Search PubMed⌕ Search

Biomedical subjects

N Stebbing

Publications and source records attributed to N Stebbing.

At least 37 records · Page 2Linked to original sources
PubMed1985

Regulation of T cell proliferation by cloned interferon-alpha mediated by Leu-11b-positive cells.

The autologous T lymphocyte proliferative response (AMLR) induced by a B lymphocyte-enriched non-T, nonadherent cell population (NT, NAC) and by a macrophage-enriched population were both suppressed by the addition of a cloned interferon-alpha (IFN-alpha Con1) directly to the cultures. Preincubation of the stimulating NT, NAC with IFN-alpha Con1 resulted in comparable suppression. In contrast, preincubation of the macrophages with IFN-alpha Con1 resulted in significant augmentation of T cell proliferation. Depletion of Leu-11b-positive cells from the NT, NAC exposed to IFN-alpha Con1 restored the autologous T cell response. Addition of IFN-alpha Con1 activated Leu-11b-positive cells, isolated from the NT, NAC population, was suppressive of the AMLR. Although NK cytotoxicity was irradiation sensitive, suppression of the AMLR by IFN-alpha Con1-activated NT, NAC was resistant, suggesting that different subsets of cells or mechanisms by the same cells may have been responsible. These observations may offer insights into the potential role of cells with the NK phenotype, Leu-11b, and IFN in contributing to immuno-regulatory changes observed in clinical states associated with elevated concentrations of IFN.

Antibodies, Monoclonal↗
PubMed1985

Stimulation of in vitro immunoglobulin production by interferon-alpha.

The effect of various natural and recombinant DNA-derived human interferon-alpha (IFN-alpha) on immunoglobulin (Ig) production by human B cells was investigated. The cell populations examined included peripheral blood mononuclear cells (PBMC) and highly purified B cell and helper T cell populations obtained by negative selection by using monoclonal antibodies and a fluorescence-activated cell sorter. In the presence of all forms of IFN-alpha tested, IgG and IgM production by PBMC increased twofold to fourfold. This increase was noted in the absence of pokeweed mitogen (PWM), was not affected by depletion of monocytes, required that IFN-alpha was present early in the culture period, and reached maximal levels around 500 U/ml IFN-alpha. Both IgG and IgM production were affected, but the magnitude of the IgM response was greater. The augmentation of Ig production was noted with the recombinant DNA-derived subtype, IFN-alpha F, two analogs, IFN-alpha Con1 and IFN-alpha Con2, as well as with buffy-coat-derived (leukocyte) IFN-alpha. The recombinant DNA-derived forms of IFN-alpha appeared to differ in their ability to augment Ig production. In the presence of PWM, IFN-alpha Con1 failed to increase Ig production by PBMC. In contrast to these results with PBMC, IFN-alpha Con1 increased the Ig production of purified B cells 10- to 20-fold in the presence of PWM. This increase reached maximal levels around 500 U/ml IFN-alpha Con1. Although purified B cells responded to IFN-alpha and PWM, maximal responses occurred in the presence of low numbers of helper T cells. Cell dilution experiments suggested that the effect observed with purified B cells was the result of the interaction of B cells with residual cells, e.g., helper T cells, remaining in the preparations.

Antibody Formation↗
PubMed1985

Human alpha and gamma interferon analogs in rabbits with herpetic keratitis.

Complete gene synthesis methods have been used to construct analogs of human interferons (IFNs): these include a consensus of the known human IFN-alpha S, designated IFN-alpha Con1 and a variant of human IFN-gamma, designated IFN-gamma 4A. These interferons, in purified form, were used topically against herpes simplex virus type 1 (HSV-1) induced ocular keratitis in rabbits. Eyes pretreated with IFN-alpha Con1 had decreased signs of infection and a lower incidence of HSV-1 positive trigeminal ganglia (3 of 14 positive) compared to the placebo treated (10 of 14 positive). IFN-alpha Con1 was as effective as natural IFN-alpha subtypes on a units basis, despite the very high specific activity of this analog. IFN-gamma 4A used under similar conditions do not result in beneficial effects with treatments beginning 24 or 48 hr before or 4 hr after virus inoculation. Rabbits with confirmed latent HSV infection were treated topically with IFN-alpha Con1 (10(6) units per eye each day) either before or before and after attempts to intentionally reactivate the infection by bilateral iontophoresis of 6-hydroxydopamine plus topical epinephrine treatment of the corneas. These IFN-alpha Con1 treatment regimens along with intentional reactivation during latency did not: (1) lessen the frequency of inducible ocular shedding episodes; (2) alter the mean time of 3-5 days between attempts to reactive latent infection and the appearance of HSV in tears; or (3) significantly change the incidence of HSV-positive trigeminal ganglia (83-100% HSV positive).

