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Biomedical subjects

I Gresser

Publications and source records attributed to I Gresser.

At least 55 records · Page 3Linked to original sources
PubMed1991

Genes for interleukin-1, interleukin-6, and tumor necrosis factor are expressed at markedly reduced levels in the livers of patients with severe liver disease.

The genes for interferon (IFN) alpha, IFN gamma, IL-1 beta, IL-6, and TNF alpha were transcribed at readily detectable levels both in liver biopsies from individuals with normal liver function and in samples of normal viable liver taken for transplantation. These results provided evidence for the concept that such multifunctional cytokines play a role in homeostasis in normal human tissues. In normal human liver, in situ hybridization studies showed that, in the absence of a detectable inflammatory response, both hepatocytes and mononuclear cells exhibited a similar degree of expression of IL-6 mRNA in keeping with the finding that IL-6 is produced by cells of different lineages. The levels of IL-1, IL-6, and TNF mRNA were found to be markedly reduced in extracts of the livers of patients with primary biliary cirrhosis and other forms of autoimmune liver disease at a time when extensive liver lesions were apparent, compared to the levels of expression of these cytokines in the livers of normal individuals. The reduced expression of IL-1, IL-6, and TNF mRNAs appeared to be a specific effect and not due to a general reduction in RNA synthesis as the IFN alpha, IFN gamma and actin mRNAs were expressed at similar levels in both normal and diseased livers. The levels of IL-1 beta, IL-6, and TNF mRNAs were also reduced in samples of liver from a patient with a drug induced fulminant hepatitis suggesting that this specific pattern of altered cytokine gene expression was characteristic of the advanced stage of severe liver disease.

Autoimmune Diseases↗
PubMed1991

Influence of the site of tumor growth on the capacity of a low tumorigenic line of Friend erythroleukemia cells to differentiate.

Friend erythroleukemia cells (FLC) passaged in mice are highly tumorigenic and multiply extensively in the livers of suckling DBA/2 mice without differentiating. In contrast, in vitro passaged FLCs injected intravenously were of low tumorigenicity, multiplied to a limited extent in the livers of suckling mice, and underwent marked differentiation from the proerythroblast to the orthochromatic erythroblast stage in the liver. The presence of characteristic C-type virions budding from the cell surface in various stages of erythroid differentiation served as a marker of the injected FLCs. When the same in vitro passaged FLCs that differentiated in the liver were injected subcutaneously in suckling mice, they formed large subcutaneous tumors consisting of sheets of undifferentiated tumor cells. It is concluded that the tumorigenicity of FLCs depended on the site of tumor growth and that there is an inverse correlation between the tumorigenic capacity and the capacity to differentiate.

Animals↗
PubMed1990

Anti-tumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend erythroleukemia cells. VIII. Role of the immune system in the inhibition of visceral metastases.

DBA/2 mice were injected i.v. with IFN alpha/beta-resistant 3CI8 Friend erythroleukemia cells (FLC) which metastasize to the liver and spleen. IFN alpha/beta treatment of FLC-injected mice increased their survival time and these mice developed a resistance to a second challenge with FLC. The efficacy of IFN alpha/beta in increasing the survival time was compared between normal immunocompetent and immunodeficient mice. The anti-tumor action of IFN was markedly reduced or abolished in newborn DBA/2 mice, in adult athymic nu/nu and beige DBA/2 mice, and in BALB/c scid/scid mice. To determine the phenotype of the effector cells involved, FLC-injected DBA/2 mice were treated with antibodies to asialo-GMI, CD4, or CD8 antigens, or with cyclosporin A or silica. IFN alpha/beta treatment proved much less effective in these mice, indicating that a variety of effector cell types participated in the IFN-induced suppression of visceral metastases. Thus, an intact immune system appears to be essential to obtain optimal therapeutic effects of IFN alpha/beta in this experimental model.

Animals↗
PubMed1990

Inhibition of mouse alpha/beta-interferon of the multiplication of alpha/beta-interferon-resistant Friend erythroleukemia cells cocultured with mouse hepatocytes.

