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Biomedical subjects

E Yefenof

Publications and source records attributed to E Yefenof.

At least 37 records · Page 2Linked to original sources
PubMed1995

Clonal dominance of RadLV-induced lymphomas.

RadLV-induced leukemogenesis begins with the emergence of a pleioclonal population of preleukemic (PL) cells, which subsequently gives rise to a monoclonal lymphoma. We have recently found that the pleioclonal-->monoclonal transition may occur early during the PL latency and long before the eruption of a full blown lymphoma. We sought to find out what causes one PL clone to become dominant. Our working hypothesis was that a dominant clone(s) at the PL stage has the ability to inhibit the development of other, recessive clones. Since some premalignant characteristics of a progenitor clone are probably maintained in the descending lymphoma, we studied whether tumors that developed after injection of a high dose (HD) of PL cells were dominant over tumors that developed after injection of a limiting dose (LD) of PL cells. To identify dominant clones, HD and LD lymphomas were mixed in a co-culture and the outgrowth of one clone over the other was determined by T beta-TCR rearrangement analysis. A checker-board combination of seven lymphomas revealed a dominance hierarchy scale. Lymphomas induced directly by the virus (without transfer) were dominant over both HD and LD lymphomas. High dose lymphomas were dominant over LD lymphomas and LD lymphomas were always recessive. The speed at which a dominant lymphoma outgrew the co-culture suggested that dominance is acquired through the ability of the prevailing cells to actively suppress the growth of recessive cells.

Animals↗
PubMed1995

A longitudinal follow-up of salivary secretion in bone marrow transplant patients.

Salivary gland dysfunction is a common sequela of the bone marrow transplantation procedure. We determined the effect of different bone marrow transplantation protocols on parotid salivary flow rate. Salivary secretion was substantially reduced during conditioning of all the recipients. A gradual flow rate reconstitution could be detected as soon as a few days after the bone marrow transplantation. Eight patients conditioned with total lymph node irradiation and chemotherapy or chemotherapy alone displayed earlier and complete recovery of saliva secretions 2 to 5 months after the grafting. Recovery was delayed and incomplete when total body irradiation was added to the conditioning regimen (seven patients). Six of these patients also developed graft-versus-host disease. The results suggest that total body irradiation induces irreversible damage to the parotid glands resulting in profound xerostomia followed by opportunistic infections. Chemotherapy with or without total lymph node irradiation does not induce such damage.

Adolescent↗
PubMed1994

Lyn tyrosine kinase signals cell cycle arrest but not apoptosis in B-lineage lymphoma cells.

Signal transduction initiated by binding of antibodies to cell surface molecules can have an important impact on the growth of tumor cells. The malignant behavior of the murine lymphoma BCL1 can be suppressed and the neoplastic cells can be induced to enter a dormant state by in vivo ligation of membrane immunoglobulin. Anti-CD19 antibodies can prolong the survival of SCID mice challenged with the human Burkitt lymphoma cell line, Daudi. Here, we show that cross-linking of membrane immunoglobulin on both murine BCL1 and human Daudi cells initiates a cascade of signals leading to the induction of both apoptosis and cell cycle arrest in vitro. Using antisense oligonucleotides, we demonstrate that the immunoglobulin-associated Lyn tyrosine kinase is required for anti-immunoglobulin-mediated cell cycle arrest but is not required for the signal leading to apoptosis. These results define a branch point in the cytosolic signaling pathways mediating cell cycle arrest and apoptosis. In Daudi cells, Lyn is also critical for cell cycle arrest induced by anti-CD19 signaling. Thus, the Lyn tyrosine kinase may be an important mediator of cell cycle arrest in neoplastic B lymphocytes and, perhaps, other cell types.

Animals↗
PubMed1994

Radiation leukemogenesis: quantitative relationship between pre-leukemic cells in the thymus and lymphoma induction.

