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Biomedical subjects

I Gresser

Publications and source records attributed to I Gresser.

At least 73 records · Page 4Linked to original sources
PubMed1987

Correlation between the lipopolysaccharide response of mice and the capacity of mouse peritoneal cells to transfer an antiviral state. Role of endogenous interferon.

Freshly harvested mouse peritoneal cells, from normal lipopolysaccharide (LPS)-responsive (Lpsn) mice, were capable of transferring an antiviral state (to vesicular stomatitis virus) to "in vitro aged" mouse macrophages permissive for viral replication. The transfer of the antiviral state was completely abrogated by addition of antibody to interferon (IFN)-alpha/beta in the co-culture medium. In contrast, even large numbers of donor peritoneal cells from LPS-hyporesponsive (Lpsd) C3H/HeJ and C57BL/10ScCR mice did not transfer an antiviral state to target cells. Although peritoneal macrophages from Lpsd mice did not transfer an antiviral state to target cells, they were nevertheless found to be in an antiviral state when first placed in culture. Injection of mice with antibody to mouse IFN-alpha/beta rendered peritoneal macrophages from both Lpsn and Lpsd mice permissive for vesicular stomatitis virus. The decay of this initial antiviral state in peritoneal macrophages during in vitro culture was far more rapid for Lpsd mice than for normal mice. Addition of antibody to mouse IFN-alpha/beta markedly enhanced the in vitro decay of the antiviral state of peritoneal macrophages. Treatment of total peritoneal cells from Lpsn mice with LPS resulted in IFN production, whereas IFN was not detected in the cellfree medium of LPS-treated peritoneal cells from Lpsd C3H/HeJ and C57BL/10ScCR mice. Genetic studies with F1 hybrids between Lpsn and Lpsd mice and with Lpsn and Lpsd recombinant inbred strains revealed a striking correlation between the capacity of peritoneal cells to transfer an antiviral state and their capacity to produce IFN after stimulation with LPS, suggesting that closely linked, if not identical, genes are in some way involved in the transfer of antiviral state as well as in the LPS response by peritoneal cells of normal mice.

Animals↗
PubMed1987

Anti-tumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. VI. Adjuvant therapy after surgery in the inhibition of liver and spleen metastases.

Adult DBA/2 mice were injected s.c. with the highly malignant, interferon-resistant 3C18 line of Friend erythroleukemia cells (FLC). Eight or 9 days after established s.c. tumors had developed, the primary tumor was excised and mice were treated i.p. with either mouse interferon alpha/beta or a control preparation. At the time of surgery, mice already had tumor cells in the liver. All control-treated mice died in the ensuing 2 weeks with extensive tumor metastases in the liver and spleen. Interferon treatment resulted in an inhibition of the development of liver and spleen metastases and a markedly increased survival time. We conclude that interferon alpha/beta is effective as adjuvant therapy after surgery for metastatic disease in mice.

Animals↗
PubMed1987

Interferon alpha/beta induces changes in the metabolism of polyenoic phospholipids and diacylglycerols in the livers of suckling mice.

Suckling mice were injected daily from birth for 10 days with potent preparations of mouse interferon alpha/beta. Interferon treatment resulted in a markedly lower concentration of polyunsaturated fatty acids (20:4 omega 6 and 22:6 omega 3) in the two principal liver phospholipids, phosphatidylcholine and phosphatidylethanolamine, than in livers of control-treated mice. This effect appeared to correlate with a low level of synthesis of polyunsaturated phospholipids in the livers of interferon-treated mice. Thus, in control mice, synthesis of species of polyunsaturated phospholipids increased markedly in the first 10 days of life, whereas in 10-day-old interferon-treated mice, the level of synthesis of species of polyunsaturated phospholipids was comparable to that in newborn mice. In parallel, a marked increase in the diacylglycerol content without change of its renewal was observed in the livers of interferon-treated mice. We suggest that interferon treatment results in an inhibition of one of the processes that leads to activation of the enzymatic systems responsible for the synthesis of species of polyunsaturated phosphatidylcholine and phosphatidylethanolamine in the liver of suckling mice. It seems likely that these results are related to the inhibition of liver cell maturation and the marked cell necrosis that are observed in interferon-treated suckling mice.

Age Factors↗
PubMed1987

Interferon messenger RNA is produced constitutively in the organs of normal individuals.

