Biomedical subjects

B Tartakovsky

Publications and source records attributed to B Tartakovsky.

At least 37 records · Page 2Linked to original sources

PubMed1994

Augmentative effects of intracellular chemotherapy penetration combined with hyperthermia in human ovarian cancer cells lines.

A significant proportion of ovarian cancer patients do not achieve a complete response to chemotherapy, due mainly to the evolution of clones resistant to cytotoxic drugs. Exploring possibilities to overcome this resistance constitutes a challenge in the study of ovarian cancer experimental therapy. In the present study, we tested the effect of hyperthermia (40 and 43 degrees C) in combination with adriamycin on three human epithelial ovarian cell lines: OC-109, OC-238, and OC-7-NU. The first was derived from the mucinous and the other two from serous cystadenocarcinomas, and all proved to be tumorigenic in nude mice. FACS analysis showed a pronounced increase in intracellular adriamycin accumulation in the presence of hyperthermia. A significant effect (P < 0.0005) observed at 40 degrees C was even more pronounced at 43 degrees C with the three cell lines. High percentages of cells (up to 70%) shifted into higher fluorescence intensities. The lines differed in their sensitivity to the hyperthermia-induced increase in adriamycin accumulation. Under mild conditions, the OC-109 line was more sensitive than the OC-238 and the OC-7-NU lines. Quantitative determination of intraneoplastic adriamycin by spectrofluorometry also showed a hyperthermia-related increase in intracellular adriamycin (P < 0.005). Our results may indicate that supranormal temperature might serve as an alternative chemosensitizer which lacks the deleterious side effects of other chemosensitizing options.

Combined Modality Therapy↗

PubMed1993

Low doses of radiation induce systemic production of cytokines: possible contribution to leukemogenesis.

Experiments were conducted to explore the possible effect of low-dose irradiation on cytokine production in mice. SJL/J and C57BL/6J mice were exposed to 3 Gy and 4 Gy respectively. At various time intervals thereafter, lung-conditioned media, bone-marrow-conditioned media and sera were collected. Interleukin-6 and macrophage-colony-stimulating-factor activities were tested. Interleukin-6 in lung-conditioned media from both strains was found to be significantly induced by irradiation. Macrophage-colony-stimulating-factor activity was greatly enhanced in sera of irradiated SJL/J mice as well as in bone-marrow-conditioned media of both strains. The kinetics of the radiation-induced interleukin 6 and macrophage-colony-stimulating-factor activity differed in the 2 strains. SJL/J and C57BL/6J mice have been previously shown to be susceptible to low-dose-radiation-induced leukemia. The coleukemogenic effects of both cytokines in 3 different models of experimental leukemogenesis is demonstrated.

Animals↗

PubMed1993

Anti-cardiolipin antibodies induce pregnancy failure by impairing embryonic implantation.

The antiphospholipid syndrome is characterized by thrombocytopenia, thrombosis, and recurrent fetal loss in association with anti-cardiolipin antibodies (ACAs) or lupus anti-coagulants. However, the causal role of these antibodies in the disease and the mechanisms by which the ACA may induce the syndrome are not clear. Recently, we have established an experimental mouse antiphospholipid syndrome induced by the mouse IgM monoclonal ACA designated 2C4C2. In the present study, we focused on the effects of immunization with the monoclonal ACA 2C4C2 on the outcome of pregnancies in BALB/c female mice. Four weeks after active immunization with the monoclonal ACA, a severe gestational failure with low pregnancy rates, low number of fetuses, and a high rate of resorptions was observed. Moreover, embryos obtained from the ACA-immunized females on day 3.5 of pregnancy were severely impaired, demonstrating developmental delay and abnormal morphology. These abnormal embryos failed also to develop in an in vitro implantation model. Furthermore, specific binding of the 2C4C2 ACA to the trophectoderm cell lineage of in vitro implanting normal embryos was observed. Thus, our studies demonstrate that the severe ACA-induced gestational failure results from an impairment of implantation and suggest that the ACA may react directly with the preimplantation embryos.