Fractionated irradiation of C57BL/6 mice induces a population of pre-leukemic (PL) cells that progress into mature thymic lymphomas after a latency of 4 to 6 months. Transfer of graded numbers of thymocytes from an irradiated mouse into recipient mice indicated that PL cells first appear in the thymus 6 weeks after irradiation. The initial proportion of the thymic PL cells is > or = 10(-5) and their frequency continuously increases with time, reaching > or = 10(-3) 10 weeks after irradiation. The PL cell population that emerges early during the pre-malignant latency consists of pleioclonal T lymphocytes. However, within 4 weeks a dominant PL clone can be detected which becomes the progenitor of a clonal lymphoma 9 to 15 weeks later. These results suggest that radiation leukemogenesis involves continuous accumulation of pleioclonal PL cells in the thymus, one of which is then selected for further maturation into frank lymphoma.

Animals↗
PubMed1994

Alternative complement pathway activation by CD4+ T cells of HIV infected individuals: a possible role in AIDS pathogenesis.

The mechanisms by which CD4+ T cells are eliminated during HIV infection are poorly understood. We have previously shown that HIV infected cell lines activate and fix C3 via the alternative complement pathway (ACP). In the present study we examined the ability of blood lymphocytes from 40 HIV+ individuals to fix C3. A large fraction of the CD4+ T cells reacted with anti-gp120 antibodies. These cells also carried C3 fragments in vivo and could further fix C3 if exposed to human serum in vitro. C3 activation occurred via the ACP. In some cases exposure of the lymphocytes to human serum under conditions allowing ACP activation resulted in partial elimination of CD4+ T cells. The results suggest that complement activation and fixation by CD4+ T cells opsonized with HIV particles or gp120 may contribute to their selective destruction.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Salivary immunoglobulins in recipients of bone marrow grafts. I. A longitudinal follow-up.

Patients receiving bone marrow transplantation (BMT) are prone to a variety of bacterial, viral and fungal infections in their oral cavity. We have therefore followed alterations in salivary Ig levels associated with BMT. Most of the patients were transplanted with allogeneic, MHC-matched BM after T cells were depleted by ex vivo treatment with an anti-lymphocytic monoclonal antibody (Campath-1) and autologous complement. Parotid saliva was collected at various time intervals before and after BMT, and IgM, IgG and IgA concentrations were determined by an enzyme linked immunosorbent assay (ELISA). A gradual fall in Ig levels was detected following patient's conditioning with a combination of chemo- and radiation therapy beginning 10 days prior to BMT. A rise in the titer of salivary Ig could be detected as early as 4 days post-BMT, which increased continuously and reached plateau levels within 2-3 weeks. However, about 3 weeks later the Ig titers decreased again and persisted at low levels for variable periods of time. A second increase in salivary Ig was detected approximately 2 months post-BMT, which persisted for prolonged periods of time. These results suggest that Ig secreted by donor B-lymphocytes and plasma cells passively transferred with the BM can rapidly reconstitute the salivary IgM, IgG and IgA of the immunocompromised recipient. However, when these cells cease to produce Ig the patients are still immunoincompetent and therefore enter a second phase of salivary Ig deficiency which may render them highly susceptible to opportunistic oral infections.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Salivary immunoglobulins in recipients of bone marrow grafts. II. Transient secretion of donor-derived salivary IgA following transplantation of T cell-depleted bone marrow.

Patients undergoing bone marrow transplantation (BMT) have decreased levels of salivary Ig over long periods of time. However, shortly after transplantation, a transient rise of Ig concentration in their saliva gland is detected. In order to trace the origin of this Ig, seven BM donors were immunized with tetanus toxoid (TT) 4-7 days prior to BMT harvesting. Four patients received BM from non-immunized donors. All but one of the patients had no detectable anti-TT IgA in their parotid saliva prior to BMT. Recipients of T cell-depleted BM from pre-immunized donors transiently displayed high titers of salivary anti-TT IgA 7-28 days after transplantation. No significant anti-TT IgA titers were detected in saliva of patients grafted with non-immunized BM. We conclude that antibody-producing cells activated in the donor are passively transferred with the BM to the recipient. IgA committed cells home to the mucosa-associated lymphoid tissues (MALT) and continue to secrete antibodies until senescence.