Administration, Topical↗
PubMed1985

Therapeutic considerations for use of immunomodulators in the treatment of ataxia-telangiectasia.

The nature of the soluble mediators of immune regulation, the lymphokines, is now being determined and this allows consideration of new approaches to treatment of disorders involving immune dysfunction, such as ataxia-telangiectasia. The immunomodulatory effects of interleukin-2, interferons, and known chemotherapeutic agents such as cyclophosphamide are considered in relation to the immune disorders of ataxia-telangiectasia. The possible etiology of the disease and its treatment are considered in relation to the immunopathologic effects that are observed.

Ataxia Telangiectasia↗
PubMed1984

Relationship between the antiviral effects of interferons and their abilities to depress cytochrome P-450.

Several hybrid human interferons have now been constructed by recombinant DNA techniques. Two of these hybrid interferons, IFN-alpha AD(Bgl) and IFN-alpha AD(Pvu) differ by only three amino acids, but IFN-alpha AD(Bgl) was fifteen times more potent than IFN-alpha AD(Pvu) in antiviral activity towards infection of mouse L-929 cells by vesicular stomatitis virus. Only the hybrid with the greater antiviral activity in the mouse depressed cytochrome P-450, aminopyrine N-demethylase and benzo[a]pyrene hydroxylase in the liver. These experiments demonstrate that minor changes in amino acid structure not only have a major effect on the antiviral properties of interferon but also influence the ability of interferon to depress cytochrome P-450 in the liver.

Aminopyrine N-Demethylase↗
PubMed1984

Modulation by a human interferon of antitumor effects of cyclophosphamide against a lymphosarcoma in hamsters.

Administration to hamsters of a highly purified human leukocyte interferon subtype, IFN-alpha A, obtained by recombinant DNA methods, abolished the efficacy of high doses of cyclophosphamide (2.5 mg/hamster) against the TBD 932 lymphosarcoma. The effect was more pronounced with concomitant than with sequential treatments and did not occur with melphalan. Antagonistic effects occurred at high interferon doses (10(5) I.U./treatment), but an additive or synergistic positive effect occurred at lower interferon doses (10(3) I.U./treatment) and at lower, non-protective, doses of cyclophosphamide. These effects may be due to immunomodulatory responses induced by the drugs involved.

Animals↗
PubMed1983

Human leukocyte interferon subtypes have different antiproliferative and antiviral activities on human cells.

The antigrowth effects of 5 different cloned human leukocyte IFN subtypes (IFN-alpha A, B, C, D, F) and 2 molecular hybrids between them (IFN-alpha AD(Bg1II) and IFN-alpha DA(Bg1II)) were examined on 6 different human cell lines. The results indicate that the interferons sort into two distinct groups: IFN-alpha B, C and F showed comparable antiproliferative activity which was greater than that of IFN-alpha A, D, AD(Bg1II) and DA(Bg1II). The interferons could also be assigned to one of two groups on the basis of their antiviral activity. IFN-alpha A, D and AD(Bg1II) were observed to be more protective than IFN-alpha B, C and F against HSV-2 and EMCV infections, i.e. the relative antiviral efficacies of the cloned IFN subtypes were the reverse of their antiproliferative activities.

Antiviral Agents↗
PubMed1983

Antiviral effects of bacteria-derived human leukocyte interferons against encephalomyocarditis virus infection of squirrel monkeys. Brief report.

Two human leukocyte interferon sub-types (IFN-alpha A and -alpha D) produced in E. coli and a hybrid interferon (IFN-alpha AD[Bgl]) consisting of the N-terminal 61 residues of IFN-alpha A and the C-terminal 104 residues of IFN-alpha D were compared for antiviral activity against EMC virus infection of squirrel monkeys. Marked reduction in viremia and a decrease in the incidence of deaths occurred with highly purified preparations of the recombinant-DNA derived interferons. Dose response studies showed that IFN-alpha D and -alpha AD (Bgl) were more effective than IFN-alpha A.