Administration of alpha/beta-interferon (IFN) exerts a marked antitumor effect in DBA/2 mice given injections i.v. of large numbers of IFN-alpha/beta-resistant erythroleukemia cells (FLC). To investigate the possible mechanisms of FLC tumor inhibition in the liver of interferon-treated mice, we developed an in vitro model consisting of a coculture of IFN-alpha/beta-resistant 3Cl8 FLC and syngeneic mouse hepatocytes. Whereas IFN-alpha/beta did not inhibit the multiplication of 3Cl8 FLC cultivated alone, it effectively inhibited the multiplication of 3Cl8 FLC in coculture with hepatocytes. The inhibitory effect was directly proportional to the amount of IFN-alpha/beta added to the cocultures, and more than 90% inhibition of FLC multiplication was noted with 1.6 x 10(5) IU/ml of IFN-alpha/beta on Day 3 of coculture. When FLC were separated from the monolayer of hepatocytes by a pored membrane (0.4 microns), the inhibitory effect on FLC proliferation was unchanged, indicating that a soluble factor(s) released from IFN-treated hepatocytes was most important in the inhibition of FLC multiplication. An inhibitory activity of FLC multiplication was detected only in the conditioned medium of IFN-treated hepatocytes but not in the conditioned medium of control hepatocytes nor in extracts of IFN-treated or control hepatocytes. The inhibitory factor(s) in the conditioned medium of IFN-treated hepatocytes was retained by an ultrafiltration membrane (Mr cut off 10,000), and its activity was completely abrogated by trypsin digestion. Its stability to treatment with 1 M acetic acid as well as lack of correlation between the antiproliferative effect and the amount of L-arginine in the medium distinguished this factor(s) from liver arginase which was also found to be a potent inhibitor of FLC multiplication in vitro. The inhibitory factor(s) was also distinguishable in its biological activity from IFN gamma, interleukin 1 alpha and beta, and transforming growth factor beta 1 and beta 2. These results suggest the possibility that the inhibitory effect of IFN-alpha/beta on the development of 3Cl8 FLC in the livers of IFN-treated mice may be mediated by an IFN-induced inhibitor of FLC multiplication.

Animals↗
PubMed1990

Importance of interferon alpha in the resistance of allogeneic C57B1/6 mice to the multiplication of Friend erythroleukemia cells in the liver.

Friend erythroleukemia cells (FLC) (H-2d) injected intravenously multiply extensively in the livers of syngeneic DBA/2 mice and not at all in the livers of allogeneic C57B1/6 mice. Our results indicate that interferon alpha (IFN-alpha) is an important factor in the resistance of allogeneic mice to the multiplication of FLC in the liver. (a) After i.v. inoculation of FLC there was an inverse correlation between the presence of IFN-alpha in the serum and the capacity of FLC to multiply in the liver. Thus, all 44 FLC-injected adult C57B1/6 mice had circulating IFN-alpha and FLC did not multiply in the liver of any of the mice. Interferon was not detected in the serum of 83% of 41 FLC-injected DBA/2 mice (and was found only at a low titer in 17% of the mice) and FLC multiplied in the liver of all mice. (b) FLC did multiply in the livers of newborn C57B1/6 mice and in the livers of irradiated adult C57B1/6 mice, and IFN-alpha was not detected in their sera. In contrast, after i.v. inoculation of FLC, IFN-alpha was detected in the sera of 3-week-old and athymic nu/nu adult C57B1/6 mice while FLC failed to multiply in the liver. (c) FLC also induced IFN-alpha in congenic B10.D2 (H-2d) mice and FLC did not multiply in the liver. We suggest that, depending on the site of tumor implantation, different host mechanisms have various degrees of importance in controlling the growth and/or rejection of allogeneic tumor cells, and that IFN-alpha is particularly important when FLC are injected i.v.

Age Factors↗
PubMed1990

Genetic transfer of a functional human interferon alpha receptor into mouse cells: cloning and expression of its cDNA.

