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J L Ambrus

Publications and source records attributed to J L Ambrus.

At least 109 records · Page 6Linked to original sources
PubMed1987

B-cell growth factor receptor expression and B-cell growth factor response of leukemic B cell precursors and B lineage lymphoid progenitor cells.

The purpose of this study was to analyze the expression of B cell growth factor (BCGF) receptors and to elucidate the biologic effects of biochemically purified natural BCGF at the B cell precursor stage of human B lineage lymphoid differentiation. The specific binding of radioiodinated high-mol-wt BCGF (125I-HMW-BCGF) and low-molecular-wt BCGF (125I-LMW-BCGF) to fresh marrow blasts from B cell precursor acute lymphoblastic leukemia (ALL) patients was initially investigated. The estimated number of radioiodinated BCGF molecules bound per blast ranged from undetectable to 24.3 X 10(3) for HMW-BCGF, and from 11.5 X 10(3) to 457.8 X 10(3) for LMW-BCGF. In 3H-TdR incorporation assays, 75% of cases showed a significant response to LMW-BCGF with a median stimulation index of 9.3. By comparison, only 33% of cases showed a significant response to HMW-BCGF with a median stimulation index of 2.4. Subsequently, B cell precursor colony assays were performed to assess and compare the biologic effects of BCGF on leukemic B lineage lymphoid progenitor cells. Among 28 cases studied, 57% responded to both HMW-BCGF and LMW-BCGF, 21% responded only to LMW-BCGF, and the remaining cases showed no proliferative response to either growth factor. The response patterns of virtually pure populations of FACS-sorted leukemic B cell precursors were essentially identical to the proliferative responses of unsorted leukemic B-cell precursors. Synergistic effects between HMW-BCGF and LMW-BCGF were observed in 80% of the cases that responded to both. The numbers of cell-bound radioiodinated BCGF molecules, the stimulation indices, as well as the number of B cell precursor colonies in BCGF-stimulated cultures showed a marked interpatient variation. Patients with structural chromosomal abnormalities (SCAs) involving 12p11-13 or patients with a Philadelphia chromosome showed a greater HMW-BCGF response at the level of leukemic progenitor cells than did other patients (P = .02). The LMW-BCGF response was significantly greater for patients with SCA than for patients without SCA (P = .04). The response of leukemic progenitor cells to HMW-BCGF or LMW-BCGF did not correlate with sex, age, disease status, FAB morphology, WBC at diagnosis, or immunophenotype. To our knowledge, this study represents the first detailed analyses of BCGF receptor expression and BCGF effects in B cell precursor ALL. The data presented provide direct evidence for the expression of functional receptors for both HMW-BCGF and LMW-BCGF in B cell precursor ALL.

Acute Disease↗
PubMed1987

Mechanism of the potentiation of thrombolysis by pentoxifylline (Trental).

Streptokinase induced thrombolysis of radioactive labeled human fibrin clots was potentiated by simultaneous treatment with pentoxifylline (Trental). This appears to be due in part to the prevention of platelet aggregation on the clot. In addition, release of t-PA and PgI2 from the endothelium and increases in red cell deformability may also play a role.

Animals↗
PubMed1986

Effect of interferon-alpha on immunoglobulin synthesis by human B cells.

We have investigated the effect of human recombinant interferon-alpha (IFN-alpha) on mitogen-induced immunoglobulin (Ig) production by peripheral blood mononuclear cells from normal individuals. Low concentrations (1 to 100 IU/ml) of IFN-alpha enhanced pokeweed mitogen-stimulated Ig production. In contrast, high concentrations of IFN-alpha (10(5) IU/ml) suppressed pokeweed mitogen-induced Ig production. Irradiation of T cells did not ablate the high dose suppression, indicating that suppression was not due to a radiation-sensitive T cell. Kinetic experiments revealed that IFN-alpha needed to be added to 10 day cultures within the first 72 hr for either enhancement or suppression to be noted. Preincubation of purified B cells with IFN-alpha suppressed Ig production as completely as when unfractionated mononuclear cells were incubated with IFN-alpha. On the other hand, preincubation of T cells or monocytes with IFN-alpha had no effect on subsequent Ig production in reconstituted mononuclear cell cultures. Mitogen-induced proliferation of purified B cells was not affected by IFN-alpha at any concentration, but Ig production by purified B cells stimulated with Staphylococcus aureus Cowan I or anti-mu and B cell differentiation factors responded to IFN-alpha with low concentration enhancement and high concentration suppression. Studies of Ebstein-Barr virus-transformed B cell lines showed that IFN-alpha caused a similar effect on the CESS line as on peripheral blood B cells, with low dose enhancement and high dose suppression of Ig production. Thus one IFN-alpha effect is to modulate Ig production, and this appears to be a direct effect on B cells. Combined with the data in the accompanying paper, the effects of IFN-alpha on B cell function are similar in vivo and in vitro.

