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Biomedical subjects

E Yefenof

Publications and source records attributed to E Yefenof.

At least 19 recordsLinked to original sources
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

Activation and fixation of C3 by human B cell lines is enhanced by interferon-gamma and tumor necrosis factor alpha.

Human B cell lines were tested for the capacity to convert C3 to C3b/iC3b through the alternative C pathway (ACP) and to fix the generated C3 fragments. The panel of lines included four Epstein-Barr virus (EBV)-negative Burkitt's lymphomas and their sublines converted with two EBV strains: the prototype B958 (B virus) and the nontransforming P3HR-1 (P virus). Comparison of these groups of parallel lines (derived from a single patient) showed that the EBV-carrying cells were more efficient in activation and fixation of C3. All cell lines activated C3 with higher efficiency when treated with interferon gamma or tumor necrosis factor alpha. After treatment, the comparative relationships between the sublines changed. The treated EBV-negative and the P virus converted sublines showed similar levels of ACP activation, while the B virus carrying sublines were more efficient. The amounts of bound C3 fragments on the activating cells correlated with the ACP efficiencies. In accordance with the elevated ACP activation capacity of the cells after cytokine treatment, the amounts of C3 fragments detected on their surfaces were higher. Among the lines tested, only two (BL28 and Ramos) were sensitive to C-mediated lysis. The lytic sensitivity of these two lines increased after treatment with the cytokines. The results indicate, therefore, that the cytokine-induced increase in ACP activation by Burkitt's lymphoma line is not sufficient to overcome resistance to C lysis.

B-Lymphocytes↗
PubMed1979

Moloney lymphoma cells express a polyprotein containing the GAG gene-coded p15 and the Moloney leukemia virus-induced cell surface antigen (MCSA).

The relationship between MCSA and the viral structural proteins in YAC Moloney lymphoma cells was further investigated by using membrane immunofluorescence and immunoadsorbent columns. As previously observed, MCSA showed only minimal capping and thereby differed in behaviour from gp70, p30 and p12 virion antigens. Whereas antibody-induced capping of gp70 did not change the membrane distribution of MCSA, co-capping was observed between MCSA and p30 and p12 gag protein antigens. This indicated that, whereas MCSA is distinct from gp70, it is linked to p30 and p12 on the membrane of living cells. It was then attempted to isolate MCSA on anti-p30 and anti-p15 immunoadsorbent columns from solubilized YAC cells. Contrary to what was expected, no MCSA was found to the anti-p30 column. On the other hand, a part (10-15%) of the MCSA was bound to the anti-p15 column, indicating that MCSA is linked to the gag p15.

Animals↗
PubMed1979

Detection of proteolytic (C 3-cleaving) activity on mouse mastocytoma (P 815) cells and other mouse cell lines by formation of cell contact with C 3-carrying mouse lymphocytes.

Mouse mastocytoma cells (P 815) formed rosettes with normal mouse spleen lymphocytes which had been coated with uncleaved human C 3; this interaction was clearly dependent on the amount of C 3. Lymphocytes treated with C 3 b or buffer alone were ineffective. Formation of cell contact could be inhibited by the presence of protease inhibitors such as diisopropyl fluorophosphate, phenyl methyl sulfonyl fluoride and tosyllysyl chloromethyl ketone. Seve n out of 13 different cell lines behaved like P 815 cells. The results strongly suggested that a proteolytic activity on mouse tumor cells led to a cooperation with uncleaved C 3 on a carrier cell to connect these two cells. We interpreted these data in analogy to the complement-dependent bridge formation mechanism (M. P. Dierich and B. Landen, J. Exp. Med. 1977. 146: 1484): uncleaved C 3, attached to mouse spleen lymphocytes as carriers, becomes cleaved by enzymes associated with the tumor cells tested; by this cleavage, the labile binding site is released on C 3 (nascent C 3 b) and anchors the C 3-carrying cell to the protease-carrying cell; since this labile binding site is short-lived, this process can be induced by membrane-associated proteases only. The nature of the proteases and the biological implications of this process are as yet uncertain.

Animals↗
PubMed1978

Relationship between Epstein-Barr virus (EBV)-production and the loss of the EBV receptor/complement receptor complex in a series of sublines derived from the same original Burkitt's lymphoma.

