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E Schlick

Publications and source records attributed to E Schlick.

53 records · Page 3Linked to original sources
PubMed1984

Comparison of in vitro and in vivo modulation of myelopoiesis by biological response modifiers.

In vitro growth and differentiation of granulocyte-macrophage progenitor cells (GM-CFU-C) requires colony-stimulating factors (CSF), and an in vivo role for CSF has also been proposed. Prostaglandins of the E series (PGE) have been reported to serve as negative feedback regulators of myelopoiesis. Here, we report evidence of augmented CSF secretion by mouse peritoneal Mo (macrophages) and bone marrow cells in vitro upon stimulation with various biological response modifiers (BRMs). Optimal induction of CSF secretion occurred after in vitro treatment of peritoneal Mo and mononuclear bone marrow cells with 50 micrograms/ml poly ICLC (polyriboinosinic-polycytidylic acid poly-L-lysine). 5 micrograms/ml lipopolysaccharide (LPS), or 500 U/ml interferon (IFN alpha,beta) for 2 days. The in vitro stimulation of CSF secretion was paralleled by an increase in PGE secretion by Mo and bone marrow cells. The PGE secretion could, however, be selectively blocked by preincubating the cells for 3 h with indomethacin (10(-7) Mol) leaving CFS production intact. In vivo treatment of mice with either maleic anhydride divinyl ether copolymer (MVE-2; 25 mg/kg) or poly ICLC (2 mg/kg) significantly increased levels of CSF in serum, as well as in culture supernatants of in vivo-treated peritoneal Mo and bone marrow cells. The increase in serum CSF levels and in secretion of CSF by peritoneal Mo and bone marrow cells was followed by a dose-dependent increase in GM-CFU-C, in nucleated bone marrow cells, and in peripheral blood leukocytes. The same BRMs also stimulated the secretion of PGE by in vivo-activated peritoneal Mo, but not by bone marrow cells. Pretreatment of the mice with indomethacin (4 mg/kg) almost completely suppressed PGE secretion by peritoneal Mo, but did not change the CSF secretion by peritoneal Mo or bone marrow cells and had no significant effect on bone marrow cellularity. Therefore, MVE-2 and poly ICLC, in addition to their immunomodulatory activity, can also have stimulatory effects on myelopoiesis, presumably mediated through secretion of CSFs. Protection and/or restoration of bone marrow function could thus either provide the opportunity for more extensive chemotherapy or could increase the number of Mo effector cells available for activation against tumor targets.

Animals↗
PubMed1984

Role of prostaglandin E and interferon in secretion of colony-stimulating factor by murine macrophages after in vitro treatment with biological response modifiers.

We have evaluated the possible role of biological response modifiers (BRMs) in myelopoiesis by investigating BRM modulated secretion of hematopoietic growth factors and inhibitors. Here, we report the evidence of augmented secretion of granulocyte and/or macrophage colony stimulating factors (CSF) by murine resident peritoneal macrophages after in vitro incubation with murine interferons (alpha, beta-mIFN; beta-mIFN; gamma-mIFN), poly ICLC (polyriboinosinic-polycytidylic acid poly-L-lysine), BM 41.332 (2-cyano-1-[(2-methoxy-6-methyl-pyridin-3yl)-methyl]-aziridine) and lipopolysaccharide (LPS). The secretion of CSF appears to be independent of the ability of the BRMs to induce IFN, as shown by the use of neutralizing antibodies against mIFN. The antiproliferative effects of IFN also did not block the BRM induced effects of CSF. The combination of alpha, beta-mIFN and poly ICLC or LPS and poly ICLC at suboptimal concentrations resulted in additive, but not synergistic effects on CSF secretion by macrophages. Histological examination of the colonies induced indicated the presence of two types of CSF, namely CSF1 and CSF3, which give rise to pure macrophage and granulocyte colonies respectively. In parallel to their effect on CSF secretion, these BRMs also caused a considerable increase in secretion of prostaglandins of the E series (PGE) by macrophages. However, the production of PGE did not interfere or influence CSF secretion, since the inhibition of the enzyme cyclooxygenase with indomethacin (10(-7) molar) 3 h before stimulation with poly ICLC, alpha, beta-mIFN, or LPS, inhibited the secretion of PGE by macrophages without affecting the secretion of CSF. Macrophages, stimulated by one of the active BRMs for 24 h, could not be restimulated by any of these agents to again secrete significant amounts of CSF or PGE, even after a 2 day resting phase. Other drugs tested (diethyldithiocarbamate, maleic anhydride divinyl ether, azimexone) failed to stimulate the in vitro secretion of significant amounts of CSF and PGE. The results presented here indicate that several BRMs can be utilized to stimulate macrophages to secrete the myelopoietic growth factor CSF, thus supporting the concept that these BRMs might be of value in reconstituting or promoting impaired granulocyte and monocyte/macrophage function.