Animals↗
PubMed1983

Antiviral activities of cloned human leukocyte interferons against herpes simplex virus type 2 infections of mice.

Human alpha-interferons (IFN-alpha s) made in bacteria were examined for antiviral activity against herpes simplex virus type 2 (HSV-2) infections of mouse L-cells in vitro, and acute cervicovaginal and lethal systemic HSV-2 infections of BALB/c mice. The recombinant DNA-derived hybrid interferon IFN-alpha AD(Bgl) showed pronounced antiviral activity in vitro, exceeding the activity of either of the parental subtypes IFN-alpha A and IFN-alpha D and that of the other hybrids IFN-alpha AD(Pvu) and IFN-alpha DA(Bgl). A combination of topical and systemic treatments with IFN-alpha A and IFN-alpha AD(Bgl) failed to protect mice from subsequent challenge with an acute cervicovaginal infection of HSV-2. Protection from lethal systemic HSV-2 infection in mice was observed when IFN-alpha AD(Bgl) and IFN-alpha AD(Pvu) were administered systemically, whereas IFN-alpha A failed to confer protection. These results suggest that for protection against infection with HSV-2, the routes of introduction of the virus and of the interferon influence the host response to interferon therapy.

Animals↗
PubMed1983

Antiviral effects of human fibroblast interferon from Escherichia coli against encephalomyocarditis virus infection of squirrel monkeys.

Recombinant DNA methodology has allowed the production of human fibroblast interferon (IFN-beta) from Escherichia coli and this material, in highly purified form, has been shown to reduce viraemia and mortality in encephalomyocarditis (EMC) virus-infected squirrel monkeys. These effects are dose related: six treatments over 4 days at 10(6) U/kg and 3 x 10(3) U/kg have comparable efficacy, whereas treatments at 10(3) U/kg are ineffective. The recombinant DNA-derived IFN-beta appears to be as effective as natural fibroblast cell-derived IFN-beta and both materials are effective by the intramuscular or intravenous routes. Thus, even though previous studies have shown that low circulating concentrations of IFN-beta are observed after intramuscular injections, the present data indicate that this slow release from the muscle can still confer protection.

Animals↗
PubMed1983

Effects of cloned human leukocyte interferons in the human tumor stem cell assay.

Clonogenic tumor cells from fresh biopsies of human cancers were cultivated in vitro and tested for sensitivity by continuous exposure to pharmacologically achievable concentrations of either of two highly purified human leukocyte interferon subtypes (IFN-alpha A and IFN-alpha D) prepared by recombinant DNA methods. The interferons were compared on a weight basis at concentrations of 0.4 and 4.0 ng/ml (equivalent to 80 and 800 units of interferon activity for IFN-alpha A and 2.0 and 20 units for IFN-alpha D). Inhibition of tumor colony-forming units (50% of control or less) was observed in 38.1% of the 273 tumors tested against IFN-alpha A, and in 16% of the 71 tumors tested against IFN-alpha D. Of the tumor types with at least ten samples tested against IFN-alpha A, the percentage of cases exhibiting inhibition was as follows: melanoma (51.7%), lung cancer (50%), myeloma (33.4%), ovarian cancer (33.9%), sarcoma (33.3%), adenocarcinoma of unknown primary (30.4%), breast cancer (28%), acute leukemia (30.8%), and renal cancer (23%). More marked inhibition (30% of control or less) was observed in 18.7% of all tumors tested against IFN-alpha A. Of 60 melanomas tested, 18 (30%) exhibited marked in vitro inhibition of growth with IFN-alpha A. Although a smaller number of tumors (71) were tested against IFN-alpha D on a weight basis, it appeared, in general, to be slightly less active than IFN-alpha A (p less than 0.01), and only 8% of tumors tested exhibited marked inhibition over the same dosage range of interferon. Comparison of the dose-response curves for the 68 tumors tested simultaneously against both interferons did not reveal marked interpatient differences in the inhibition curves, although IFN-alpha D was slightly less active overall. Tumors exhibiting at least 50% inhibition of tumor colony formation also proved to be sensitive to a significantly larger number of cytotoxic drugs (tested simultaneously) than the tumors not inhibited with interferon (p less than 0.0001 for IFN-alpha A). We conclude that the in vitro clonogenic assay may aid in targeting tumor types most likely to exhibit interferon sensitivity and assist in case selection for entry into clinical trials with cloned interferons.

