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Biomedical subjects

A Peled

Publications and source records attributed to A Peled.

At least 55 records · Page 3Linked to original sources
PubMed1994

Myeloblastic cell line expresses osteoclastic properties following coculture with marrow stromal adipocytes.

Osteoclasts are derived from hemopoietic precursors in the marrow. Their differentiation pathway is still undefined, but an important role was observed for the marrow microenvironment in the regulation of osteoclastogenesis. Various marrow stromal cell subtypes were used to study their possible role in the formation of osteoclasts from myeloblast (M1) cells. Interactions between M1 cells and the 14F1.1 endothelial-adipocyte stromal cell line were demonstrated in a coculture model. M1 cells attached to the adherent layer of 14F1.1 cells and formed distinct foci reminiscente of "cobblestone areas." Following these interactions, M1 cells developed specific enzymatic activities and became multinucleated. Both mononuclear and multinuclear M1 cells became positive to tartrate-resistant acid phosphatase (TRaP) and ATPase, a feature characteristic of osteoclasts, and were also responsive to calcitonin. Furthermore, they attached to mineralized bone particles and their membrane changed into a ruffled border at the zone of interaction with the bone matrix. We thus demonstrated that marrow endothelial-adipocytes may play a role in regulating the differentiation of myeloblasts into osteoclasts.

Acid Phosphatase↗
PubMed1993

Lymphomagenesis in AKR.Fv-1b congenic mice.

In the AKR.Fv-1b congenic strain the Fv-1n allele of the AKR/J mice was substituted with the Fv-1b allele, thereby limiting viral replication and spread of the endogenous N-tropic murine leukemia virus. As a result of this genetic change AKR.Fv-1b mice develop a low spontaneous incidence (7%) of T-cell lymphomas and about 28% of Ly-1+ B-cell lymphomas are observed in old mice. Characteristic changes in thymus subpopulations of AKR/J mice (related to the formation of the dual tropic mink cell focus inducing (MCF) type virus in the thymus) were not observed in the thymus of AKR.Fv-1b mice. In contrast to the low susceptibility to spontaneous T-cell lymphoma development, these mice were highly sensitive to fractionated irradiation or to radiation leukemia virus (a mixture of N- and B-tropic viruses) induced T-cell lymphoma. Potential lymphoma cells (that would ultimately develop into Ly-1+ B-cell lymphomas) were demonstrated in bone marrow and spleens of 16-24-month-old mice. Analysis of the Ly-1+ IgM+ B-cell population in spleens of 18-month-old mice revealed a significant increase in this population (35% versus 2% in young spleens). The spontaneous Ly-1+ B-cell lymphoma incidence could be enhanced (up to 77%) by in vivo administration of anti-CD8 monoclonal antibody or IL-4 to 18-month-old mice. Virological analysis of T/B-cell lymphomas for class I MCF viruses indicated that Class I MCF development was tightly correlated with T-lymphoma development (except radiation induced tumors that showed no MCF provirus involvement). In contrast, Ly-1+ B-cell lymphoma development was independent of Class I MCF pathogenic virus involvement.

AKR murine leukemia virus↗
PubMed1993

Analysis of Ly-1+ B-cell populations and IgH rearrangements in "normal" spleens and in lymphomas of AKR/J and AKR Fv-1b mice.

AKR mice are highly susceptible to development of spontaneous T-cell lymphoma. Thymus removal at the age of 1-3 months greatly reduces T-cell lymphoma. Lymphomas that have the characteristics of T- and/or B-cells occur sporadically in peripheral lymphoid tissues of old thymectomized AKR/J mice. These thymectomized mice were shown to carry dormant potential lymphoma cells. Transplantation of lymphoid cells from 8-12-month-old AKR/J mice, thymectomized at the age of 6 to 8 weeks, into intact or thymectomized young recipients yielded 80-100% Ly-1+ pre-B or B-cell lymphomas. In the AKR-Fv-1b congenic strain the Fv-1n allele of AKR/J mice was substituted with the Fv-1b allele, thereby limiting viral replication and spread of the endogenous N-tropic murine leukemia virus. As a result of this restriction in virus spread, AKR-Fv-1b mice develop a low spontaneous incidence (7%) of T-cell lymphomas and about 28% of Ly-1+ B-cell lymphomas at old age. In spleens of 15-18-month-old thymectomized AKR/J mice and intact AKR-Fv-1b mice, 30-60% of the B-cells were of the Ly-1+ B type. Analysis of the IgH locus in these normal old spleens and Ly-1+ B lymphomas indicated mono- or oligoclonality. One particular IgH rearrangement was identified in many individual old spleens and tumors. A second specific IgH rearrangement was found in some tumors. Possible mechanisms involved in the expansion of Ly-1+ clones and their progression into tumors are discussed.