Abortion, Habitual↗

PubMed1993

Monoclonal anticardiolipin antibodies derived from mice with experimental lupus erythematosus: characterization and the induction of a secondary antiphospholipid syndrome.

The primary antiphospholipid syndrome and the antiphospholipid syndrome in systemic lupus erythematosus (SLE) patients (defined as secondary antiphospholipid syndrome) are characterized by the presence of anticardiolipin antibodies, thrombosis, thrombocytopenia, and recurrent fetal loss. To determine the role of anticardiolipin antibodies in the pathogenesis of antiphospholipid syndrome, monoclonal anticardiolipin antibodies were derived from mice in which experimental lupus was induced by a murine monoclonal anti-16/6 Id antibody. Two murine monoclonal anticardiolipin antibodies (2C4C2, 2C4D1) were generated and characterized. The 2C4C2, but not the 2C4D1, monoclonal antibody demonstrated remarkable lupus anticoagulant activity. Furthermore, these murine anticardiolipin monoclonal antibodies appear to recognize antigenic epitopes similar to those recognized by anticardiolipin antibodies found in sera of SLE patients. The monoclonal anticardiolipin antibody 2C4C2 was injected into naive female mice. Following immunization, the mice developed high titers of autoantibodies reacting with cardiolipin, DNA, nuclear extract, 16/6 and anti-16/6 Id, and anticardiolipin antibodies. As early as 8 weeks after immunization these mice exhibited significant leukopenia, thrombocytopenia, and proteinuria with immune complex glomerulonephritis. Moreover, mating of 2C4C2-injected mice with allogenic males resulted in low pregnancy rates and a low number of fetuses with a high percentage of fetal loss. These studies provide a new experimental model for secondary antiphospholipid syndrome demonstrating the role of anticardiolipin antibodies in the pathogenesis of this syndrome.

Animals↗

PubMed1993

Production of colony-stimulating factor 1 by T cells: possible involvement in their interaction with antigen-presenting cells.

Colony-stimulating factor 1 (CSF-1) is required for the growth and differentiation of mononuclear phagocytes, and is also involved in modulating various activities in mature cells. We report herein that T-cell lines produce 4.6 and 1.5 kb mRNA species of CSF-1, and express the CSF-1 protein on their outer membranes, as determined by immunofluorescence staining with anti-CSF-1 antibodies. The CSF-1 protein is biologically active. Interested by the possible immunoregulatory function of CSF-1, we assessed its effect in an assay of antigen presentation to the T cell lines. We found that anti-CSF-1 antibodies inhibited T-cell stimulation. Moreover, soluble CSF-1 could not overcome this inhibition, but exerted a significant inhibitory activity on the interaction between T cells and antigen-presenting cells leading to T-cell activation and proliferation in vitro. Based on these observations we propose that T-cell CSF-1 may be involved in the interaction of these cells with CSF-1 receptor bearing antigen-presenting cells.

Amino Acid Sequence↗

PubMed1992

The natural interleukin-1 receptor antagonist prevents interleukin-1-induced preterm delivery in mice.

OBJECTIVES: Interleukin-1 has been implicated in the mechanisms responsible for preterm parturition in the setting of intrauterine infection. This cytokine is produced by human decidua, stimulates prostaglandin production by intrauterine tissues, and induces preterm parturition in mice. The purpose of this study was to determine whether pretreatment with the natural interleukin-1 receptor antagonist can block interleukin-1-induced preterm parturition in mice. STUDY DESIGN: Balb/CJ female mice impregnated by B6D2 F-1 male mice were randomly allocated to one of the following treatment groups: (1) saline solution (n = 15), (2) human recombinant interleukin-1 alpha or human recombinant interleukin-1 beta (n = 12), (3) human recombinant interleukin-1 receptor antagonist (n = 13), and (4) human recombinant interleukin-1 receptor antagonist plus human recombinant interleukin-1 (n = 24). RESULTS: An interleukin-1 dose of 10 micrograms per mouse induced preterm parturition in all cases. Pretreatment with interleukin-1 receptor antagonist (dose 1 mg per animal) prevented interleukin-1-induced preterm parturition. Interleukin-1 receptor antagonist administration was not associated with demonstrable side effects including behavioral changes, vaginal bleeding, duration of pregnancy, and pregnancy outcome. CONCLUSION: Our results suggest that interleukin-1-induced preterm delivery in mice is mediated by the interleukin-1 receptor.