Adolescent↗
PubMed1993

Cancer dormancy: isolation and characterization of dormant lymphoma cells.

"Tumor dormancy" is an operational term used to describe a prolonged quiescent state in which tumor cells are present, but tumor progression is not clinically apparent. Although clinical examples of tumor dormancy abound, little is known regarding the mechanisms underlying this state. Here we utilize an antibody-induced dormancy model of an aggressive murine B-cell lymphoma (BCL1) and show that the induction of the dormant state is accompanied by dramatic changes in tumor cell morphology and cell cycle status. These data indicate the feasibility of altering the malignant phenotype of transformed cells by specific signals originating at the cell surface, and they suggest new opportunities for therapeutic intervention in cancer.

Animals↗
PubMed1993

Mitogenic activation of phosphoinositide turnover and DNA synthesis in murine CD4+8+ thymocytes.

Eighty percent of the lymphoid cells in the murine thymus are premature CD4+8+ (double positive) thymocytes. The vast majority of the double-positive cells do not maturate and die in the thymus. Although these cells are subjected to thymic selection processes, their activation competence has been an enigma. We have separated out CD4+8+ cells and studied their early and late responses to several mitogens. Concanavalin A, anti-CD3 (145-2C11) or anti-Thy1 (G7) monoclonal antibodies enhanced phosphoinositide turnover in double-positive thymocytes. However, DNA synthesis in the mitogen-stimulated cells was only accomplished if IL-2 or IL-4 was added. Alternatively, DNA synthesis could be induced by the calcium ionophore A23187 and phorbol myristate acetate (PMA). The latter mode of activation did not require the addition of exogenous lymphokines. CD4+8+ thymocytes did not secrete IL-2 or IL-4 following activation by either mitogens or A23187 and PMA. These findings demonstrate that CD4+8+ thymocytes resemble mature T cells in their ability to respond with DNA synthesis when activated by T-cell mitogens and IL-4 as well as IL-2. The results also delineate the difference between receptor mediated mitogenesis and pharmacological stimulation.

Animals↗
PubMed1993

Induction of B cell tumor dormancy by anti-idiotypic antibodies.

Long-term dormancy of murine B-cell lymphomas can be experimentally induced by immunizing the host with the idiotype expressed on the tumor. Interaction of the cells with anti-idiotype antibodies is sufficient to induce and maintain the dormant state. The growth of lymphoma cells interacting with anti-idiotype antibodies is arrested and they undergo dramatic changes in their morphology, cell-cycle status and oncogene expression. Regrowth of a tumor after long-term dormancy results from the emergence of a tumor cell variant that no longer responds to the antibodies with growth inhibition. These data demonstrate the feasibility of reversing a malignant phenotype of cells by specific growth arrest signals and suggest new approaches for therapeutic intervention in cancer.

Animals↗
PubMed1992

Induction of IL-4 secretion by the radiation leukemia virus (RadLV): role in autocrine growth stimulation of RadLV infected pre-leukemic cells.

Intrathymic inoculation of radiation-leukemia virus (RadLV) into C57BL/6 mice induces a population of pre-leukemic (PL) T cells which progress into clonal, mature thymic lymphomas after a latency period of 3 to 5 months. In order to understand how PL cells are retained in the thymus for a prolonged period of time we determined whether RadLV infected cells secrete and/or respond to a T-cell growth factor that may be involved in the long-term maintenance of a thymic PL-cell pool. We have previously found that in vitro proliferation of RadLV-infected PL cells is IL-4-dependent. Here we show that RadLV induces IL-4 secretion and IL-4 receptor (IL-4R) expression in normal thymic lymphocytes. RadLV-infected PL thymocytes express IL-4R and secrete IL-4. Their IL-4 secretion could be enhanced if incubated in the presence of RadLV and this enhancement was inhibited by anti-RadLV antibodies. Several RadLV-induced lymphoma lines secreted IL-4 and/or expressed IL-4R, but these features were not essential for their continuous growth. The results suggest that RadLV induces IL-4-dependent autocrine growth which maintains a population of PL T cells in the thymus. Transition from a PL state to overt thymic lymphoma involves emancipation of a PL cell from IL-4 dependency.