Age Factors↗
PubMed1993

Mixed phenotype murine leukemias.

Cell lines were derived from eight individual leukemias induced by X-rays in NFS mice. First typed as null cells (surface immunoglobulin negative, Thy-1 negative), they turned out to have a mixed phenotype with myeloid cytochemical markers, pre-B surface antigens and molecular markers of pro-B lymphocytes. They represent murine models for mixed phenotype (pro-pre-B-myeloid) leukemias.

Animals↗
PubMed1992

Termination of the B cell lymphoma dormant state in thymectomized AKR mice.

AKR mice are highly susceptible to spontaneous T cell lymphomagenesis and thymus removal at the age of 1 to 3 mo greatly reduces its development. Twelve-mo-old AKR mice thymectomized at young age were shown previously to carry potential lymphoma cells that could be triggered to develop into B cell lymphomas (80 to 100%) after removal from their host "restrictive" environment into young histocompatible hosts. Additional attempts were made to terminate the potential lymphoma cell dormant state in 12-mo-old thymectomized AKR mice. Replenishment of some deficiencies caused by thymectomy at a young age, including a s.c. syngeneic thymus graft or a single injection of the dual tropic recombinant virus isolates DTV-71 or MCF-247 into 12-mo-old thymectomized AKR mice resulted in Ly-1+ pre-B or B cell lymphoma development in 80 to 98% of these treated mice. In vivo elimination of T cell subsets by administration of cyclosporin A or by mAb expressed on Th cells (anti-CD4) or cytotoxic T cells (anti-CD8) stimulated the progression of dormant potential lymphoma cells towards B cell lymphoma development. The most striking results were observed after administration of anti-CD8 mAb: 90 to 100% of these treated mice developed Ly-1+ B cell lymphomas within 80 days. The effect of rIL-2 on dormant PLC was also tested. Administration of rIL-2 to 12-mo-old thymectomized mice terminated tumor dormancy in 94% of the treated mice within 66 days. Tests of the resulting B lymphomas for dual tropic recombinant virus/mink cell focus-inducing virus infection indicated that the breakdown of tumor dormancy did not result from development of pathogenic class I mink cell focus-inducing viruses. These results suggest that T cell subsets and/or their products are involved in the proliferation arrest of potential lymphoma cells present in thymectomized AKR mice.

Animals↗
PubMed1992

Thy-1 antigen-mediated adhesion of mouse lymphoid cells to stromal cells of haemopoietic origin.

Thy-1 antigen is one of the widespread cell surface antigens. The antigen is expressed in the cells of a wide variety of different tissues and species and its pattern varies considerably during development and among species. Although the Thy-1 is one of the members of Ig-superfamily its function(s) remain unknown. Here we show that monoclonal antibodies to mouse Thy-1.2 antigen prevent adhesion of Thy-1.2-positive mouse T-leukemic cells 127 to monolayers of two mouse bone marrow stromal cell lines (14F1.1 and MBA-15). The same antibodies do not prevent adhesion of cell 127 to monolayers of two other mouse bone marrow stromal cell lines (MBA-2.1 and MBA-1.1.1) and to a wide spectrum of different normal and tumor mouse cell lines. A characteristic of the cell line 14F1.1 is the ability to support growth of mouse haemopoietic stem-cells. This data suggest that cells of stromal lines 14F1.1 and MBA-15 contain on their surface a specific ligand for the Thy-1 molecule. Cell-cell interaction via this ligand and the molecule on the cell surface may be an important step for development of certain lineages of cells.

Animals↗
PubMed1992

Absence of negative growth regulation in three new murine radiation-induced myeloid leukemia cell lines with deletion of chromosome 2.

