Cachectin/tumour-necrosis-factor production by cancer patients.
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Glycoproteins↗
Biomedical subjects
T Hahn
Publications and source records attributed to T Hahn.
Increase of vulnerability to lymphotoxin in cells infected by vesicular stomatitis virus and its further augmentation by interferon.
The cytotoxic effect of lymphotoxin (LT) and its modulation by interferon (IFN) was quantitatively assessed in uninfected and vesicular stomatitis virus (VSV)-infected cultured cells. Preparations of human LT, which were depleted of IFN, had a significant cytotoxic effect on VSV-infected HeLa, SV-80, WISH, and Vero cells. IFN, most notably IFN-gamma, further potentiated destruction of the infected cells by these LT preparations, when applied on the cells at sub-antiviral IFN concentrations. In contrast, no cytotoxic effect could be observed in any of the examined cells, when applying LT, IFN, or their combination, in the absence of viral infection. Infected cells in which VSV replication was suppressed by treatment with antiviral concentrations of IFN also resisted destruction by LT. These findings indicate that LT cytotoxicity can be selectively directed against virus-infected cells and that IFN can augment this cell-killing mechanism when failing to exert an antiviral effect.
Animals↗
Activated interferon system in healthy homosexual men.
More than 50% of a group of healthy homosexuals in Israel were found to have an activated interferon (IFN) system as evidenced by markedly elevated blood IFN levels, increased in vitro production of IFN by unstimulated peripheral blood mononuclear cells and HuIFN-alpha and HuIFN-gamma production by appropriately stimulated cells, and a surprisingly high incidence of an antiviral state of cells. This pattern resembles that found in persons with acute viral illness, and is unlike that found in normal healthy controls. The type of IFN in the blood was found to be unusual in that it was mainly HuIFN-alpha, pH 2-labile, a type of IFN found in certain collagen diseases as well as in homosexual men suffering from Kaposi's sarcoma or lymphadenopathy. Natural killer (NK) cytotoxic activity was found to be somewhat lower than that found in normal controls, although no correlation was found between blood IFN levels and NK activity. Mean (2'-5')-oligoisoadenylate synthetase levels in cell extracts were intermediate between normal controls and patients with viral illness. Likewise no correlation was found between enzyme levels and blood IFN levels. The highly activated IFN system found in certain homosexuals, as well as the increased spontaneous production of IFN by unstimulated mononuclear cells, suggest the possibility of the presence of a virus, active or latent, in these individuals. This virus could be a retrovirus such as HTLV-III or LAV which have recently been isolated from AIDS patients. The special type of IFN present could be the response to a novel virus in an unusual situation. On the basis of recent reports, we speculate that homosexuals with highly activated IFN systems who produce pH 2-labile HuIFN-alpha could be at increased risk for developing AIDS.
Acquired Immunodeficiency Syndrome↗
Involvement of cytotoxins in the immune response to viral infection.
A human cytotoxin (CTX) with an Mr of 17,500 was purified to homogeneity from cytokine preparations by the use of a monoclonal antibody against that protein. Sendai virus and, to a lesser extent, the lectin phytohemagglutinin were found to induce effective production of that CTX in cultures of human peripheral-blood mononuclear cells, the first - by stimulating monocytes to produce the proteins, and the latter - by stimulating T cells. With both kinds of inducers, CTX production correlated to a marked increase in the cellular levels of mRNA for CTX, as quantitated by translation of that mRNA, to biologically active CTX, in microinjected Xenopus oocytes. Crude CTX preparations, as well as purified CTX, were found to be selectively cytotoxic to metabolically depressed and to virus infected target cells; they effectively killed cells which were treated with inhibitors of macromolecule synthesis, such as cycloheximide, or infected by viruses, such as VSV, but failed to exert a cytotoxic effect in the absence of such sensitizing treatments. IFN, most notably IFN-gamma, further potentiated destruction of virus-infected cells by the purified CTX, when applied on these cells at subantiviral concentrations, while uninfected cells remained resistant to CTX following treatment with IFN. Formation of the 17.5K CTX in response to viral infection and the selective cytotoxic effect of that protein on cells infected by viruses, indicate a role of CTX in the defense against viral infections.
Animals↗
Use of monoclonal antibodies to a human cytotoxin for its isolation and for examining the self-induction of resistance to this protein.