Animals↗
PubMed1992

Treatment of premalignancy: prevention of lymphoma in radiation leukemia virus-inoculated mice by cyclosporin A and immunotoxin.

Radiation leukemia virus (RadLV)-induced preleukemic (PL) latency is characterized by the appearance of virus-infected PL cells in the thymus. The survival of these PL cells is dependent upon autostimulation with interleukin 4 (IL-4). We have intervened prophylactically in RadLV-induced preleukemia by using cyclosporin-A (CSA), which inhibits IL-4 production, and an immunotoxin (ITx) that kills PL cells. CSA efficiently inhibited IL-4 secretion from RadLV-induced PL and leukemic cells, and its administration to PL mice caused a significant delay in their death. An ITx consisting of anti-RadLV glycoprotein-70 (gp70) antibody coupled to ricin A chain efficiently inhibited protein synthesis in virus-infected cells in vitro and, when injected into PL mice, also delayed their death. Combined treatment with CSA and ITx prevented 75% of the treated PL mice from developing lymphoma. These results show that the development of malignancy from a premalignant state can be averted by a combination of therapeutic modalities that decrease the size and growth rate of the premalignant cell population.

Animals↗
PubMed1992

Expression of the complement regulatory proteins CD21, CD55 and CD59 on Burkitt lymphoma lines: their role in sensitivity to human serum-mediated lysis.

On a panel of nine human B cell lines we showed that the expression of the complement regulatory factors complement receptor type 2 (CR2; CD21), decay-accelerating factor, (DAF; CD55) and homologous restriction factor (HRF20, CD59) is not correlated. All lines expressed DAF, six lines carried detectable amounts of CR2 and three carried HRF20. Upon incubation in human serum, under conditions which allowed the activation of complement through the alternative pathway, the CR2-carrying lines bound C3 fragments and two of them (Ramos and one of its two sublines) were damaged. These two lines had the lowest DAF expression, less than 50% of the cells reacted with the IA10 monoclonal antibody. By modulating the expression of the complement regulatory molecules, the lytic sensitivity of the B cell lines could be altered. Blockade of DAF on the HRF20-, CR2+ lines with the specific monoclonal antibodies increased their sensitivity to lysis by human serum. With the DAF- and HRF20+ cells significant lytic effect was obtained only when they were pretreated with both of the specific antibodies. Interferon-gamma or tumor necrosis factor-alpha treatment elevated the amount of CR2 on the low-CR2 expressor line (Ramos/HR1K) which thereafter bound higher amounts of C3 fragments and was lysed when incubated in human serum. This line had relatively low DAF level and lacked HRF20. The cytokine treatment did not alter the expression of these molecules. The CR2+ Ramos and the CR2- Rael cells were treated with 5-azacytidine which induced HRF20 and increased DAF expression. In parallel with this change Ramos cells became resistant to C-mediated lysis. The experiments with the panel of human B cell lines showed thus that cytolysis through activation of complement in homologous serum can be regulated at several steps by cell surface molecules. While expression of CR2 was required for C3 fixation, DAF and HRF20 inhibited lysis. By independent modulation of the quantities of these molecules, cells acquired or lost their sensitivity.

Antibodies, Monoclonal↗
PubMed1991

Radiation leukemia virus (RadLV)-induced leukemogenesis is associated with an increased number and activity of thymic macrophages.