Murine radiation-induced acute myeloid leukemia (RI-AML) may be considered as the experimental counterpart of human secondary leukemia. Three new myelomonocytic cell lines derived from RI-AML and carrying a partially deleted chromosome 2 are described. The RI-AML cells responded with increased proliferation after being incubated with the hemopoietic growth factors rG-CSF, rGM-CSF and IL-3. Increased proliferation of the same extent without any effect in differentiation, was also demonstrated in the RI-AML cells after incubation with IL-6 and with mouse lung conditioned medium (CM) and Krebs ascites tumor cells CM which induce differentiation in normal and most leukemic myeloid cells. Down-regulation of the c-myc gene and induction of (2'-5') oligo-adenylate synthetase (reflecting autocrine interferon secretion), two essential mechanisms operating during arrest of growth and concomitant differentiation, were demonstrated to be absent in RI-AML cells. In contrast, the M1 cells responded to the above differentiating factors with growth arrest and differentiation and with appropriate c-myc down-regulation and synthetase induction. The genetic basis for the distinct RI-AML cells' behavior may be connected with the loss or structural and/or functional abnormalities of DNA sequences located in the deleted part of chromosome 2 or in the respective allele. The presently described new RI-AML cell lines may be used for studies concerning myeloid leukemogenesis in general and secondary leukemia in particular.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

Initiation and promotion in radiation-induced myeloid leukemia.

Acute myelomonocytic leukemia develops in 10-30% of irradiated (300 rad) SJL/J mice, after a lag period of around one year. Additional treatment with dexamethasone shortly after irradiation increased leukemia incidence up to 50%. Experiments were conducted in order to demonstrate the existence of preleukemic cells in irradiated mice and to explore the possible role of dexamethasone, cyclophosphamide, and different hemopoietic growth factors on their promotion to overt leukemia. Transplantation of bone marrow cells from mice exposed to 300 rad plus dexamethasone into appropriate recipients, performed 4-5 months after leukemogenic treatment, resulted in acute myeloid leukemia (AML) development of donor origin in 70% of the recipients. Transfer of fractionated preleukemic bone marrow showed that the highest AML incidence developed in the recipients of fractions enriched in early hemopoietic precursors. The promoting effect of dexamethasone on preleukemic cells was confirmed by demonstrating its similar coleukemogenic effect whether administered within several hours or 130 days after radiation. Treatment with cyclophosphamide shortly after radiation could not replace the dexamethasone effect but was found to be complementary to the coleukemogenic effect of dexamethasone. Early administration of hemopoietic growth factors (starting 14 days after radiation and dexamethasone) showed that colony-stimulating factor (CSF) 1 increased the AML incidence (75%) and reduced its latency. Treatment with recombinant granulocyte-CSF (rG-CSF) had a reduced effect and recombinant granulocyte-macrophage CSF (rGM-CSF) had no promoting effect. However, administration of different factors several months after the leukemogenic treatment revealed that rGM-CSF increased AML incidence (75%) and shortened its latency, whereas rG-CSF and CSF-1 had no effect. In contrast, the late administration of recombinant interleukin 6 reduced AML incidence significantly (23%). The present results indicate that murine radiation induced AML is a multiphase process involving radiation induced preleukemia that can be promoted by different treatments.

Animals↗
PubMed1991

Involvement of wild-type p53 in pre-B-cell differentiation in vitro.

Wild-type p53 protein is a growth modulator whose inactivation has been found to be a key event in malignant transformation. Reconstitution of wild-type p53 in the p53-nonproducer, Abelson murine leukemia virus-transformed pre-B-cell line L12 gave rise to stably growing clones. Wild-type p53-producer derived cell lines exhibit an altered cell cycle, however. More cells with an extended G0/G1 phase were found than in the p53-nonproducer parental cell line. Furthermore, when injected into syngeneic mice, these cells induced a lower incidence of tumors and these tumors were less aggressive. Analysis of immunoglobulin expression revealed that wild-type p53 induced the expression of cytoplasmic immunoglobulin mu heavy chain. In addition, these derived cells lines exhibited increased levels of a B-cell-specific surface marker, B220. These results suggest that wild-type p53 may function as a cell differentiation factor that can induce development of pre-B cells into a more advanced stage in the pathway of B-cell maturation. In these pre-B cells, wild-type p53 may induce cell differentiation without terminal growth arrest of the cell population.

Abelson murine leukemia virus↗
PubMed1991

Expression of alpha-smooth muscle actin in murine bone marrow stromal cells.

