflammatory action of tilorone and its interferon inducing activity was studied in rats. Tilorone (20-100 mg/kg, p.o.) was dose-dependently effective on both carrageenin oedema and passive Arthus, suggesting that the pharmacological property of the compound is different from nonsteroidal antiinflammatory medicaments which were weak inhibitors of passive Arthus. The antiinflammatory action of tilorone had a time-lag and priming with tilorone 24 hrs prior to inflammatory insult was required to demonstrate maximal efficacy. This time course change was similar to that of serum interferon level. In addition, a high correlation was observed between the antiinflammatory activity and the serum interferon level. However, the antiinflammatory action was scarcely affected even if the serum interferon level was remarkably lowered by treatment of an inhibitor of protein biosynthesis, cycloheximide. These findings suggested that the antiinflammatory action of tilorone could be dissociated from its interferon inducing activity.

Comparative Evaluation of Specific Vaccines and Immuno‐Modulators in Disease Control of Beef Cattle

Two field trials were undertaken to evaluate specific vaccines and Biological Response Modifiers (B.R.M.) with regard to disease control of beef cattle. Clinical data and laboratory results strongly suggested a genetically determined resistance to transportation stress of some cattle breeds, with possible important consequences on the occurrence of multi-factor diseases. Plenty of calves showed detectable levels of serum interferon and a remarkable activation of at least some lymphocyte populations in the first days after arrival. In general, B.R.M.-treated cattle could better react against environmental pathogens, as evidenced by both clinical and laboratory findings. Several data emerged that even the efficacy of specific vaccines could be largely accounted for by a positive modulation of non-specific immunity; this latter feature can be mainly referred to adjuvants and/or some bacterial antigens.

Study of immune function of cancer patients influenced by supplemental Zinc or Selenium-Zinc combination

Since hair Zn and serum Zn are usually decreased in cancer patients, and Zn deficiency may reduce the function of T-cells, granulocytes, and Nk cells, we observed in cancer patients the influences of the Zinc or Selenium-Zinc on DNCB skin delayed hypersensitivity mediated by T cell, and the effects of Zinc on oxidative metabolic function of neutrophils and level of serum interferon that potentiate NK cell activity. The results showed that DNCB skin reaction was strengthened, the oxidative metabolic function of neutrophils and serum interferon level were increased by the drugs. It is reasonable to expect that Zinc or Selenium-Zinc is instrumental in restoring failing immunocompetence of cancer patient.

Serum Levels of Interferon-gamma, Cytotoxic Factor and Soluble Interleukin-2 Receptor in Childhood Hemophagocytic Syndromes.

Serum levels of interferon (IFN)-gamma, cytotoxic factor (CF) and soluble interleukin-2 receptor (sIL2R) were assayed in relation to hyperferritinemia in eleven cases of malignant histiocytosis (MH), seven of virus-associated hemophagocytic syndrome (VAHS) and one of familial erythrophagocytic lymphohistiocytosis (FEL). IFN-gamma was markedly elevated (>10,000 U/ml) in 5 MH cases and only in one case of VAHS. CF was significantly elevated (> 150 U/ml) in 5 MH and 4 VAHS/FEL patients. sIL2R were remarkably elevated (> 10,000 U/ml) in 5 MH and 4 VAHS patients. In individual cases, the patterns of these parameters were quite different, suggesting the existence of a variable pathophysiology in cases with hemophagocytic syndromes. In terms of the patients' outcome, high IFN-gamma or sIL2R levels were associated with a poor prognosis while high CF appeared to be associated with a better prognosis.

The interferon system in carcinoma of the cervix. Effect of radiation and chemotherapy

Thirteen patients with advanced carcinoma of the cervix were studied for parameters of the interferon system compared with 40 age-matched and sex-matched controls. All patients had measurable serum interferon levels; controls did not. All patients had non-antibody-type interferon-inhibitory activity, and controls had none. Interferon-synthesizing potential was higher in controls than in patients. After successful radiation and chemotherapy, these parameters normalized in the patients. No change was seen in one patient who did not respond to therapy.