Crude preparations of cytotoxins (CTXs) produced by human peripheral blood mononuclear cells exert a marked cytotoxic effect when applied to cells in the presence of cycloheximide but in its absence can induce resistance to cytotoxicity. To examine the relationship between these cytotoxic and protective activities, we attempted to fully dissociate the CTX from the other proteins secreted by mononuclear cells. Mice injected with preparations of the cytokines secreted by peripheral blood mononuclear cells developed significant titers of serum antibodies to CTX(s). Splenocytes of such immunized mice were fused with NSO myeloma cells; a few among the resulting hybridoma cells secreted CTX-binding antibodies. Immunoadsorbents constructed with a monoclonal antibody produced by one of these hybridomas were used to purify to homogeneity a CTX (Mr approximately 17,500) from crude preparations of cytokines, by a single adsorption and elution cycle. Purified CTX was cytotoxic in the presence of cycloheximide but in its absence induced resistance to cytotoxicity; this resistance was manifested by decreased vulnerability to CTX in a subsequent incubation in the presence of cycloheximide. We conclude that CTX itself can induce certain changes in cells, which are reflected in resistance to its own cytotoxic effect.
Animals↗
Interferon deficiency syndrome.
Activation of the interferon (IFN) system is an early defence mechanism against viral infections. The virus stimulates production of IFN by nucleated cells including the peripheral blood mononuclear cells (PBMC), and this IFN in turn activates several IFN-dependent immune mechanisms including the induction of an anti-viral state in cells, which prevents or retards further intracellular viral replication. In an ongoing study of 1,500 individuals of all ages and with various illnesses, we found 15 cases (representing 5% of patients with acute viral disease) in whom the IFN system response during an acute viral illness was absent or grossly deficient. There was no detectable IFN in the blood, PBMC did not produce IFN-alpha and IFN-gamma or produced minimal amounts of one of them in vitro following appropriate stimulation, and the patients' PBMC were not in an anti-viral state. These patients had severe progressive or fulminant viral disease, often ending fatally. IFN therapy appears to be beneficial in these cases, as it rapidly induced a cellular antiviral state in most cases, stimulated in vitro IFN-alpha and IFN-gamma production by PBMC, and led to rapid recovery in seven of the nine patients who received treatment for at least 3 days. In our opinion IFN replacement therapy should be commenced as early as possible in such cases, and before irreversible cell and organ damage occur.
Adolescent↗
Translation of mRNA for human lymphotoxin in microinjected Xenopus oocytes.
Synthesis and secretion of biologically active human lymphotoxin (LT) can be detected in Xenopus laevis oocytes following their inoculation with poly(A+) RNA from human stimulated peripheral blood lymphocytes, but not in oocytes inoculated with RNA from unstimulated lymphocytes or from fibroblastoid cells. In size-fractionating mRNA of stimulated lymphocytes most LT activity is found to be coded for by RNA with an approximate sedimentation value of 19 S.
Animals↗
Intramuscular human interferon-beta injections in treatment of condylomata acuminata.
A two-part study was done to assess the value of human fibroblast interferon (IFN-beta) in the treatment of condylomata acuminata. The first part was an open study of different IFN-beta preparations, which showed that intramuscular injection was the most suitable mode of administration of IFN-beta. In the double-blind placebo section 22 patients were given injections of 2 X 10(6) units IFN-beta or placebo for 10 consecutive days and followed up for 3 months. In 9 of the 11 in the IFN-beta group and 2 in the placebo group lesions disappeared from about 5 weeks after completion of the course of injections. After 3 months 8 of the non-responders were given a course of IFN-beta and all responded to treatment. None of those who had responded has had a recurrence, the disease-free period now being 12 months. Changes in (2'-5')oligo A synthetase levels in white blood cells confirm that intramuscular injections of IFN-beta produce a systemic response.
2',5'-Oligoadenylate Synthetase↗
[Advantages and hazards of preventing infection following cesarean section--clinical and bacteriologic results of a high-dosage treatment with mezlocillin and oxacillin short-term preventive following clamping of the umbilical cord].