Animals↗

PubMed1992

Multiphase process involved in radiation induced murine AML.

Exposure of 3 month old SJL/J mice to a single dose of 300 r yielded 15-30% acute myelomonocytic leukemia (AML) development at a mean latency of 1 year. Additional treatment with dexamethasone shortly after irradiation increased leukemia incidence to 50%. All tumors were characterized by a partial deletion of one allele of chromosome 2 and the same deletion was detected in bone marrow and spleen cells of most irradiated mice, irrespective of the development of the disease. The presence of potential leukemic cells (PLC) in mice 4 months after the leukemogenic treatment was confirmed by transplantation studies. In these experiments PLC transition into overt AML seemed to be dependent on their transfer into irradiated recipients. Thus, exposure to 300 r results in the initiation of potential leukemic cells. Experiments were conducted in order to explore the possible role of radiation, cytokines and different hemopoietic growth factors on PLC promotion to overt leukemia. Exposure to 300 r, beside PLC initiation, was found to trigger the production of IL-6 and CSF-1; the additional administration of dexamethasone further increased CSF-1 levels. In vivo administration of CSF-1 into mice carrying radiation-induced PLC was most effective in PLC promotion to overt AML development.

Animals↗

PubMed1991

Systemic administration of interleukin-1 induces preterm parturition in mice.

Interleukin-1 has been postulated as a signal for the initiation of preterm labor and delivery. Interleukin-1 is produced by human decidua, stimulates prostaglandin production by intrauterine tissues, and is present in the amniotic fluid of women with preterm labor and intraamniotic infection. The purpose of these studies was to determine whether interleukin-1 could induce parturition in an animal species. Timed-pregnant C3H/HeJ inbred mice (n = 24) (genetically endotoxin resistant) were randomized to receive either recombinant human interleukin-1 or sterile phosphate-buffered saline solution between days 15 and 17 of gestation (normal length of pregnancy, 20 to 21 days). Three consecutive subcutaneous injections of interleukin-1 or phosphate-buffered saline solution were administered within 6 hours. Examinations of the animals were performed by blinded observers. Parturition occurred within 24 hours in all of the interleukin-1-treated mice and in none of the control group. Vaginal bleeding was first noted 4 hours after the first interleukin-1 injection, and delivery began within 12 hours after the last interleukin-1 injection. Premature delivery occurred in all interleukin-1-injected mice. Laparotomy revealed that there were no remaining fetuses in utero. All mice in the control group delivered spontaneously between days 20 and 22. We conclude that systemic administration of interleukin-1 induces preterm labor and delivery in mice.

Animals↗

PubMed1991

Cytokines modulate preimplantation development and pregnancy.

Using two different models of pregnancy failure in mice, we show in this communication that preimplantation embryonic development can be controlled, in vivo, with cytokines. In one model, described by us previously, CSF-1 is shown to block gestations in plugged females due to its induction of defective early development. Pregnancies and preimplantation development are shown here to be restored to normal by TNF alpha or GM-CSF but not by TGF beta 1. In the second model, we reveal that CBA/J females plugged by various male strains produce spontaneously an extremely high proportion of abnormal precompaction embryos. Normal morulae and blastocysts, able to further develop and implant in vitro, are shown here to be induced by TNF alpha and to a lesser extent by GM-CSF and IL-1 alpha. These results suggest strongly that cytokines are potent modulators of early development. They may provide new and interesting insights into early events of mammalian embryonic development.

Animals↗

PubMed1991

Colony-stimulating factor-1 blocks early pregnancy in mice.