Human fibrotic bone marrow (BM) stroma has been shown to contain alpha-smooth muscle actin (alpha-SMA)-positive cells. These closely resemble myofibroblasts that were described in other fibrotic tissues. We studied the expression of alpha-SMA in a series of murine BM-derived stromal cell lines to investigate the cellular origin and functional significance of myofibroblast-like cells in hematopoietic tissues. Although these cell lines differed in their biologic properties, most of them expressed alpha-SMA under certain conditions. Cells expressing alpha-SMA constituted a minor population in post-confluent, growth-arrested cultures. However, the incidence of cells expressing alpha-SMA increased significantly when cultures were transferred to nonconfluent conditions. A similar increase in alpha-SMA-positive cells occurred after a strip of cells was scraped away from the confluent cell layer; the cells of the affected area acquired alpha-SMA-positive contractile phenotype. The relationship between alpha-SMA expression and hematopoietic activity was studied using a cloned cell line of BM origin (14F1.1). The ability of these endothelial-adipocyte cells to support hematopoiesis in vitro was maximal under confluent conditions, whereas their expression of alpha-SMA under such conditions was residual. Moreover, in long-term BM cultures supported by confluent 14F1.1 cells, stromal areas associated with proliferating hematopoietic precursors, known as "cobblestone areas," were devoid of alpha-SMA-positive cells. These observations suggest that the expression of alpha-SMA is reversible and inversely related to hematopoietic activity.

Actins↗
PubMed1991

Prevention of spontaneous AKR T cell lymphomagenesis by 24-666, a virus isolated from an AKR B cell lymphoma.

Injection of a nonlymphomagenic ecotropic virus 24-666 isolated from a B cell lymphoma of AKR origin into young AKR mice (1-60 days old) inhibited spontaneous T cell lymphoma development. The reduction in T cell lymphoma incidence (16/106-15%) was accompanied with the appearance of B cell lymphomas (16/106-34%) in older mice (500 days mean latency). Infection of newborn to 60-day-old AKR mice with 24-666 prevented changes in thymus subpopulations and expression of MuLV-related cell surface antigens, normally observed in the thymus of 5- to 6-month-old AKR mice prior to lymphoma development. Thymuses of 24-666-infected 9- to 12-month-old mice lacked recombinant dual tropic virus (DTV) expression and retained the thymus pattern of 2-month-old AKR mice. At 12 months after 24-666 administration a striking decrease in Thy1.1 level and in the CD4+ CD8+ population and an increase in CD4- CD8- cells and in mu+ B cells, predominantly Ly1+, were observed. The presence of B cells in these thymuses was also reflected in the high response of thymocytes to LPS blastogenesis accompanied by a decreased response to PHA. Although T cell lymphoma development was markedly reduced by 24-666 administration, the establishment of potential lymphoma cells (PLC) was not affected. Transfer of lymphoid cells from 12-month-old grossly normal 24-666-infected mice to the appropriate recipients resulted in a high incidence (64-80%) of B cell lymphoma development. Thus, 24-666 seems to act through interference with the establishment of DTV in the thymus, thereby preventing PLC promotion to overt T cell lymphomas. Lack of the favorable microenvironment for PLC development in the T cell pathway enables PLC development in the B cell pathway in older mice.

Aging↗
PubMed1991

Prevention of spontaneous AKR T cell lymphomagenesis by elimination of potential lymphoma cells with antibody to specific gp 71 determinants.

AKR mice, highly susceptible to spontaneous T cell lymphomagenesis, were protected from developing the disease by a course of daily treatment with antibody 18-5 to gp 71 determinants (administered from birth to 10 days). Potential lymphoma cells (PLC) identified among bone marrow cells of untreated AKR mice since birth (using the transplantation bioassay method) were eliminated following treatment with antibody 18-5. Namely, transplantation of bone marrow cells and thymocytes of 250-day-old untreated AKR mice into (AKR/J x DBA/2)F1 and/or AKR recipients yielded 86-93% T cell lymphoma of AKR origin at a short mean latent period of 38-42 days. In contrast, transfer of lymphoid cells from 18-5-treated mice at a matching age caused only 7-13% T cell lymphoma of AKR origin. The accelerating effect of MCF 247 on lymphoma development in untreated AKR mice was not effective in 18-5-treated mice, probably due to lack of PLC that are promoted by MCF 247 to overt T cell lymphoma. The characteristic changes in thymus subpopulations preceding lymphoma development and coinciding with PLC identification in the thymus of untreated mice was prevented by 18-5. It is suggested that prevention of lymphoma development in AKR mice by passive antiviral immunotherapy involves elimination of PLC representing the initial tumorigenic phase in AKR lymphomagenesis.

Aging↗
PubMed1991

Involvement of wild-type p53 protein in the cell cycle requires nuclear localization.