Between August 1980 and August 1981 a prospective randomised study was conducted at the Krankenhaus Nordwest , Dept. of OBGYN , Frankfurt, to investigate the efficacy of a short term prophylaxis using mezlocillin and oxacillin ( Optocillin ) in reducing infections after Caesarean section (6 gs Optocillin after clamping the umbilical cord and after 8 and 16 hours, respectively). Both the study group (sg) and the control group (cg) consisted of 50 patients each. Both groups were statistically homogeneous . Infections were significantly reduced by the prophylaxis: sg 26%/cg 64% - p less than 0,001, febrile morbidity: sg 10%/cg 38% - p less than 0,001, endometritis: sg 6%/cg 20% - p less than 0,08, UTI: sg 18%/cg 36% - p less than 0,05, wound infections: sg 2%/cg 18% - p less than 0,02. Severe infections, however, were seen in neither group. The duration of infections was shorter in the sg. The various postoperative infections were associated with different risk factors (rf) - endometritis: green amniotic fluid, operating time greater than 75 min; cervical dilatation less than 2 cm, UTI: PROM (greater than 6 hs), operating time less than 75 min, internal monitoring, cervical dilatation greater than 2 cm, wound infections: green amniotic fluid, internal monitoring, frequent vaginal examinations (greater than 6), cervical dilatation greater than 2 cm and operating time greater than 75 min. The prophylaxis was especially effective in the presence of the following rfs: green amniotic fluid, internal monitoring, frequent vaginal examinations (6), operating time greater than 75 min and when associated with combined rfs. The reduction of wound infections following the prophylaxis can be ascribed to the elimination of organisms (Staph. spec., enterococci,) at the site of operation.(ABSTRACT TRUNCATED AT 250 WORDS)
Cesarean Section↗
Alkaline phosphatase activity in fresh intestinal mucosa and cultured mucosal explants.
Alkaline phosphatase (AP) activity is an accepted marker of epithelial cell differentiation and integrity in intestinal mucosal explant systems. In experiments involving AP it is usually expressed as activity per unit protein in tissue culture. It has been previously demonstrated that during organ culture a considerable amount of protein and nucleic acid (NA) may leave the cell and enter the surrounding medium. It may therefore not be appropriate to measure enzyme synthesis in relation to total tissue protein. In this study we attempted to gather additional information on enzyme dynamics and tissue integrity during organ culture of intestinal mucosal explants from children with celiac disease (CD) on a normal diet (ND) (n = 21), children with CD on a gluten-free diet (GFD) (n = 12), and patients with gastrointestinal disorders other than CD (controls) (n = 17). We confirmed the leakage of protein, NA, and AP from the tissue explant into the medium, and normalized the AP data by expressing AP as total AP in tissue plus medium per total NA in tissue plus medium. In patients with CD on a ND, the AP level at time 0 was 9.58 (+/- 12.2) mIU/micrograms NA and after 24 h culture rose to 21.9 (+/- 15.7) mIU/micrograms NA. In patients with CD on a GFD the baseline AP level was 24.9 (+/- 34.8) mIU/micrograms NA, and this value rose after culture to 28.6 (+/- 17.9) mIU/micrograms NA. In the controls the initial AP activity was 17.2 (+/- 15.7) mIU/micrograms NA, and the increase was to 38 (+/- 27.6) mIU/micrograms NA.(ABSTRACT TRUNCATED AT 250 WORDS)
Alkaline Phosphatase↗
(2'-5') Oligo A synthetase in human polymorphonuclear cells increased activity in interferon treatment and in viral infections.
The interferon (IFN)-induced enzyme 2-5A synthetase was found in human peripheral blood polymorphonuclear cells (PMNL). The average enzyme activity in a group of 15 patients with various viral infections was significantly higher (25-fold) than in healthy individuals. Eight patients with multiple sclerosis and six patients with bacterial infections were found to have normal 2-5A synthetase levels in the PMNL. Relationship of PMNL 2-5A synthetase levels to IFN was confirmed by finding enzyme increases in PMNL incubated in vitro with IFN, as well as in patients undergoing IFN therapy. These findings suggest that in PMNL, as in other cells, the level of 2-5A synthetase can be regulated by IFN and can be increased as a result of IFN information in diseases.
2',5'-Oligoadenylate Synthetase↗
Enhanced release of lymphotoxins by interferon-treated cells.
Pretreatment of human peripheral blood lymphocytes with interferon significantly enhances the release of lymphotoxins (LTs) observed at subsequent incubation of the cells, for 3 hr, with phytohemagglutinin (PHA). Fractionation of the LTs by gel filtration shows that interferon (IFN) strongly increases the release of certain LTs produced by these cells, while it has little effect on the release of others. The release of LTs from the IFN-treated cells is dependent on stimulation by PHA, requires Ca2+ ions, and can be blocked by prostaglandin E1, but it is independent of protein synthesis.
Cytotoxicity, Immunologic↗
Interferon system in acute viral hepatitis.