Animals↗
PubMed1983

The effect of low lead doses in vitro and in vivo on the d-ala-d activity of erythrocytes, bone marrow cells, liver and brain of the mouse.

The d-ala-d activity in erythrocytes (RBC), femur bone marrow, liver and brain of mice was determined using a modification of the method of Berlin and Schaller (1974). In vitro incubation of lead acetate (PbAc) with these tissues resulted in a dose-dependent inhibition of the d-ala-d activity. The lead concentration which caused a 50% inhibition of the d-ala-d activity after 10 min incubation [ED-50(10 min)] was 0.78 mg PbAc/femur bone marrow, 3.72 micrograms PbAc/ml RBC, 15.85 micrograms PbAc/g brain and 43.05 micrograms PbAc/g liver. An increase in the incubation time to 60 min reduced these ED-50 values between 44% for the erythrocytic enzyme and 67% for the brain enzyme. In vivo treatment of mice with oral lead administration (absorbed dose range: 1-100 micrograms PbAc/kg b.w.) for 1 or 3 months led to a dose-dependent and organ-specific inhibition of the d-ala-d activity. After 3 months of oral lead supply the maximum enzyme inhibition (54%) was found in the bone marrow. At the same time the lowest enzyme inhibition could be seen in the brain which retained 73% of its activity. The erythrocytic and liver enzyme activity was 71% and 72% resp. of the appropriate control. Within 3 weeks after completing the oral lead administration the brain enzyme activity was completely restored. The erythrocytic and liver enzyme activities were still significantly, but not very markedly inhibited, whereas the bone marrow d-ala-d remained seriously depressed. According to these experiments, the lead dose which causes a long term inhibition of the bone marrow and erythrocytic d-ala-d activities is assumed to range between 50 and 100 micrograms PbAc/kg b.w. and day, as an absorbed dose.

Animals↗
PubMed1983

The action of azimexone on the cells of the hemopoietic system in mice, especially after damage with X-rays.

Mice were exposed to single doses of whole body X-irradiation (1 - 2 - 4 Gy) or were treated with sulphur mustard (15 mg/kg body weight i.p.). This treatment caused a reduction of the pluripotent stem cells in the bone marrow, of the total count of nucleated bone marrow cells in the femora and of the WBC in the peripheral blood. The size distribution of the bone marrow cells showed three separate peaks. From the histological examination of the bone marrow of X-irradiated mice it was deduced that the first peak represents erythrocytes, the second lymphocytes and the third peak the precursors of red and white blood cells. Multiple doses (25 - 50 - 100 mg/kg body weight) of azimexone, an immunomodulating substance, led after moderate doses of X-rays (2 Gy) or sulphur mustard to a more rapid recovery of the various parameters. In particular a stimulant action of azimexone on the pluripotent stem cells of mice not subjected to the injurious agents could also be demonstrated.

Adjuvants, Immunologic↗
PubMed1983

Immunosuppressive activity of human chorionic gonadotrophin preparations in vivo: evidence for gonadal dependence.

Human chorionic gonadotrophin preparations (hCG), when injected ip daily for 4 days, suppress the delayed-type hypersensitivity (DTH) response of mice to sheep red blood cells. Preparations of crude hCG, purified hCG subunits, and hCG that was formed by recombining the purified subunits showed immunosuppressive activity in accord with their gonadotrophic activity. The immunosuppressive effects in male and female mice were comparable. However, removal of the gonads completely abrogated the immunosuppressive activity of hCG in both males and females, suggesting that the effect of hCG is mediated by a factor released from the gonads. We conclude that the hCG molecule itself exhibits immunosuppressive activity in vivo in both male and female mice and that the gonads are required for the expression of this activity.