Transfection of wild-type p53 into a pre-B, p53 nonproducer cell line yielded the generation of stable clones. Although constitutively expressing the growth-suppressor wild-type p53 protein, these cells proliferate continuously in vitro. However, expression of wild-type p53 in these cells altered their cell cycle pattern and reduced their growth in vivo. When the same parental cells were transfected with a plasmid coding for a wild-type p53 lacking nuclear localization signals, a wild-type cytoplasmic p53 protein was expressed. Expression of this cytoplasmic p53 product did not exert any changes in the growth of the parental cells, suggesting that wild-type p53 affects the cell cycle only when localized in the nuclear cell compartment.

Animals↗
PubMed1991

Validity of the in vitro system as a correlate of the in vivo model of RadLV lymphomagnesis.

Adult BL/6 mice are highly sensitive to lymphomagnesis by the radiation leukemia virus variant A-RadLV (80-100% T-cell lymphoma incidence after a latency of 70-110 days). This study shows that the in vivo elimination of T-cell subsets (including suppressor and cytotoxic T-cells) achieved by the repeated administration of cyclophosphamide, cyclosporin A, anti CD4 or anti CD8 mAb shortly after virus infection did not interfere with the lymphomagenic pathway. No reduction in the high lymphoma incidence or tumor latency was observed following the different treatments. Thus the suggestion on the basis of in vitro studies that the early phase of A-RadLV lymphomagenesis is associated with suppressor T-cells which abrogate a potential anti-tumor immune response has not been confirmed in these studies.

Animals↗
PubMed1991

Frequent p53 mutations in chemically induced murine fibrosarcoma.

Patterns of p53 expression were investigated in chemically induced fibrosarcoma tumors and cell lines. Most, if not all, cell lines were found to carry alterations at the protein level, reflected in the overproduction of greatly stabilized p53 proteins. In many cases, this was accompanied by formation of complexes with hsc70. Hence, all of these lines may be expressing one sort or another of mutant p53. The mutant nature of the p53 gene was directly verified, in a number of cases, by PCR-amplified cDNA cloning. In one line, no p53 protein was made at all; this turned out to be because of a mutation in a splice donor site, resulting in the production of an aberrant mRNA. In all other cases, mRNAs carrying mis-sense mutations were present, and were sometimes expressed along with wt p53 mRNA. When tested in an in vitro transformation assay, all cloned mutants possessed a discrete oncogenic activity, while having lost the ability to interfere with oncogene-mediated transformation. The system described here could potentially be very helpful in elucidating the significance of p53 mutations.

Animals↗
PubMed1990

Characteristics of potential lymphoma-inducing cells in mice sensitive or resistant to lymphomagenesis by radiation leukemia virus variants.

The relationship between the H-2-associated responsiveness of mice to radiation leukemia virus variants (A-RadLV and D-RadLV) lymphomagenesis and the characteristics of early occurring potential lymphoma-inducing cells (PLC) among thymus and bone marrow cells of these virus-infected mice was investigated. Sensitivity to virus-induced T-cell lymphomagenesis was shown to involve early occurrence of Thy-positive PLC, found predominantly among thymocytes, whereas resistance was rather related with early identification of PLC-Thy-negative cells mostly among bone marrow cells. PLC were further characterized in the sensitive (BL/6 + A-RadLV) and resistant (BL/6 + D-RadLV) situations by testing in parallel the tumorigenic potential (using the transplantation bioassay method) and type of thymus and bone marrow cell populations separated by different methods such as size fractionation by centrifugal elutriation, cytotoxic elimination of lymphocytes, or panning. The early occurring PLC among thymocytes of BL/6 mice 10-20 days following infection with A-RadLV were shown to be cortisone-resistant, Thy+, CD4+, and/or CD8+ medium size dividing thymocytes. PLC among thymocytes of BL/6 mice + D-RadLV, identified among the medium and large cell fractions, were shown to be cortisone-resistant Thy-, CD4-CD8- lymphocytes. High tumorigenic potential of PLC was demonstrated only among unseparated or separated (on size basis) bone marrow cells of BL/6 + D-RadLV (72-84%), whereas unseparated or separated fractions of bone marrow from BL/6 + A-RadLV had a low lymphomagenic potential (15-20%). The parallelism between the bone marrow fractions that induced optimal thymus cellularity following reconstitution of lethally irradiated mice and optimal lymphomagenicity stress the prothymocyte characteristics of PLC among bone marrow cells of BL/6 mice infected with D-RadLV. It is suggested that in resistant and sensitive haplotypes RadLV variants infect different cell populations and thereby induce PLC which differ in their capacity to present associative MuLV antigens with self H-2.

Animals↗