Antineoplastic Agents↗
PubMed1983

Influence of various purified interferons on effects of drugs in mice.

Direct determinations indicate that some types of interferon increase the duration of hexobarbital-induced sleep time and decrease acetaminophen toxicity. Pretreatment of mice with cloned human leukocyte interferon subtype A, IFN-alpha A, did not increase hexobarbital sleep time but pretreatment with mouse interferon or a hybrid human leukocyte interferon, IFN-alpha AD (Bgl), increased the duration of the effect of the barbiturate. Hybrid IFN-alpha AD (Bgl) also decreased the lethality of acetaminophen. These findings are predictable based on reports of hepatic cytochrome P450 depression resulting from treatment with some interferons.

Acetaminophen↗
PubMed1983

Importance of treatment regimen of interferon as an antitumor agent.

A highly purified hybrid human leukocyte interferon, IFN-alpha AD, produced in Escherichia coli, has been used to define optimum treatment conditions for L1210 leukemia in mice. Treatments prior to tumor inoculation were ineffective. Treatments from the third day post-tumor inoculation were most effective, and treatments every third day were more effective than were regimens involving more frequent treatments. IFN-alpha AD was effective in vivo against tumors formed from a line of L1210 cells resistant to IFN-alpha AD in cell cultures. These and other results indicate the importance and nature of indirect mechanisms of action for efficacy of interferons against tumors.

Animals↗
PubMed1983

Effects of nephrectomy on the pharmacokinetics of various cloned human interferons in the rat.

The pharmacokinetics of two human leukocyte interferon (IFN) subtypes (IFN-alpha A and IFN-alpha D) and two molecular hybrids [IFN-alpha AD(Bgl) and IFN-alpha AD(Pvu)] was studied in rats receiving single i.v. injections, 5.0 X 10(6) I.U./kg, of these materials. All four preparations were highly purified and resulted in plasma decay curves with similar elimination half-lives of 95.3 +/- 13.5 min. The four IFN-alpha subtypes investigated showed differences when their clearances are compared, suggesting that the 13 residue differences between amino acids 92 and 165 affect the clearance. The fact that only IFN-alpha D has an apparent volume of distribution (Vd beta) of 12.9 +/- 3.4 liters/kg whereas the other three IFN-alpha subtypes have Vd beta of 5.7 +/- 1.0 liters/kg suggests that the amino acid differences between residues 1 and 61 affect the Vd beta. Only in the case of IFN-alpha D did functional nephrectomy significantly (P = .02) increase the apparent volume of distribution at steady state. Functional nephrectomy before i.v. injection resulted in a 4-fold decrease in IFN-alpha AD(Bgl) and IFN-alpha AD(Pvu) clearance, an 8-fold decrease in IFN-alpha A clearance and a 10-fold decrease in IFN-alpha D clearance. The elimination half-life of each interferon was unchanged after nephrectomy. Intramuscular administration of the IFN-alpha subtypes in rats produced low plasma concentrations. IFN-alpha D peaks at 39 +/- 10 I.U./ml of plasma, whereas IFN-alpha A reaches 201 +/- 53 I.U./ml, IFN-alpha AD(Bgl) reaches 396 +/- 47 I.U./ml and IFN-alpha AD(Pvu) results in a maximum plasma concentration of 747 +/- 66 I.U./ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1982

Natural and cloned human leukocyte interferon in herpesvirus infections of rabbit eyes.

Human buffy-coat interferon and a leukocyte subtype (LeIF-A) obtained by gene cloning in Escherichia coli were equally effective in ameliorating the course of herpetic keratitis in rabbits when applied topically at a daily dose of 0.5 X 10(6) units per eye for six days commencing one day before infection. When given intramuscularly at the same dose, there was no alteration in the course of the disease. Topical treatments with LeIF-A were equally effective in suppressing epithelial damage seven days after infection, regardless of whether treatment commenced one day before infection or two days after infection. However, treatment from the day before infection also caused a significant decrease in epithelial defect two days after infection.

Administration, Topical↗