A cDNA coding for the human interferon alpha receptor has been cloned using a gene transfer approach. This consists of transferring human DNA to mouse cells and selecting for cells sensitive to human interferon alpha. The transfected cells expressed the human interferon alpha receptor, and a 5 kb human DNA was isolated from a secondary transfectant. This DNA defects an mRNA present in human cells and was used to clone a 2.7 kb cDNA from a library constructed from human Daudi cells. The sequence of the cDNA is presented. It codes for a glycoprotein of 557 amino acids with an N-terminal hydrophobic region and a single transmembrane-spanning segment. Mouse cells expressing the cDNA become sensitive to the antiviral activity of and express binding sites for human interferon alpha, demonstrating that the cloned cDNA encodes a functional human interferon alpha receptor.

Amino Acid Sequence↗
PubMed1990

Modulation of expression of MHC antigens in the kidneys of mice by murine interferon-alpha/beta.

We have analyzed the effects of interferon-alpha/beta on MHC expression in the murine kidney, and compared these results with the MHC modulating effects of interferon-gamma. Natural murine interferon-alpha/beta was administered to B10.BR mice (H-2k), i.p., twice daily for 3 days. Expression of MHC antigens was assessed on day 4 by immunoperoxidase staining with biotinylated monoclonal antibodies to class I (KkDk) and class II (I-Ak) antigens. Interferon-alpha/beta significantly decreased the number of class II-positive renal cortical dendritic cells from 62.0/mm2 to 12.6/mm2 (P less than 0.001). A similar but less dramatic decrease was seen in cardiac dendritic cells. Little or no change in class II expression was observed in proximal tubules or glomeruli. Interferon-alpha/beta induced marked class I staining in the glomerulus, arterial endothelium, and Bowman's capsule. Proximal tubule cells also showed increased class I expression, but were less responsive than glomeruli. Thus, the effects of interferon-alpha/beta contrast with those of interferon-gamma, which increases class II expression on proximal tubules, induces relatively more class I expression in proximal tubules than glomeruli, and increases class II-positive dendritic cells. Furthermore, these results suggest that treatment with interferon-alpha/beta may have a complex effect on the immune response to a renal allograft due to its differential effects on class I and class II cell surface expression.

Animals↗
PubMed1990

Biologic effects of interferons.

If one were to review articles on IFN published between 1957 and 1967 it would become apparent that virtually none of the tenets held then are still valid today. Whereas IFN was long considered to be a specific antiviral substance without any effect on normal cellular metabolism, we accept today that it affects normal cell division and many specialized cellular functions. In this respect it is not unique; IFN is a prototype of a family of similar substances now called cytokines that all appear to function as regulatory molecules. It was held that the production of IFN constituted a specific response to a viral infection. Today we believe that IFN is an integral part of a cytokine network and that they and other cytokines may be produced constitutively at low levels. These substances exert multiple effects on virtually all cells. They play an important role in host defense against viral and parasitic infections, and in the resistance to experimental tumors. IFN can be shown to exert effects on the immune system and on lymphocyte circulation. Lastly, because of the multiplicity of their biologic effects, they may even contribute to the pathogenesis of certain diseases. Thus, when large amounts of IFN are administered or induced in newborn mice they can cause liver, kidney, and pulmonary disease. The field of IFN and cytokine research continues to expand and there is an increasing number of therapeutic applications. Twenty years from now, scientists and clinicians may be surprised that we understood so little of how IFN act and how inadequately we used them to treat disease.

Animals↗
PubMed1989

Microvascular injury in pathogenesis of interferon-induced necrosis of subcutaneous tumors in mice.