50 INTERFERON PRODUCTION IN NEWBORNS: THE EFFECT OF DIPYRIDAMOLE

The ability of dipyridamole to stimulate interferon production in adults is known since 1978. The aim of our investigation was to reveal the existance of such ability in newborns. 43 newborns with both uncomplicated and complicated respiratory infections were examined. They received dipyridamole (CurantylR) orally in a single dose equal to 2-3 mg/kg body weight. Control group consisted of 50 newborns with identical disease not treated with dipyridamole. Serum level of interferon was determined before treatment and at 24, 48, 72 and 96 hours after the treatment. Interferon titers before treatment in both groups were below 1:8. In newborns treated with dipyridamole interferon titers at 24 and 48 hours were 1:16 and 1:45, respectively, and decreased to the basic level after 72-96 hours. Interferon titers in the control group did not change significantly. Our results suggest that newborns react to interferonogen dipyridamole in similar way as do adults and elder children.

Host-mediated antiviral activity ofLactobacillus casei against cytomegalovirus infection in mice

The protective effect of heat-killed Lactobacillus casei (LC) against murine cytomegalovirus (MCMV) infection was examined. ICR mice treated once with LC 1 day or 2 days before challenge survived lethal infection, but untreated or Lactobacillus fermentum (LF)-treated mice did not. The protective effect was evidenced by an increase in plaque-forming units (PFU) per 50% lethal dose (LD50) and a decrease in titers of infectious viruses replicated in the target organs. This was further confirmed by severity of histopathological damage to the target organs, especially the liver. LC neither inactivated MCMV nor inhibited its replication in mouse embryonic fibroblasts (MEF). The spleen cells from LC-treated mice inhibited its replication in MEF on co-cultivation. Augmentation by LC of splenic natural killer (NK) cell activity correlated with survival of mice from otherwise lethal MCMV infection. Cytotoxic activity of peritoneal cells and level of serum interferon (IFN) were elevated after MCMV infection, but they were not associated with survival of mice nor with treatment of LC. The protective effect of LC was not clear in NK-deficient beige mutant (bgJ/bgJ) mice, when compared with that in their littermate (bgJ/+) mice. Poor protection of bgJ/bgJ mice by LC treatment correlated with failure to induce NK cell activity by LC treatment in the mutant mice. Thus, it is likely that LC protects mice from MCMV infection by augmentation of NK cell activity.

Elevated Serum Interferon Levels in Patients With Bell's Palsy

Serum interferon (IFN) levels were analyzed in patients with Bell's palsy to study the immune response in the disease. Serum samples from 91 patients were assayed for antiviral activity using a bioassay. The IFN levels in the serum were elevated in the acute and convalescent phases as compared with control subjects. The serum IFN-gamma levels were analyzed by radioimmunoassay in 32 of the patients: the IFN-gamma levels were alike in the acute and convalescent phases and the control subjects. Neutralization with specific antisera against IFN-alpha, -beta, and -gamma on 15 serum samples of 11 patients with elevated IFN activity showed a complex pattern that indicates that the antiviral activity was due to a mixture of IFNs and possibly also due to other factors. The elevated IFN levels indicate a low-grade antiviral response that may reflect the reactivation of a viral infection.

<I>Chlamydia trachomatis</I>接種マウスの免疫応答

We examined the immune response against Chlamydia trachomatis (serovar L2) inoculation in mice by measuring the serum interferon (IFN) level, 2'-5'A synthetase (2-5A(S] activity, antibody titers (IgM, IgG) and the spleen weight as parameters of infection. The interferon activity was detected 6 hrs (400 U/ml) and the activity peaked 12 hrs (450 U/ml) after inoculation, and then gradually decreased thereafter (24 hrs: 12 U/ml, 36 hrs: undetectable). It was found that Chlamydia trachomatis induces IFN as well as bacteria. To monitor the behavior of IFN action after serum IFN was cleared, 2-5A(S) activity in the spleen cell extract was measured. It was found that the activity reached its peak 1 to 2 days after inoculation and then decreased as well as in infectivity of Chlamydia trachomatis. The activity however was almost not detected in sera of mice after inoculation of heat-inactivated Chlamydial organism (56 degrees C, 10 min). This may indicate that intact Chlamydial organisms were required for induction of IFN. IFN induced in mice was stable in pH 2.0 treatment and IFN induced by Newcastle disease virus inhibited growth of Chlamydia trachomatis in L929 cell cultures in a dose-dependent manner. The weight of the spleen gradually increased and reached its peak (2- to 3-fold of the control) in 3 to 5 days after inoculation, and then gradually decreased to the control level. IgM and IgG antibodies to Chlamydia trachomatis were detected by immunofluorescence method and enzyme-linked immunosorbent assay, respectively. The antibody IgM was detected as early as 2 days and reached its peak 3 to 4 days after inoculation.(ABSTRACT TRUNCATED AT 250 WORDS)