Animals↗
PubMed1983

Prostaglandin E synthesis and release by murine macrophages and human monocytes after in vitro treatment with biological response modifiers.

Prostaglandins of the E series (PGE), produced by mononuclear phagocytes, have many biological activities and are involved in the regulation of myelopoiesis and of the cytotoxic activities of macrophage (M phi) and natural killer (NK) cells. Since one of the possible effects of biological response modifiers (BRMs) on immune regulation might be modulation of PGE production, resident peritoneal murine M phi (mM phi) and elutriated human blood monocytes (hM) were incubated with BRMs and the supernatants were then assayed for PGE. Control mM phi produced about 4.9 ng PGE/10(5) mM phi over a 24 hr period. Lipopolysaccharide (LPS, 1-5 micrograms/ml), polyinosinic-polycytidylic acid complexed with poly-L-lysine (Poly ICLC, 0.1-10 micrograms/ml) and murine alpha, beta-interferon, (IFN, 10-1000 U/ml) all caused a highly significant increase in PGE-secretion. BM41.332, a 2-cyanoaziridine (25-50 micrograms/ml), was found to be less stimulatory, whereas the pyran copolymer MVE-2 (25-50 micrograms/ml), and Azimexone (25-50 micrograms/ml) had marginal effects on PGE-production. Kinetic studies showed that the plateau of PGE-production by mM phi occurred during the first 24 hr of incubation, and mM phi which were washed after a 24 hr incubation period could not be restimulated to produce more PGE. PGE release by hM was increased after stimulation with LPS, Poly IGLC and BM41.332, whereas human IFNs (alpha and beta) induced a slight decrease in PGE production. As in the murine studies, Azimexone and MVE-2 had no detectable effect. The ability of some BRMs to augment PGE-secretion by mM phi and hM may contribute to their negative effects on host responses, such as suppression of NK cell activity.

Adjuvants, Immunologic↗
PubMed1982

Bone marrow cells of mice under the influence of low lead doses.

The influence of lead on the number of nucleated bone marrow cells and pluripotent stem cells in femur bone marrow was investigated in mice. It was found that neither a single nor 10 days' oral administration of lead at doses of 10-1,000 micrograms PbAc/kg b.w. led to any change in the bone marrow cellularity. After 1 month's oral administration of 1,000 micrograms PbAc/kg b.w., on the other hand, there was a significant reduction of nucleated bone marrow cells and pluripotent stem cells in the femur bone marrow of up to 20% in comparison with controls. Within 14 days after completing the lead administration, however, normal values in the bone marrow cellularity were found again. Three months' oral administration of lead at doses of 100 and 1,000 micrograms PbAc/kg b.w. led to a significant reduction in nucleated bone marrow cells and pluripotent stem cells in the femur bone marrow of up to 28% compared with the controls. In contrast to the experiments with 1 month's oral administration of lead the regeneration of the bone marrow was not completed 14 days after completing the administration of the lead. These results show that lead at doses above 100 micrograms PbAc/kg b.w. causes on long-term administration a clear reduction of the nucleated bone marrow cells combined with a depressed regeneration ability of the pluripotent stem cells.

Animals↗
PubMed1982

Enhancing activity of various immunoaugmenting agents on the delayed-type hypersensitivity response in mice.

Six immunoaugmenting agents were tested in the delayed-type hypersensitivity reaction (DTH) in normal BALB/c X DBA/2 mice. The agents tested, levan, lentinan, mannozym, maleic anhydride divinyl ether, polyriboinosinic-polycytidylic acid-poly-L-lysine, and highly purified L-cell interferon, gave significant increases in the DTH response above the sheep red blood cell control. The schedule of doses for each agent corresponded with previous experiments from this laboratory of the maximum natural killer cell activity, macrophage activation, and interferon induction. Highly purified L-cell interferon was capable of eliciting a significant DTH response when given 4 hr after the initial challenge with sheep erythrocytes. In addition, lambda-carrageenan, a macrophage-cytotoxic agent which can render the macrophage inactive, was found to suppress the DTH response to levels slightly above phosphate-buffered saline controls. The carrageenan-induced suppression of the DTH response could be abrogated by coadministration with immunoaugmenting agents to levels attained with the immunoaugmenting agents alone.