Virus production, EBV (P3HR-1 substrain) superinfectability, IdUrd inducibility, EBV receptor and complement (C3) receptor expression were assessed in two independently maintained jijoye lines, the derived P3HR-1 clone that releases a growth inhibitory and cytopathic, non-transforming viral mutant, and in non-producer sublines derived from the P3HR-1 line by the spontaneous cessation of virus production. Both jijoye lines were superinfectable, inducible, and carried EBV and C3 receptors. Virus-producing P3HR-1 cells and recently derived non-producer sublines lacked EBV-receptors and C3 receptors, could not be superinfected, but were IdUrd inducible. Two long-passaged, non-producer sublines of P3HR-1 reexpressed EBV and C3 receptors to an equal degree (different in the two sublines). EBV-superinfectability became partially reestablished in the subline with the higher expression of EBV and C3 receptors. These findings support the hypothesis that the EBV-receptor/C3 receptor negativity of the producer P3HR-1 sublines and their recent non-producer derivatives is due to negative selection by the growth-inhibitory, cytopathic P3HR-1 virus variant. The closely linked disappearance and reappearance of EBV-receptors and complement receptors gives further support to the idea that these two receptors are either identical or closely linked constituents of the cell membrane.

Antigens, Viral↗
PubMed1978

Shedding of anti-IgM from antibody-coated human lymphoma lines: differences between Epstein-Barr virus-negative lines and their virus-converted sublines.

In vitro converted, Epstein-Barr (EBV) genome-carrying cell lines showed a reduced ability to shed surface-bound antibodies, compared to their EBV-free parental B lymphoma lines. On the other hand, antibody degradation was higher with EBV-positive cells. Analysis of antibody-coated single cells revealed that cells which failed to redistribute or cap their ligand-bound surface components at 37 degrees C, were also capable of shedding bound antibody. This suggests that capping and shedding are essentially independent phenomena, although both may be influenced by the same virally induced change in the lateral mobility of membrane constituents.

Antibodies, Anti-Idiotypic↗
PubMed1978

Inhibition of DNA metabolism in human B lymphocytes by a substrain of Epstein-Barr virus (P3HR-1): a method for virus quantitation.

Pretreatment with the P3HR-1 substrain of Epstein-Barr virus (EBV) inhibited approximately 85% of the DNA stimulation induced by Staphylococcus aureus in human B lymphocytes. In parallel experiments, the DNA stimulation induced by the transforming B95-8 substrain of EBV was almost completely inhibited by prior exposure to P3HR-1 virus. Phytohemagglutinin stimulation was only slightly inhibited, whereas the DNA synthesis of continuously growing Raji cells was inhibited to a considerable extent. The degree of DNA inhibition was correlated with the induction of the EBV-determined antigens (membrane, early, and nuclear antigens) in sensitive indicator cells.

B-Lymphocytes↗
PubMed1978

Human blood lymphocyte fractionation with special attention to their cytotoxic potential.

In studies concerning the natural cytotoxic activity of human blood lymphocytes we have found that: 1. T cell, which rosette with sheep erythrocytes can be separated by centrifuging on Ficoll the lymphocyte and erythrocyte mixture without previously pelleting and incubating in the cold. 2. Lysis of marker erythrocytes with ammonium chloride impairs the cytotoxic activity of lymphocytes. Incubation at 37 degrees C for 12 hr prior to the test restores the activity to some extent. 3. A high proportion of the so call "null" fraction i.e. cells remaining in the interface after removal of B cells (passage on nylon column) and sedimentation of E rosettes, sediments as rosettes with sheep EAC'indicating that these cells carry low density E and C3 receptors. Rosetting with SRBC or ox EAC' gave significantly lowr values. On a per cell basis the "null" fraction was the most efficient one in natural cytotoxicity. Depletion of cells with low affinity E or E and C3 receptors left highly active subfractions.

Ammonium Chloride↗
PubMed1977

Immunization of mice with syngeneic Moloney lymphoma cells induces separate antibodies against virion envelope glycoprotein and virus-induced cell surface antigens.

Immunization of mice with heavily irradiated syngeneic Moloney lymphoma cells evokes antibodies against the major viral envelope antigen, gp71, and the Moloney virus-induced cell surface antigen (MCSA). A9HT cells, an L-cell subline, react with the antibodies against the viral envelope antigen only; this reaction can be completely inhibited by virus or purified gp71. Reactivity to Moloney lymphoma cells (YAC) was only partially inhibited (maximum 30%) or not at all. This can be attributed to the reaction of the YAC cells with antibodies directed against MCSA, a nonvirion cell surface component according to both biological and biochemical evidence. Antibody-induced capping of gp71 or p15(E) did not change the membrane distribution of MCSA or H-2, indicating that these antigens represent distinct entities on the cell surface. MCSA showed only minimal capping and thereby differed in behavior from both H-2 and virion antigens. gp71 could be capped by the mouse antiserum as revealed by subsequent staining with monospecific anti-gp71 antiserum. Under ordinary test conditions this reactivity is overshadowed by the reaction against MCSA. The lack of MCSA capping reflects a difference in anchorage of this antigen.

Antibodies, Viral↗