DBA/2 mice were injected sc with cells from the highly malignant Friend erythroleukemia cell (FLC) 3Cl8 subline, which is resistant to mouse interferon alpha/beta, or with the ESb lymphoma. When interferon alpha/beta was injected intratumorally or peritumorally, tumor growth was markedly suppressed, and established vascularized tumor nodules became progressively necrotic. Tumor necrosis was of the coagulation type that usually results from deprivation of blood flow. Morphologic examination of approximately 1,000 blood vessel profiles and approximately 2,000 endothelial cells in 1-micron Epon sections of sc 3C18 FLC tumors showed that interferon treatment resulted in rapid and pronounced vascular endothelial cell damage that preceded tumor necrosis. No inflammatory cell infiltrate was observed. Our results suggest that interferon alpha/beta exerted an antitumor effect in these tumor models by damaging tumor blood vessels, causing disruption of tumor blood flow, which led to ischemic tumor necrosis.

Animals↗
PubMed1989

Antitumor effects of interferon.

Both natural and recombinant interferons have shown definite antitumor activity in some patients with some malignancies. The history of the development of interferon as an antitumor agent is reviewed, with special attention to its use in mice bearing 'spontaneously' appearing tumors and in mice injected with tumorigenic viruses or transplantable tumor cells. Interferon can inhibit the growth of primary tumors as well as the development of metastases. These experimental results have provided some indications as to the probable optimal regimens of interferon administration in man. Although the mechanisms of interferon's antitumor activity are unknown, it seems likely that interferon can act directly on the tumor cells as well as on the tumor bearing host.

Animals↗
PubMed1988

Genes for IFN-beta-2 (IL-6), tumor necrosis factor, and IL-1 are expressed at high levels in the organs of normal individuals.

The gene of a cytokine designated IFN-beta-2, or IL-6, and recently identified as identical to the B cell-stimulatory factor 2, is transcribed at high levels in the spleen, liver, kidney, and peripheral blood leukocytes of normal individuals. The number of IFN-beta-2/IL-6 transcripts present endogenously in normal human tissues (0.6 to 16 copies/cell) is comparable to that present in normal cells induced in vitro with human rTNF. This is in marked contrast to the absence of detectable IFN-beta-1 transcripts (less than 0.0003 copy/cell) in the same samples of human tissue. The expression of the IFN-beta-2/IL-6 gene is closely associated with that of two other cytokines TNF, and IL-1. Thus, significant levels of IFN-beta-2/IL-6, TNF, IL-1 alpha, and IL-1 beta, mRNA were detected in all the samples of normal tissue tested and those samples which contained high levels of IFN-beta/IL-6 mRNA also contained high levels of TNF, and IL-1 beta mRNA. These results suggest that these cytokines may function in consort as regulators of cellular growth and function in normal tissues.

Gene Expression Regulation↗
PubMed1988

Tumor necrosis factor alpha induces early morphologic and metabolic alterations in Friend leukemia cell tumors and fibrosarcomas in mice.

Morphologic and metabolic studies have been carried out on Friend leukemia cell (FLC) tumors (grown in DBA/2 mice) or fibrosarcomas (grown in C3H/HeN or C3H/HeJ mice) shortly after peritumoral injection of recombinant mouse tumor necrosis factor (TNF) alpha. Marked vascular congestion and focal extravasation of erythrocytes were observed as soon as 1 hr after injection of either FLC tumors or fibrosarcomas with TNF. Focal areas of disaggregation of tumor cells were observed 1 hr after injection of TNF. Intraluminal thrombi (composed of degranulated platelets and fibrin) were detected 3 and 6 hr after TNF treatment, and were associated with areas of depletion of endothelial cell cytoplasm. To correlate these morphologic changes in the tumor with alterations in tumor metabolism, NMR spectroscopy and biochemical studies were undertaken on freshly dissected FLC tumors and fibrosarcomas shortly after injection of TNF. The earliest metabolic alterations observed after 1 hr in TNF-treated FLC tumors of fibrosarcomas were: (i) increase in the average intratumoral pH; (ii) decrease in the levels of ATP. These phenomena were not associated with a reduced glycolytic capacity of TNF-treated tumors as, at these early times after injection, the levels of lactic acid were virtually the same for TNF-treated or control treated tumors. Alterations in the levels of some products of phospholipid degradation (GroPCho, GroPEtn, GroP and Cho) also occurred in these tumors as early as 3 hr after TNF treatment. These metabolic changes were not observed in ascitic FLC tumors after TNF treatment. We suggest that TNF induces alterations in tumor blood vessels which subsequently lead to changes in tumor metabolism and tumor degeneration.