The use of RNA blot hybridization with DNA or RNA probes of high specific activity has shown that interferon (IFN)-alpha mRNA is present constitutively in the spleen, kidney, liver, and peripheral blood leukocytes of normal individuals. A single band (approximately equal to 1.2 kilobases) was detected in poly(A)+ RNA isolated from human organs. This RNA hybridized specifically to human IFN-alpha 1 DNA and comigrated with mature IFN-alpha mRNA from virus-induced human peripheral blood leukocytes. No IFN-beta RNA transcripts were detected in any of the tissues tested. IFN-gamma mRNA was detected in only one sample of normal human spleen, which also contained an unusually high level of IFN-alpha mRNA. The use of a modified S1 mapping technique revealed the presence of IFN-alpha 1 and -alpha 2 transcripts only. No IFN-alpha 4, -alpha 5, -alpha 6, -alpha 7, -alpha 8, or -alpha 14 transcripts were detected in the same sample. The detection, in all the samples tested, of a characteristic pattern of expression of IFN genes, different from that obtained following induction, together with the low number of transcripts present (less than or equal to 0.03 copy per cell) suggest that specific IFN genes are transcribed constitutively in vivo.

Gene Expression Regulation↗
PubMed1987

Studies on the expression of spontaneous and induced interferons in mouse peritoneal macrophages by means of monoclonal antibodies to mouse interferons.

Monoclonal antibodies (MAbs) to mouse interferons (MuIFN) have been used to characterize the interferon-like activities spontaneously expressed in mouse peritoneal macrophages freshly explanted from normal pathogen-free mice. Injection of mice with MAbs to MuIFN-alpha or -beta resulted in a significant increase of vesicular stomatitis virus (VSV) multiplication in peritoneal macrophages. Addition of these MAbs to freshly explanted mouse macrophages accelerated the decay of the antiviral state to VSV during the 'ageing' in vitro of these macrophage cultures. Furthermore, these MAbs to MuIFN-alpha or -beta markedly inhibited the transfer of the antiviral state from freshly explanted peritoneal cells or macrophages to syngeneic macrophages 'aged' in vitro permissive for virus replication. These effects were not observed using a non-neutralizing antibody to MuIFN-alpha, nor with a MAb to MuIFN-gamma. In all experiments sheep polyclonal antibodies to MuIFN-alpha/beta were more effective than the corresponding amount of MAbs to MuIFN-alpha or -beta. A mixture of both these MAbs was more effective than either alone. Interferons produced after stimulation of peritoneal macrophages with Newcastle disease virus (NDV) and of total peritoneal cells with lipopolysaccharides (LPS) have also been characterized by means of MAbs to IFNs. The results of neutralization studies with these antibodies indicated that MuIFN-beta was the major component of peritoneal cell IFN (induced by both NDV and LPS) and MuIFN-alpha was a minor component (13 to 17%). These data indicate that both MuIFN-alpha and -beta, but not MuIFN-gamma, are spontaneously present in/on mouse peritoneal macrophages and are produced after stimulation with NDV or LPS.

Animals↗
PubMed1987

Toxic effects of recombinant tumor necrosis factor in suckling mice. Comparisons with interferon alpha/beta.

Newborn Swiss and A2G mice were given daily subcutaneous injections for 1 week of highly purified recombinant mouse tumor necrosis factor (TNF) or mouse interferon alpha/beta. Both treatments resulted in inhibition of growth of suckling mice and severe fatty changes and necrosis in the liver. The simultaneous injection of polyclonal antibody to interferon alpha/beta abrogated the effects of interferon but did not block the effects induced by TNF. The kidneys of TNF-treated suckling mice could be distinguished from interferon-treated mice by the absence of glomerular basement membrane abnormalities and the presence of numerous rounded eosinophilic hyaline granules within the cytoplasm of the proximal tubules. Treatment of suckling mice with TNF and interferon alpha/beta induced similar changes in the spleen and thymus. Interferon treatment of suckling A2G mice resulted in the appearance of pulmonary cysts, which were not observed in TNF-treated mice. It is concluded that the pattern of lesions induced in suckling mice by mouse TNF is both similar and different from that induced by mouse interferon alpha/beta.

Animals↗
PubMed1986

Anti-tumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. V. Comparisons with the action of tumor necrosis factor.

A number of similarities and dissimilarities in the anti-tumor effects of TNF and interferon alpha/beta have been observed in DBA/2 mice injected with Friend erythroleukemia cells (FLC). Mouse TNF exerted marked anti-tumor effects in mice injected either s.c. or i.p. with FLC lines 3C18 or 3 gamma R8 resistant in vitro to the cytotoxic effects of TNF. Likewise, mouse interferon alpha/beta had anti-tumor activity in mice injected with these FLC, resistant to the action of interferon alpha/beta or gamma in vitro. The results of histopathologic examination and 31P nuclear magnetic resonance analyses of 3C18 FLC s.c. tumors injected with TNF resembled the results previously obtained for 3C18 FLC tumors injected with interferon alpha/beta, although the effects of TNF occurred more rapidly. Injection of mice with antibody to mouse interferon alpha/beta or gamma did not abrogate the anti-tumor effects of TNF in mice injected i.p. with FLC. Our results suggest that in this experimental system the anti-tumor effects of TNF, like interferon alpha/beta, do not result from a direct effect on the tumor cells themselves but are host-mediated.

