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Biomedical subjects

Z Ben-Ishay

Publications and source records attributed to Z Ben-Ishay.

At least 19 recordsLinked to original sources
PubMed1991

Improved prognosis in mice with advanced myeloid leukemia following administration of GM-CSF and cytosine arabinoside.

Acute myeloid leukemia (AML) was induced in C57Bl mice through the i.v. innoculation of C-1498 cell line. One week later, i.e. at mid-term disease, the leukemic mice received an i.p. injection of 200 ng rmGM-CSF and 24 h later, two consecutive i.p. cytosine arabinoside (ara-C) injections at 6 h intervals (2 x 200 mg/kg). The leukemic mice received 3-4 weekly courses of combined therapy and survived 4-5 weeks following leukemia induction. Control mice received ara-C only and survived 2-3 weeks. Moreover, leukemic mice administered both GM-CSF and ara-C had a lower marrow leukemic load than mice treated with ara-C only. From these findings, we conclude that therapy of murine AML with combined rmGM-CSF and ara-C is more effective than ara-C only. Leukemic mice treated with GM-CSF and ara-C had a longer life expectancy and a smaller leukemic load than mice administered ara-C only.

Animals↗
PubMed1990

Cumulative bone marrow stromal damage caused by X-irradiation and cytosine-arabinoside in leukemic mice.

A study of treated murine acute myeloid leukemia (AML) with an emphasis on the bone marrow stromal function is reported. Leukemia was induced in C57Bl mice through intraperitoneal (i.p.) inoculation of C-1498 myelogenous leukemic cells. The leukemic mice were administered: (1) total body lethal X-irradiation (t.b.i.); (2) two i.p. cytosine-arabinoside (Ara-C) injections followed by X-irradiation. Control mice received similar regimens. Bone marrow of experimental and control mice was processed for stromal cell cultures (SCC) and in vitro engraftment of hematopoietic cells onto the cultures. The results of this study indicate that the bone marrow stromal deficiency which occurs in leukemia is aggravated by Ara-C and irradiation treatments. Moreover, SCC of treated leukemic mice sustain in vitro hematopoiesis only to a limited degree. Stromal deficiency, as possible cause for graft failure in bone marrow transplanted leukemic patients, is discussed.

Animals↗
PubMed1990

Bone marrow stromal elements in murine leukemia: decreased CSF-producing fibroblasts and normal IL-1 expression by macrophages.

A study of bone marrow stromal elements in murine acute myeloid leukemia (AML) was carried out. Our previous studies had indicated marrow stromal deficiency in murine AML. In the current investigation, separate stromal cells were cultured and the results obtained have shown that, while marrow stromal macrophages are normal in leukemia and express adequate amounts of IL-1, the fibroblasts are markedly reduced. However, if sufficient fibroblasts are pooled in vitro, they produce adequate amounts of CSF. Test of TNF alpha in leukemic cells CM, as possible cause of marrow stromal inhibition in leukemia, had not disclosed this cytokine. Further, it was observed that total body lethal irradiation of leukemic mice aggravates the stromal deficiency, confirming results of our previous investigations. It is concluded that bone marrow stromal deficiency in murine AML is due to decreased fibroblasts and, implicitly, reduced CSF production.

Animals↗
PubMed1989

Long-term survival of murine erythroid progenitors in long-term bone marrow culture and stromal cell culture: differentiation in peritoneal diffusion chamber culture.

Bone marrow cells of normal and cytosine-arabinoside (Ara-C) treated C57B1 mice were cultured in primary long-term culture (LTBMC) for a period of eight weeks. Non-adherent cells collected at weekly culture feedings consisted of neutrophils, macrophages and megakaryocytes. These were transferred into a) secondary peritoneal diffusion chamber cultures (DC) and b) secondary stromal cell cultures (SCC) first, and then into tertiary DC cultures. While in LTBMC and SCC there was no evidence of erythropoiesis, many erythroid colonies developed in DC cultures. It appears that undifferentiated erythroid progenitors may have a long survival in LTBMC and SCC devoid of erythropoietin and then differentiate in vivo in DC cultures in host mice without specific erythropoietic stimuli. Terminal differentiation and maturation of erythroid progenitors occurs to a limited extent in conventional DC cultures. The large number of erythroid colonies in DC observed in the present study could be due to increased sensitivity of undifferentiated erythroid progenitors from LTBMC to physiological levels of Epo in host mice of DC.

Animals↗
PubMed1988

Haemophagocytosis and other haematological aspects of Mycobacterium lepraemurium disease of mice.