Adenosine Triphosphate↗
PubMed1988

Antibody to mouse interferon alpha/beta abrogates resistance to the multiplication of Friend erythroleukemia cells in the livers of allogeneic mice.

Friend erythroleukemia cells (FLC) (H-2d) injected intravenously into adult syngeneic DBA/2 or allogeneic C57B1/6 (H-2b) or C3H (H-2k) mice lodge in the liver but only multiply in the liver of syngeneic mice. Our results indicated that endogenous IFN-alpha/beta was a crucial factor in preventing the multiplication of FLC in the liver of adult allogeneic mice. (a) Treatment of allogeneic adult C57B1/6 or C3H mice with polyclonal antibody to mouse IFN-alpha/beta (but not antibody to IFN-gamma) completely abrogated the resistance to the multiplication of FLC in the liver and 87% of tumor-injected, antibody-treated C57B1/6 mice died with extensive tumor involvement of the liver. In contrast, after intravenous inoculation FLC do not multiply at all (or very rarely) in the liver of adult C57B1/6 mice left untreated or treated with a variety of control globulins, and no deaths occurred. (b) 8 h after intravenous inoculation of FLC, poly(A)+ RNA hybridizable with specific DNA probes for mouse IFN-alpha or -beta (but not -gamma) was present in the liver of injected C57B1/6 mice. Using the expression of the Mx protein as an indicator of the presence of IFN-alpha/beta, we showed that Mx+ congenic C57B1/6 mice injected with FLC exhibited a marked increase in the expression of the Mx protein in the liver, spleen, kidney and lung, and this increase was blocked by treatment of mice with antibody to IFN-alpha/beta. The possibility that different host mechanisms are elicited depending on the site of tumor growth in allogeneic mice is discussed. IFN-alpha/beta appears to be of particular importance in determining the resistance of the liver to FLC in allogeneic mice.

Age Factors↗
PubMed1988

Effectiveness of mouse interferon alpha/beta compared to single-agent chemotherapy in increasing survival time of mice after intravenous inoculation of Friend erythroleukemia cells.

DBA/2 mice received an iv injection of 2 X 10(6) Friend erythroleukemia cells (FLCs; approximately equal to 4 X 10(5) lethal dose50), which multiplied rapidly in the liver and spleen and killed all untreated or control treated mice between 7 and 12 days. Daily interferon (IFN) treatment resulted in a very marked increase in survival time and apparent cure of 4 of 22 tumor-inoculated mice. In contrast, treatment of tumor-injected (iv) mice with cyclophosphamide, 5-fluorouracil, and methotrexate increased survival time by only a few days; and treatment of mice with cisplatin, vincristine, doxorubicin, bleomycin, or etoposide was ineffective. However, when FLCs were injected ip, both cytostatic drugs and IFN exerted an antitumor effect. We conclude that IFN alpha/beta was particularly effective in inhibiting the development of liver and spleen metastases and in increasing mouse survival time after iv inoculation of FLCs.

Animals↗
PubMed1988

Interferon treatment markedly inhibits the development of tumor metastases in the liver and spleen and increases survival time of mice after intravenous inoculation of Friend erythroleukemia cells.