Animals↗
PubMed1986

Anti-tumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant friend leukemia cells. IV. Definition of optimal treatment regimens.

Mouse interferon alpha/beta exerted a similar anti-tumor effect in DBA/2 mice injected i.p. with Friend erythroleukemia cells (FLC) either sensitive or resistant to interferon as determined by both in vitro and in vivo assays. Using this tumor system we attempted to define optimal treatment regimens for interferon administration. Interferon was most effective when injected at the site of tumor inoculation rather than at a distant site. Two factors seemed of especial importance: the amount of interferon injected and the frequency of interferon administration. Thus, for daily administration of interferon, the antitumor effect was directly related to the amount of interferon injected. For a given total dose of interferon, repeated administration of small doses of interferon was more effective than administration of a larger dose at more widely spaced intervals. The anti-tumor efficacy of interferon was independent of the number of FLC inoculated when 10(2) to 10(5) FLC were injected, but interferon treatment was less effective when 10(6) or 10(7) FLC were injected. The relevance of these results to the use of interferon in patients with cancer is discussed.

Animals↗
PubMed1986

The antitumor effects of interferon.

Interferons show antitumor activity in patients with various malignancies. The mechanism(s) of the antitumor effects are not altogether clear. In one experimental animal model discussed herein, mice were injected with Friend erythroleukemia cells and treated with mouse interferon alpha/beta. The results suggest that interferon does not act directly on the tumor cells but acts via host mechanisms that are still ill defined.

Animals↗
PubMed1986

Human interferons active on murine cells induce pulmonary cysts in A2G mice.

Suckling A2G mice were injected daily from birth for 8 days with highly purified human lymphoblastoid interferon (IFN) or recombinant interferons-alpha 1 or -alpha 2 rIFN-alpha 1, rIFN-alpha 2), or mouse interferon-alpha/beta (IFN-alpha/beta), or control preparations. Only mouse IFN inhibited the growth of suckling A2G mice and induced liver cell necrosis. At 56 days the mice were killed and the lungs examined for the presence of pulmonary cysts. Human lymphoblastoid IFN and rIFN-alpha 1 (and mouse IFN-alpha/beta), which exhibited significant biological activity on mouse cells in culture, induced pulmonary cysts in A2G mice. rIFN-alpha 2, which showed little or no activity on mouse cells, did not induce pulmonary cysts.

Animals↗
PubMed1986

Biological activities and receptor binding of two human recombinant interferons and their hybrids.

Two human recombinant lymphoblastoid interferon-alpha subtypes, LyIFN-B (alpha 8) and LyIFN-D (alpha 1), and 10 hybrids generated therefrom were produced in Escherichia coli and purified. The antiviral and antiproliferative activities and the induction of (2'-5')oligoadenylate synthetase were compared to their receptor binding affinities. The IFN subtypes and their hybrids had similar specific antiviral activities on bovine cells. On human cells both the specific antiviral and antiproliferative activities of LyIFN-B were about 30-fold higher than those of LyIFN-D. This difference in activity could be attributed partly to the N-terminal amino acids 1 to 60 and partly to amino acids 61 to 92. A third domain affecting the biological activities was found within the carboxy-proximal segment from amino acids 93 to 150. The differences in these activities were found to correlate with their ability to bind the receptor, suggesting that the differences in activity might be due to altered binding of the IFNs to the cellular receptors. In contrast, the induction of (2'-5')oligoadenylate synthetase did not follow the same activity profile. On mouse cells, the efficiency of the hybrids was affected by at least four sites on the IFN protein. A hybrid with the N-terminal segment 1 to 60 from IFN-B and amino acids 61 to 166 from IFN-D had a specific antiviral activity on mouse cells as high as on human cells corresponding to a 500- and 5000-fold increase in specific activity compared to IFN-D and IFN-B, respectively. We suggest that on mouse cells the IFN activity may be more dependent on conformational differences than on human cells, which in turn might reflect a less precise fit to the mouse receptor than to the human receptor.

2',5'-Oligoadenylate Synthetase↗
PubMed1986

Mouse peritoneal cells confer an antiviral state on mouse cell monolayers: role of interferon.