Activation of the interferon system is an early antiviral immune defence mechanism. In 16 patients, whose viral hepatitis (A, B, and non-A, non-B) ran a normal course, blood interferon levels rose and cells were rapidly induced into an antiviral states. However, in 6 patients with acute fulminant hepatitis, the antiviral interferon system was grossly defective. Blood interferon levels were not measurable in 5 of them; in all 6, the mononuclear cells were not in an antiviral state and did not produce interferon-alpha or interferon-gamma when stimulated, but their intracellular antiviral mechanism was intact because small amounts of exogenous interferon induced an antiviral state in vitro. 5 of the patients with fulminant hepatitis received interferon-alpha therapy, with rapid activation of their interferon systems, accompanied by rapid and uncomplicated recoveries in 3. It is suggested that interferon be given a trial as an early treatment for severe viral hepatitis.
Acute Disease↗
Variation of (2'-5') oligo A synthetase level in lymphocytes and granulocytes of patients with viral infections and leukemia.
Using a simplified technique for the determination of oligoisoadenylate synthetase activity, we have compared the cellular level of this interferon (IFN)-induced enzyme in multiple samples of peripheral blood leukocytes. In mononuclear cells (PBMC) of healthy donors the enzyme level was remarkably constant, but in the cells of about 85% of patients with viral infections enzyme activity was significantly elevated. In contrast, the incidence of elevated activity in bacterial infections was low. Synthetase activity could be also detected in granulocytes, although normally its level in these cells was considerably lower than in PBMC. A sharp increase in the enzyme level in granulocytes was found in cells exposed in vitro to IFN, as well as in cells from patients undergoing IFN therapy. Increased synthetase activity was also detected in the granulocytes of patients with viral infections. We have also determined the level of the enzyme in patients with various types of leukemias. In a large proportion of the patients with acute lymphoblastic leukemia (ALL) we found severely decreased enzyme levels (10-20% of control value). The decreased activity could usually be correlated to predominance of blast cells in the peripheral blood.
2',5'-Oligoadenylate Synthetase↗
The interferon system in patients with malignant disease.
Since the interferon (IFN) system involves both IFN producing and IFN responding cells, it is possible to study separately these phenomena, relating them to disease entities as well as to response to therapy. Numerous studies in animals and man suggest effectiveness of IFN and IFN inducer therapy in cancer. However, the competency of the various components of the endogenous IFN system in malignancy has received little attention. These studies show that in malignancy there may be (1) a high incidence of elevated blood levels of IFN; (2) a deficient response of peripheral blood mononuclear cells to endogenous and exogenous IFN; and (3) increased uninduced in vitro IFN production by these cells. These findings indicate that cancer patients are equipped with the ability to produce IFN and suggest that it may be the deficient response of their cells to IFN that plays a role in the development and progression of the disease. Furthermore, the finding of increased spontaneous "uninduced" production of IFN by cells from cancer patients suggest the possibility of an intracellular inducer such as found in persistently virus-infected cells.
Histiocytoma, Benign Fibrous↗
Treatment of life-threatening viral infections with interferon alpha: pharmacokinetic studies in a clinical trial.
The effectiveness of human leukocyte interferon (IFN alpha) therapy was studied in 15 patients with acute life-threatening viral illnesses. All patients were critically ill, many close to death, when IFN therapy was begun. Included were six patients with acute fulminant hepatitis, four immunosuppressed patients with spreading herpes simplex, three severely ill patients with encephalitis, one case of severe fulminant juvenile laryngeal papillomatosis, and one of postmeasles dermatitis. Twelve of the 15 patients recovered, some dramatically, including 3 of the 6 fulminant hepatitis patients. Pharmacokinetic studies showed defective antiviral IFN responses in most of the patients--in particular, absence of in vivo IFN production. Because the patients were not producing IFN in response to the viral infection, the peripheral blood mononuclear cells were not primed into an antiviral state. Treatment with IFN alpha led to the rapid development of an antiviral state of the cells, which paralleled clinical recovery. In our opinion, IFN is the treatment of choice in acute viral infections, often lifesaving, provided it is given early in the infection before irreversible cell and tissue damage has taken place. Its use is most effective in those seriously ill patients with defective antiviral IFN responses.
Adolescent↗
[A comparative, materials science study on an epoxy resin test material for special models].
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Chemical Phenomena↗
[A case of Lindau disease with unusual manifestations].
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Adenocarcinoma↗