CBA mice inoculated i.v. with 2 x 10(8) viable MLM were observed at intervals for 5 months. In the bone marrow, haematopoietic cells were progressively displaced by MLM-laden phagocytes; depletion of erythroid cells began earlier and was more pronounced than that of myeloid cells. Transiently, mild anaemia and profound leucopenia were noted. The spleen was enlarged and the site of increasing histiocytosis and extramedullary haematopoiesis which was accompanied by displacement of splenic parenchyma. The liver was enlarged and its parenchyma contained scattered islands of haematopoietic elements. Lymph node cells had been largely replaced by MLM-laden macrophages by the end of the process. Thus, MLM infection exerts important effects on haematopoiesis of susceptible mice and is accompanied by active extramedullary haematopoiesis. In addition, the haemophagocytosis, observed most commonly in immuno-compromised patients infected with certain viral or mycobacterial pathogens, was observed late in the course of MLM disease of mice.

Animals↗
PubMed1988

Enhanced capacity of cytosine-arabinoside-treated murine bone marrow to maintain hematopoiesis in long-term culture.

A study of bone marrow of C57B1 mice administered cytosine-arabinoside (Ara-C) was carried out in long-term bone marrow culture (LTBMC). Two days after administration of two consecutive i.p. Ara-C injections (200 mg/kg each) at 6-h intervals, the bone marrow becomes hypocellular, yet in the process of regeneration, with an enriched and/or concentrated content of progenitors and stem cells. Ara-C-treated marrow was observed to sustain hematopoiesis in vitro better than physiological marrow; it produced a higher cell yield, a higher proportion of young-type myeloid cells, and higher levels of granulocyte-macrophage colony-forming cells and colony-forming units in diffusion chamber than control marrow. In addition, stromal cell cultures (SCC), devoid of hematopoiesis and engrafted with hematopoietic cells from LTBMC of Ara-C-treated marrow, were observed to produce hematopoietic cells for longer periods of time than SCC engrafted with control cells. In view of its increased capacity for regeneration, it is suggested that regenerative marrow should be used in autologous bone marrow transplantation in humans.

Animals↗
PubMed1987

Pre CFU-F in bone marrow cultures from children with hematopoietic disease including acute leukemia.

Stromal precursor cells from bone marrow aspirates of children have been studied in culture. In 7 day liquid cultures normal individuals and patients with acute leukemia in remission grew 110 +/- 50 CFU-F and 100 +/- 40 CFU-F (colony forming unit--fibroblasts) respectively, per 6 X 10(5) buffy coat mononuclear cells. Staining with monoclonal antibodies suggests that stromal cells from CFU-F colonies are fibroblasts. CFU-F colony growth from the bone marrow of patients with active leukemia was low. After cultivation periods of more than 21 days, we observed, in addition, still more immature, clonogenic fibroblast precursor cells, "pre CFU-F", and round cells attached to stromal cells from pre CFU-F colonies. From the round cells, we have passaged pre CFU-F and CFU-GM (colony forming unit--granulocytic, monocytic) in secondary cultures. Our observations are in agreement with the concept that the bone marrow stromal cell matrix serves as a sanctuary for reversibly attached clonogenic cells of both the hematopoietic and fibroblast lineages.

Acute Disease↗
PubMed1987

CFU-F circulating in cord blood.

CFU-F (colony forming units-fibroblast) were studied from cord blood and, as controls, from normal bone marrow of older children and adults. Numbers of CFU-F in cord blood buffy coat cells are lower by a factor of 10 in comparison to bone marrow CFU-F. Cytomorphology and staining with monoclonal antibody identify the progeny cells of CFU-F as fibroblasts. Cord blood CFU-F derived fibroblasts have properties supporting hematopoiesis: They produce CSF (colony stimulating factor) to which fresh cord blood CFU-GM (colony forming units-granulocytic, monocytic) react by colony formation in a dose-response manner. In addition, fibroblast colonies discharge clonogenic round cells into the medium forming CFU-GM and CFU-F colonies in secondary methyl cellulose cultures. We conclude that fetal blood contains clonogenic stromal cells (CFU-F) that give rise to fibroblasts with properties of hematopoietic support.

Adult↗
PubMed1987

Immune impairments and antibodies to HTLVIII/LAV in asymptomatic male homosexuals in Israel: relevance to the risk of acquired immune deficiency syndrome (AIDS).