To elucidate the mechanisms underlying the suspected immune-related pregnancy failures in humans, we established experimental systems to induce pregnancy blocking and abortion in mice. One system, based on the preimmunization of C57BL/6J females with a syngeneic regressor tumor, is described. Such females fail to develop normal gestations when mated to C57BL/6J x DBA/2 F-1 (B6D2F-1) males or DBA/2 males but sustain normal pregnancies when impregnated by CBA/J or C57BL/6 males. An investigation into the cause of these male-specific pregnancy failures led us to identify colony-stimulating factor-1 (CSF-1) as responsible for both pregnancy-block and resorption of embryos. Indeed, injection of very small amounts of CSF-1 into plugged females, for the first 5 days of pregnancy, was sufficient to block B6D2F-1-induced gestations but had no effect on CBA/J-mated females. It also induced a high rate of fetal resorptions in the sensitive mating. These results suggest a novel mechanism underlying pregnancy failures: a mechanism based on cytokines and their effect on early embryonic development in certain mating combinations.

Abortion, Spontaneous↗

PubMed1991

Fertility impairment and improved fetal survival induced by a tumor cell line in mice.

The BL6-T2 tumor, a regressor melanoma line in C57BL/6J mice shown by us previously to be abortifacient, has been cloned in vitro. Clones obtained have been tested in vivo for tumorigenicity and effect on gestations, in order to correlate the immunogenicity of the tumor and its effect on fetal survival. Results demonstrate that high immunogenicity and impairment of fertility do not occur in the same tumor clones. We also show that this tumor produces and secretes GM-CSF and CSF-1 and that trophoblast cells express in situ mRNA encoding for the CSF-1 receptor. We consequently hypothesize that this tumor exerts its abortifacient effect not via its strong immunogenicity but via cytokines it secretes.

Abortion, Spontaneous↗

PubMed1990

Rescue of interleukin-1 activity by leucovorin following inhibition by methotrexate in a murine in vitro system.

We have recently shown that methotrexate (MTX) inhibits interleukin-1 (IL-1) activity in vitro. This effect may play an important role in the rapid antiinflammatory action of MTX in rheumatoid arthritis. In the present study, we showed that the inhibition of IL-1 activity in vitro by MTX is dependent on folate pathways since, after the addition of leucovorin, the inhibitory effect of MTX was abolished. These findings may shed more light on the mechanism of action of MTX in rheumatoid arthritis. They also point to the fact that some IL-1 activities may be dependent on intracellular folate pathways.

Animals↗

PubMed1990

Methotrexate: mechanism of action in rheumatoid arthritis.

Most studies of immune function in rheumatoid arthritis (RA) patients treated with methotrexate (MTX) show only marginal effects on humoral or cellular immune responses. These include measurements of lymphocyte subsets, proliferative responses to mitogens, immunoglobulin production, rheumatoid factor and immune complexes. The mechanism of action of MTX in RA might be more antiinflammatory than immunosuppressive. This is supported by the rapid clinical response to drug treatment and by data from in vitro and animal studies. The inhibition of interleukin-1 (IL-1) activity or other inflammatory cytokines by MTX may play an important role in the antiinflammatory effect of MTX. MTX effects in RA are not fully understood and further studies are needed to clarify its mechanism of action. MTX has crucial effects on the cascade of events initiated by some cytokines (IL-1, IL-6, tumor necrosis factor), which plays a major role in RA and other inflammatory diseases.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1989

Correlation between the biologic functions and the generation of lymphokines in T cell clones.

We have recently reported that various murine T cell clones produce IL-1. Based on this observation we have analyzed in the present study the correlation between the biological functions and the generation of different lymphokines in (T,G)-A--L specific CD4+ clones. One subset of clones--the "helper clones"--were found to provide help to primed B cells, in vitro. These cells could be shown to produce IL-1, IL-2, and B cell stimulatory factor 1 (IL-4) activities and to express mRNA encoding for these three cytokines. The second subset of clones, termed "proliferative clones", were unable to help B cells in vitro but expressed vigorous Ag-dependent proliferations. These cells did not express IL-1, IL-2, or IL-4 activities. They produced another lymphokine(s) which may be granulocyte-macrophage-CSF, or some other factor recognized by the HT2 cell line. This study further substantiates the link between T cell activities and lymphokine repertoire with a special emphasis on the potential role(s) of T cell-derived IL-1.