The radiation leukemia virus (RadLV) is a chronic leukemia retrovirus that induces thymic lymphomas in C57BL/6 mice after a latency of 3 to 6 months. During the pre-leukemic (PL) period, the number of thymic macrophages gradually increased up to 100 fold. Of the cells in a RadLV-induced lymphoma, 0.3% were large macrophages packed with infected lymphoma cells. These thymic lymphoma macrophages (TLM) also ingested RadLV-induced lymphoma cells in vitro. Cultured RadLV-induced lymphoma lines could activate and fix C3 fragments through the alternative complement pathway (ACP). C3-bound lymphoma cells elicited an oxidative burst (OB) response in TLM but not in bone-marrow macrophages (BMM). However, IL4 treatment of BMM rendered them capable of responding with an OB following triggering by C3-opsonized cells. Thymic macrophages (TM) responded moderately with OB to C3-opsonized cells and this response was elevated if the TMs were treated by rIL4. The OB reaction of the TLMs could be partially inhibited by anti-LFA-I or anti-MALA-2 antibodies, and was completely inhibited by anti-CR3 antibodies. These results suggest that IL4 can prime macrophages for triggering an OB reaction and that the interaction between C3-opsonized cells and IL4-primed macrophages is mediated primarily through CR3.

Animals↗
PubMed1991

Quantitation, in vitro propagation, and characterization of preleukemic cells induced by radiation leukemia virus.

Intrathymic (i.t.) inoculation of radiation leukemia virus into C57BL/6 mice induces a population of preleukemic (PL) cells that can progress into mature thymic lymphomas upon transfer into syngeneic recipients. A minimum of 10(3) PL thymic cells are required to induce lymphomas in the recipient. Most of the individual lymphomas developed in mice which were inoculated with cells of a single PL thymus, derived from different T-cell precursors. PL thymic cells could be grown in vitro on a feeder layer consisting of splenic stromal cells. Growth medium was supplemented with supernatant harvested from an established radiation leukemia virus-induced lymphoma cell line (SR4). The in vitro-grown PL cells were characterized as Thy-1+, CD4+, CD8- T-cells, most of which expressed radiation leukemia virus antigens. Cultured PL cells were found to be nontumorigenic, based on their inability to form s.c. tumors. However, these cells could develop into thymic lymphomas if inoculated i.t. into syngeneic recipients. A culture of PL cells, maintained for 2 mo, showed clonal T-cell receptor arrangement. Lymphomas which developed in several recipient mice upon injection with these PL cells were found to possess the same T-cell receptor arrangement. These results indicate that PL cells can be adapted for in vitro growth while maintaining their preleukemic character.

Animals↗
PubMed1991

Production of heparanase by normal and neoplastic murine B-lymphocytes.

The production of heparanase, an endoglycosidase capable of degrading heparan sulfate from the subendothelial extracellular matrix (ECM), was investigated in various murine B-lymphoid tumors representing distinct maturation stages of the B-cell lineage. We found that heparanase is produced and released by 3 out of 4 pre-B lymphomas and by 4 B lymphomas examined. In contrast, 5 plasmacytomas and resting normal B lymphocytes, expressed little, if any, heparanase activity. Treatment with LPS resulted in high expression of the enzyme by normal B-lymphocytes, but there was no effect on the constitutive production of heparanase by myeloma or B-lymphoma cells. Our results indicate that heparanase is produced by B cells during discrete stages of their maturation. We suggest that heparanase may play a role in B-cell migration by enabling pre-B and B lymphocytes to leave the bone-marrow compartment and recirculate among peripheral lymphoid organs.

Animals↗
PubMed1991

The function of human NK cells is enhanced by beta-glucan, a ligand of CR3 (CD11b/CD18).

Cells responsible for the natural killer (NK) effect in the human blood can be collected in the low-density lymphocyte subset and the majority of them express CR3. In addition to the iC3b binding site the CR3 molecules possess an epitope which binds beta-glucan. Ligands of this site can deliver activation signals to CR3-carrying monocytes and neutrophils. We found that the function of NK cells was also potentiated by preincubation with beta-glucan. The treatment increased the proportion of target-binding lymphocytes and of the damaged target cells in the conjugates. The monoclonal antibody OKM-1, directed to the beta-glucan-binding site of CR3, abrogated this effect. Another CR3-reactive monoclonal antibody, M522, known to activate monocytes and neutrophils, enhanced the NK function.

Antibodies, Monoclonal↗