We have studied 288 Israeli asymptomatic male homosexuals (MHS) to determine the prevalence of antibodies to HTLVI and HTLVIII and their correlation with impairments of the immune system and serum interferon (IFN). Seropositivity for HTLVI, HTLVIII, or both was found in 1.4, 8.3, and 0%, respectively. Significant decreases in the total peripheral T cells, TH cells, and TH/TS ratio as well as elevated alpha IFN serum levels were found in the MHS group in comparison with normal controls. Although no difference in the prevalence of either immune derangements or elevated serum IFN was observed between HTLVIII/LAV-seropositive and HTLVIII/LAV-seronegative MHS, the decreases in total T cells, TH cells, and TH/TS ratios were significantly greater in the seropositive MHS. These results indicate that (a) immune impairments and IFN system activation occur commonly in homosexuals, precede their exposure to HTLVIII/LAV, and probably reflect this group's increased risk for AIDS and (b) HTLVIII/LAV infection of MHS aggravates further their preexisting immune impairments.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Pre-CFU-f: young-type stromal stem cells in murine bone marrow following administration of DNA inhibitors.

Occurrence of young-type stromal stem cells (defined here as "pre-CFU-f") in murine bone marrow is reported in this study. Two consecutive intraperitoneal (i.p.) cytosine arabinoside (ara-C) injections were administered to C57B1 mice (2 X 200 mg/kg at 6-h intervals). Two days later the bone marrow was collected and assayed for colony-forming units-fibroblastoid (defined here as "CFU-f"). In additional experiments, ara-C-treated marrow was exposed in vitro to hydroxyurea (HU; "hydroxyurea killing test"), prior to plating, to establish the cycling state of stromal stem cells. In separate cultures of ara-C-treated marrow, replating of adherent cells was carried out up to quaternary sub-cultures. The results indicate ara-C-treated marrow produces approximately 20% "huge" fibroblastoid colonies (approximately 5 mm diameter versus 0.5-2 mm normal size); most stromal stem cells producing huge colonies are cycling cells; and adherent cells from primary ara-C-treated marrow cultures replated to secondary cultures produce adherent layers with double the number of cells than in the control secondary cultures. We conclude that the ara-C-treated murine bone marrow contains certain young-type cycling stromal stem cells which we refer to as pre-CFU-f. These stem cells produce huge fibroblastoid colonies in culture, indicating that they probably go through more cell cycles than CFU-f during the culture period. Alternatively, pre-CFU-f may have a higher self-replicative capacity than CFU-f.

Animals↗
PubMed1985

Effects of chemotherapy on bone marrow stroma in mice with acute myelogenous leukemia. Correlation with CFU-C and CFU-D.

This study describes changes in bone marrow stroma in murine acute myelogenous leukemia (AML). The AML was induced in C57B1 mice by intravenous (i.v.) transfusion of C4198 myelogenous leukemic cells. In untreated leukemic mice, the colony-forming unit fibroblasts (CFU-F) were severely inhibited. In leukemic mice treated by three chemotherapy protocols of cytosine-arabinoside (Ara-C) and adriamycin there was a 200% increase in the life span as compared to untreated leukemic animals and marked reduction of marrow leukemic load. In these mice the stromal inhibition was temporarily relieved, expressed by peaks of CFU-F2-3 days following each protocol. In between the peaks, CFU-F decreased to subnormal levels, remaining low to the end of the disease. In normal mice administered a similar chemotherapy regimen, there were peaks of CFU-F activation after each protocol and normal levels in between the peaks. Granulocyte/macrophage progenitors (CFU-C) of leukemic-treated and normal-treated mice showed increased levels following each chemotherapy protocol. Whereas CFU-C decreased below normal levels in leukemic mice towards the end of the disease, the level of these progenitors remained high in normal mice receiving Ara-C and adriamycin. Colony-forming units in diffusion chamber (CFU-D) showed mild fluctuations in both leukemic and normal mice receiving three protocols of Ara-C and adriamycin. It is possible that despite treatment, the bone marrow stroma in leukemia becomes irreversibly deficient towards the end of the disease and cannot support the residual normal hematopoiesis.

Animals↗
PubMed1978

Migration of lymphoid cells to the bone marrow of rat following eradication of cells in DNA synthesis and in mitosis.

Eradication of replicating bone marrow cells of rat by means of combined administration of single doses of hydroxyurea and vinblastin is followed within 9--10 h by an inflow of lymphoid cells of extramedullary origin in the range of 13,200,000/femur. The rat bone marrow with a high content of lymphoid cells was previously shown to be concentrated in stem cells. The factor(s) which convey the 'information' of decrease of replicating marrow cells to extramedullary sites is at present unknown.