Animals↗

PubMed1989

The effects of methotrexate on the production and activity of interleukin-1.

To explore the possibility that the mechanism of action of methotrexate (MTX) in rheumatoid arthritis (RA) is related to modulation of interleukin-1 (IL-1), the effects of MTX on IL-1 production and activity were evaluated. Human peripheral blood mononuclear cells and murine peritoneal and splenic cells were stimulated by lipopolysaccharide to produce IL-1. No inhibition of IL-1 synthesis or secretion caused by MTX treatment could be demonstrated either in vitro or in vivo, in patients with RA or in mice treated with MTX. We did show, however, that MTX had an inhibitory effect on IL-1 activity in 2 assays that demonstrate 2 different functions of IL-1. In a 2-step assay using LBRM-33-1A5 (1A5) and CTLD cells, MTX inhibited the secretion of IL-2 by 1A5 lymphoma cells in response to phytohemagglutinin and IL-1. In an assay using D10.G4.1 (D10) cells, MTX inhibited IL-1-induced proliferation of the D10 T cell clone. No effect of the drug on IL-2 activity was observed. The results demonstrate that MTX is capable of inhibiting some IL-1 activities without affecting IL-1 production or secretion. We propose that the inhibition of IL-1 activity or IL-1-dependent events may be one of the mechanisms of action of MTX in RA.

Animals↗

PubMed1989

CSF-1 induces resorption of embryos in mice.

We have shown previously that C57BL/6J female mice inoculated with the syngeneic BL6-T2 regressor tumor resorb a high proportion of embryos sired by B6D2F1 or DBA/2 males but not embryos engendered by CBA/J or C57BL/6J males. In this present report, we provide a mechanism elucidating the nature of the fetal wastage observed. It was found that the BL6-T2 tumor secretes constitutively GM-CSF and CSF-1. Based on the hypothesis that those cytokines could interfere with normal fetal development, we injected semi-purified GM-CSF or CSF-1 into pregnant females, for five days. Results show that CSF-1 was able to induce a high rate of fetal resorption whereas GM-CSF had no effect.

Abortifacient Agents↗

PubMed1988

IL-1 is an autocrine growth factor for T cell clones.

Activation of Th lymphocytes requires that Ag be presented on the surface of accessory cells displaying Ia Ag. A number of studies have concluded that the T cell also requires IL-1 from accessory cells. However, we recently reported that one murine T cell clone (D10.G4.1) produced its own IL-1-like activity after encountering APC (9). In this report, we demonstrate that 1) IL-1 production is a common property of murine T cell clones, 2) T cell IL-1 activity is blocked by anti-IL-1-alpha antiserum, 3) IL-1-alpha mRNA can be directly visualized in individual cloned T cells using in situ hybridization techniques, and 4) IL-1 appears to serve an autocrine role in the activation of T cell clones inasmuch as anti-IL-1-alpha antiserum blocks cell proliferation when the T cell is the only IL-1 source.

Animals↗

PubMed1988

Immunization with a syngeneic regressor tumor causes resorption in allo-pregnant mice.

The purpose of our studies is to establish experimental systems in which one can deliberately disrupt the apparent maternal tolerance toward the semiallogeneic fetuses. Bases on the hypothesis that immunization against tumor-associated antigens may lead to a subsequent immune response directed against cross-reacting fetal antigens, we have immunized C57BL/6J female mice with a syngeneic regressor tumor. Mice were subsequently mated to B6D2F1, DBA/2, CBA/J or C57BL/6J males. We show that a high proportion of embryos sired by either B6D2F1 or DBA/2 males undergo resorption whereas those engendered by CBA/J or C57BL/6J males remain fully protected.

Animals↗