Adjuvants, Immunologic↗
PubMed1981

The influence of low lead doses on the reticulo-endothelial system and leucocytes of mice.

The half-life of the indian ink elimination (carbon clearance method) was used as a measure of the RES activity. A significant increase of the RES activity in mice was found already after a single intraperitoneal (i.p.) administration of 20, 50, or 100 micrograms PbAc/kg body weight (b.w.). A significant RES stimulation could also be demonstrated after a single or 10-day oral administration of lead at doses of 10-1,000 micrograms PbAc/kg b.w. No RES stimulation occurred, however, after 30-day oral administration of lead. On determining the reactivity of the RES to 1 microgram endotoxin/kg b.w. it was found that it was already limited after a single and 10-day oral lead administration. After 30-day oral administration of lead (doses 10-1,000 micrograms PbAc/kg b.w.) the reactivity of the RES was completely suppressed. After a single and 10-day oral administration of lead (doses 10-1,000 micrograms PbAc/kg b.w.) we observed a marked leucocytosis. This effect was most clearly seen after a dose of 100 micrograms PbAc/kg b.w.; the leucocyte counts were increased by up to 50% in comparison with controls. After 30-day oral administration of lead, such a leucocytosis was no longer detectable. In accordance with the findings on the RES, the leucocytosis that is normally induced in the animals by 1 microgram endotoxin/kg b.w. was significantly reduced or completely suppressed both after single and also after 10 and 30 days' oral administration of lead at doses of 100 and 1,000 micrograms PbAc/kg b.w. These results show that the resistance state of the mouse is impaired already by low doses of lead.

Administration, Oral↗
PubMed1980

The action of small doses of lead on erythrocyte D-aminolevulinic acid dehydratase in the mouse.

After a single intraperitoneal administration of lead in very small doses [1--100 micrograms Pbac/kg body weight (bw)], there was a dose-dependent, highly significant inhibition of erythrocyte D-aminolevulinic acid dehydratase (D-ALA-D) activity in mice. The maximal inhibition occurred between 3 and 24 h post injection (p.i.). After that, a rapid recovery of the D-ALA-D activity took place so that four days after lead administration, enzyme activity exceeded even the normal value. Only after eight days p.i. did the D-ALA-D value return to the initial level after a biphasic course. After 10 i.p. injections of 0.1 to 10 micrograms Pbac/kg bw, there was again a dose-dependent, highly significant inhibition of the erythrocyte D-ALA-D activity in mice. The maximal inhibition was shown to be 24 h after the last lead injection. In contrast to the single i.p. administration, however, we found a monophasic course for the return of D-ALA-D activity. The D-ALA-D values did not exceed the normal range at any time after 10 i.p. lead injections. Ten and 30 days oral administration of lead corresponding to i.p. doses exhibited similar results in D-ALA-D inhibition.

Animals↗
PubMed1980

Lead in blood and tissues of mice after administration of low lead doses.

Lead levels in whole blood could be determined reliably up to a lower limit of 2 micrograms/100 ml blood, using a modified micromethod of the graphite tube furnace technique. Lead contents of various tissues were also determined by using the automated graphite tube furnace after wet ashing of the organs with nitric acid in autoclaves. Animal experiments with mice showed no measurable increase in blood lead level after a single, 10- or 30-days oral administration of lead in doses of 10--1000 micrograms lead acetate/kg body weight/day. However, these doses led to a rise in tissue lead content. There was a clear dependence of tissue lead content on type of organ examined, lead dose and duration of lead exposure. According to our experiments, the threshold dose which leads to a long-term increase in tissue lead content is assumed to be about 100 micrograms lead acetate/kg body weight/day, orally administered.

Animals↗