Animals↗
PubMed1978

Growth of diffusion chamber hematopoietic colonies derived from spleen cells of rats administered hydroxyurea.

Donor rats of the Hebrew University strain were administered a single intraperitoneal injection of hydroxyurea (400 mg/kg body weight). 1--3 h following the administration of the drug, a suspension of spleen cells, the majority of which consisted of lymphocytes, was prepared. Spleen cells were placed in diffusion chambers and these were implanted in the peritoneal cavity of preirradiated mice. 5--8 days following implantation, erythroid and granulocytic colonies developed in 30.3% of the diffusion chambers studied. However, in most chambers, macrophages were observed. In control experiments with implantation of spleen cells of normal rats, granulocytic colonies did not grow and in only 3.1% of the chambers erythroid colonies were noted. Macrophage colonies, however, developed in all 32 control cultures. Our previous studies showed that administration of a single dose of hydroxyurea strips the rat bone marrow of approximately 50% of replicating cells within 9--10 h. The results of the present study indicate that such a severe depletion of rat marrow cells results in early committment of spleen stem cells to various blood cell lines.

Animals↗
PubMed1978

Erythroid "bursts" in semi-solid agar diffusion chambers: effect of cyclophosphamide administration to host and of hydroxyurea to donor animals.

Growth of erythroid bursts was induced in peritoneal diffusion chambers in a semi-solid agar medium. Mice of the "Sabra" strain received single i.p. injections of cyclophosphamide (45 mg/kg) 24 h prior to implantation of chambers. Rats of the Hebrew University strain, used as donors, received single i.p. injections of hydroxyurea (400 mg/kg), 9 h prior to being killed. Ten to fourteen days after chamber implantation, several erythroid colonies of ten to several hundred cells developed in the semi-solid agar medium. The erythroid cells in the colonies were benzidine-positive and at various stages of maturation. We suggest that growth of erythroid "bursts" in diffusion chambers, in hosts which had not received any specific erythropoietic stimuli, was made possible by a high concentration of BFU-E in the door marrow. The BFU-E enriched rat bone marrow resulted from administration of hydroxyurea which, after preferentially killing erythroblasts in cycle, stimulated mobilization of stem cells for the replenishment of the depleted compartment.

Agar↗
PubMed1977

Effects of hydroxyurea pretreatment of donor rats on growth of haematopoietic diffusion chamber colonies in mice.

A single dose of hydroxyurea (HU) (400 mg/kg body weight) was injected i.p. into rats. Hydroxyurea, a potent DNA synthesis inhibitor, killed bone marrow cells in the S-phase of the cell cycle. 9-10 h after HU administration, the rat bone marrow contained large numbers of necrotic cells and appeared predominantly lymphoid. Within 24-48 h of HU injection, resumption of normal haematopoiesis was observed. Rat bone marrow, 9-10 h following HU administration, was implanted in peritoneal diffusion chambers (DC) in irradiated mice. The results obtained suggest that pretreatment of donor rats with HU increases the bone marrow content of progenitor cells. The stem cell-enriched marrow was conductive to enhanced growth of DC colonies in irradiated mice.

Animals↗
PubMed1977

Macrophages and/or fibroblasts in hematopoietic diffusion chamber cultures.

An ultrastructural study of diffusion chamber (DC) hematopoietic colonies derived from rat bone marrow is reported. The emphasis is placed on the structural features of macrophages and fibroblasts in cultures. The observations indicate that the two cell types are normal components of DC cultures. In older cultures both macrophages and fibroblasts contain large lipid droplets, sometimes causing difficulty in the precise characterization of the cell type. The possible origin of fibroblasts from adventitial cells if sinuses or of larger blood vessels of the bone marrow implanted in diffusion chambers is discussed. It is suggested that fibroblasts exert an enhancing influence on the growth of blood cells in DC cultures, comparable to feeder layers in in vitro cultures.

Animals↗
PubMed1976

Macrophage killing capacity. Aspects of mechanism.

Immune macrophages have the capacity to kill in mixed macrophage cultures (MMC) allogeneic macrophages bearing the alloantigens used for immunization. The killing is expressed by a lytic mechanism as neither phagocytosis nor fusion between effector and target cells could be detected by E.M. T but not B lymphocytes isolated from immune spleen cells, are able to "arm" syngeneic nonimmune macrophages and render them cytotoxic. It is suggested that mediator(s) and/or membranal components are released from T cells and attach to macrophages. Such an "arming" factor enables the macrophage to recognize and kill target cells.

Animals↗