Vesicular stomatitis virus and encephalomyocarditis virus do not multiply in the majority of peritoneal macrophages freshly explanted from 4- to 8-week-old male or female mice. However, when peritoneal macrophages were cultivated in vitro for 3 to 5 days, these cells became permissive for both viruses. The loss of antiviral state in "aged" macrophages paralleled a significant decrease in the intracellular levels of (2'-5')oligo-adenylate synthetase activity. Although biologically active interferon was not detected in the nutrient medium of macrophage cultures, freshly harvested peritoneal cells could confer an antiviral state on monolayer cultures of mouse cells (aged macrophages, embryonic fibroblasts, and L cells) but not on heterologous chicken embryo, rabbit kidney, or human cells infected with vesicular stomatitis virus or encephalomyocarditis virus. The conferred antiviral state required at least 7 h to develop in target cells and was totally inhibited by the presence of antibody to mouse interferon alpha/beta but not to interferon gamma in the cocultures. Heterologous guinea pig and rabbit peritoneal cells could not transfer an antiviral state to target mouse cells. Donor peritoneal cells from mice preinjected with antibody to interferon alpha/beta could not transfer an antiviral state to target mouse cells. This ensemble of results indicating that freshly harvested peritoneal cells transfer interferon (which is responsible for inducing an antiviral state in susceptible mouse target cells) adds further experimental evidence that interferon is spontaneously expressed in normal mice and plays an important role in maintaining some host cells in an antiviral state.

Animals↗
PubMed1986

Antibody to mouse alpha/beta interferon abrogates Pichinde virus-induced liver lesions in suckling mice.

Infection of newborn C3HeB/FeJ mice with the arenavirus Pichinde resulted in stunted growth, severe liver cell degeneration, and death. Administration of sheep anti-mouse alpha/beta interferon globulin completely abrogated liver lesions in virus-infected mice, although it did not decrease the incidence of mortality. These results indicate that endogenous interferon may be responsible for some manifestations of viral disease.

Animals↗
PubMed1986

31P-nuclear magnetic resonance analysis of interferon-induced alterations of phospholipid metabolites in interferon-sensitive and interferon-resistant Friend leukemia cell tumors in mice.

Adult DBA/2 mice were given injections s.c. with either interferon-sensitive (745) or -resistant (3Cl-8) Friend erythroleukemia cells (FLC). After tumor nodules had developed, mouse interferon-alpha/beta was injected daily into the tumor. 31P-Nuclear magnetic resonance (NMR) spectroscopy examinations were undertaken on freshly dissected tumors at different days of treatment with either interferon or control preparations. Analysis of 745 FLC tumors in untreated mice at different days of tumor growth (day 8 to 13 after tumor implantation) showed marked increases in the levels of phosphorylcholine (PCho), glycerophosphorylethanolamine (GroPEtn) and glycerophosphorylcholine (GroPCho). In contrast high levels of PCho, GroPEtn and GroPCho were already detectable in the 3Cl-8 FLC tumors on day 8, and no significant changes were observed during subsequent tumor growth. The intracellular pH value remained practically constant in both FLC tumors. Daily intratumoral administration of either partially purified (10(7) IU/mg of protein) or highly purified (10(9) IU/mg of protein) mouse interferon-alpha/beta to both cell tumors resulted in decreases in the levels of PCho, GroPEtn and GroPCho and in increases in the intracellular pH with respect to tumors treated with control preparations or left untreated. Two days of daily treatment of mice with interferon sufficed to induce these metabolic changes which preceded the appearance of necrosis in the tumors. Treatment of FLC tumors with X-rays on day 12 of tumor growth did not result in any comparable metabolic changes 2 days after irradiation. Changes in the levels of phospholipid metabolites were not observed when 745 or 3Cl-8 cells were cultivated in the presence of interferon. As interferon induced these changes in both interferon-sensitive and -resistant tumors we conclude that interferon treatment results in host-mediated effects on the biosynthesis and/or catabolism of tumor cell phospholipids.

Animals↗
PubMed1985

Cytochemistry of the tubular aggregates found in hepatocytes of interferon-treated suckling mice.

Administration of mouse interferon to neonatal mice induces the formation of tubular aggregates within hepatocytes. These aggregates are composed of networks of small tubules which are continuous with the granular endoplasmic reticulum. The tubules are bounded by trilaminar unit membranes and exhibit glucose-6-phosphatase activity. These features suggest that the tubular aggregate is an interferon-induced alteration of the endoplasmic reticulum.

Animals↗
PubMed1985

Effects of long-term treatment of human carcinoma cells with interferon alpha.

Three tumor cell lines derived from human colon, urinary bladder and ovarian carcinoma were serially passaged in the continuous presence of human interferon alpha for extended periods of time. Phenotypic changes induced by interferon differed among these three cell lines. Thus interferon enhanced colon tumor cell aggregation but inhibited the aggregation of bladder tumor cells. The antiproliferative activity of interferon was more pronounced in bladder and ovarian cells than in colonic cells. However, the tumorigenicity of parental and cloned colon tumor cells injected i.p. or s.c. was markedly reduced by passage of the cells with interferon. Interferon treatment reduced the tumorigenicity of ovarian tumor cells when these cells were injected i.p. but not when injected s.c. The tumorigenicity of bladder tumor cells was not affected by interferon.

Animals↗