To investigate the effect of interferon treatment on the development of tumor metastases, DBA/2 mice were injected i.v. with 2 X 10(6) Friend erythroleukemia cells (FLC) (equivalent to about 5 X 10(5) LD50). FLC multiplied rapidly in the liver and spleen and all untreated or control treated mice died between 7 and 12 days. Daily treatment of mice with potent preparations of mouse interferon alpha/beta was initiated 3 to 72 hr after i.v. inoculation of tumor cells, at times when FLC were already present in the liver and spleen. Interferon treatment resulted in a 100 to 1,000-fold inhibition of the multiplication of FLC in the liver and spleen and a marked increase in mean survival time. Small numbers of tumor cells persisted in the liver and spleen in some interferon-treated mice and could be recovered by bioassay several weeks after tumor inoculation. Most interferon-treated mice died with tumor in the ensuing months. Three of 34 interferon-treated mice were considered cured as they were alive at 386, 325 and 284 days after tumor inoculation. Daily treatment of tumor-inoculated mice with human recombinant interferons alpha D and alpha BDDD, which had antiviral activity on mouse cells in culture, also increased the survival time of mice injected i.v. with FLC. The use of the interferon-resistant 3C18 line of FLC suggests that the marked inhibition of development of established liver and spleen metastases was not due to a direct effect of interferon on the tumor cells, but was host-mediated.

Animals↗
PubMed1988

Interferon-induced glomerular basement membrane and endothelial cell lesions in mice. An immunogold ultrastructural study of basement membrane components.

Newborn Swiss mice were injected daily for the first week of life with mouse interferon alpha/beta. This treatment resulted in a delay in the maturation of the kidney and the development of glomerular abnormalities. The width of the glomerular basement membrane (GBM) was increased up to tenfold and was characterized by a marked thickening of the endothelial aspect of the GBM. The endothelial cells lining the capillary loops were also abnormal with many dilated regions of the rough endoplasmic reticulum that contained amorphous electron-opaque material. Immunogold studies showed that type IV collagen and laminin/entactin were distributed throughout the thickened GBM, and also within the dilated rough endoplasmic reticulum of the endothelial cells. These results show that the interferon-induced lesion within the glomerulus is associated with an accumulation of normal GBM components and that endothelial cells are involved in this pathologic process.

Animals↗
PubMed1987

Nuclear magnetic resonance analysis of tumor necrosis factor-induced alterations of phospholipid metabolites and pH in Friend leukemia cell tumors and fibrosarcomas in mice.

The alterations induced on the pool sizes of five phospholipid metabolites, glycerol 3-phosphorycholine, glycerol 3-phosphorylethanolamine, phosphorylcholine, sn-glycerol 3-phosphate, and choline were studied by nuclear magnetic resonance (NMR) spectroscopy in murine tumors injected with recombinant murine tumor necrosis factor (TNF). Solid tumors were obtained by s.c. injection of either Friend leukemia cells (clones 3C1-8 and 745) in DBA/2 mice or murine fibrosarcoma cells (HeN4) in C3H/HeN mice. After tumor nodules had developed, TNF or bovine serum albumin was injected intratumorally. Treatment of both tumors with TNF resulted in a marked inhibition of tumor growth. 31P-NMR analyses of Friend leukemia cell tumors (and tissue extracts), 6 h after injection of TNF, showed: (a) a 1.5- to 3.5-fold decrease in the pool sizes of glycerol 3-phosphorylcholine and glycerol 3-phosphorylethanolamine; (b) a 7- to 8-fold increase of sn-glycerol 3-phosphate; (c) a 2- to 3.5-fold decrease of phosphorylcholine; (d) an alkaline shift (0.2 units) in intratumoral pH. Similar metabolic alterations occurred in TNF-treated HeN4 fibrosarcoma. 1H-NMR analyses of Friend leukemia cell tumor extracts also indicated, 6 h after tumor injection with TNF: (a) elevated choline levels (9X); (b) a 19-fold increase in the ratio [choline]/[phosporylcholine]; (c) elevated (1.4X) levels of lactic acid; and (d) a 1.6-fold decrease in the [taurine]/[glycine] ratio. The results are interpreted in the light of possible alterations in the activity of enzymes controlling the de novo biosynthesis and catabolism of phospholipids. We concluded that NMR spectroscopy can be a useful means to monitor the level of some phospholipid precursors and/or derivatives as early markers of therapeutic efficacy in intact neoplastic tissues.

Animals↗