Antibody Formation↗
PubMed1986

Production of B cell growth factor by normal human B cells.

Although it has been demonstrated that malignant human B cell lines are capable of producing B cell growth factor (BCGF), production of BCGF by normal B cells has not been shown. In this study, we demonstrate BCGF production by normal B cells, achieved by using human peripheral blood B cells prepared by a positive selection technique and stimulated with Staphylococcus aureus Cowan I (SAC) for 12 hr. SAC was removed from the supernatants by anti-SAC-coupled Sepharose. Supernatants absorbed with this antibody were functionally free of SAC, as demonstrated by their inability to activate resting B cells. B cells stimulated with SAC for 12 hr produced BCGF activity that was generally unmeasurable in supernatants by 36 hr. Characterization of BCGF produced by SAC-stimulated B cells revealed a m.w. of 32,000 by high-performance liquid chromatography sieving and sodium dodecyl sulfate-polyacrylamide gel electrophoresis; this BCGF was found to have an isoelectric point of 6.7. Furthermore, this BCGF lacked interleukin 1, interleukin 2, interferon, and B cell differentiation factor activity. This observation that BCGF can be produced by normal human B cells is significant because it demonstrates for the first time that normal B cells have the ability to provide their own growth factors or the growth factors for other B cells.

B-Lymphocytes↗
PubMed1986

Identification and characterization of a B cell activation factor (BCAF) produced by a human T cell line.

A human T cell line, Peer, that expresses the T cell helper phenotype produces discrete activation and growth factors for tonsillar B cells. The B cell activation factor produced by Peer is biochemically and physiologically distinct from other lymphokines known to enhance B cell proliferation, namely, interleukin 1, interleukin 2, interferon, and previously characterized B cell growth factors (BCGF). The BCGF produced by Peer is functionally similar to previously described BCGF but has a m.w. of approximately 30,000 daltons. The identification and characterization of a T cell-derived activation factor that can induce apparently resting (Go phase) B cells to enter S phase in the absence of an exogenous first signal has important implications in the additional dissection of the complex steps in the human B cell cycle.

B-Lymphocytes↗
PubMed1986

Interferon inactivator(s) in patients with AIDS and AIDS-unrelated Kaposi's sarcoma.

Interferon inhibitory activity was found in the plasma of 11 of 14 patients with the acquired immune deficiency syndrome (AIDS). This was not seen in 75 normal persons, including six whose specimens were randomly and blindly interspersed among the patient samples. Plasma from a single patient with the AIDS prodrome (AIDS-related complex), who later demonstrated AIDS, did not contain interferon inhibitors but did contain high levels of interferon. Three patients with AIDS-unrelated Kaposi's sarcoma had neither significant levels of interferon nor interferon inhibitory activity. The existence of interferon inhibitory activity in the plasma has to be taken into account when interferon preparations are administered therapeutically.

AIDS-Related Complex↗
PubMed1986

Human T4+ lymphocytes produce a phagocytosis-inducing factor (PIF) distinct from interferon-alpha and interferon-gamma.

Unstimulated peripheral blood mononuclear cells from patients with angiocentric T cell immunoproliferative disorders and concanavalin A-stimulated normal peripheral blood mononuclear cells secrete a phagocytosis-inducing factor (PIF) that induces a fivefold to 50-fold enhancement of phagocytosis of IgG-coated ox red blood cells by U937 cells. We investigated the identity, production, and mechanism of the action of PIF. PIF activity was demonstrated in supernatants from nine of 44 phytohemagglutinin-stimulated interleukin 2 (IL 2)-dependent T cell lines and clones derived from purified T4+ cells, but was not found in supernatants from 26 lines and clones derived from phytohemagglutinin-stimulated T8+ cells. In addition, PIF was produced by four of four antigen-specific T cell lines and clones after stimulation with the appropriate antigen and antigen-presenting cells, and by HUT-102, a human T cell lymphotropic virus type I-transformed T cell line. PIF from all of these sources caused significant inhibition of U937 proliferation. This proliferation-inhibiting activity co-purified with phagocytosis-enhancing activity in sizing procedures and isoelectric focusing, which yielded an estimated m.w. of 35,000 to 55,000 and an estimated isoelectric point of 5.0 to 6.0 for PIF. In contrast, IL 2, recombinant interferon-alpha, and recombinant interferon-gamma had no effect on phagocytosis by U937 cells, and antibodies to interferon-alpha and interferon-gamma did not block the phagocytosis-inducing activity of PIF-containing supernatants. PIF appears to be a distinct lymphokine produced by a subset of T4+ lymphocytes, possibly those that proliferate in response to antigen. PIF may be important in the induction of erythrophagocytosis, which is associated with certain T cell immunoproliferative disorders.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1986

Regulation of in vitro human leukocyte interferon production: effect of prostaglandin synthetase and phosphodiesterase inhibition.

A great variability exists in the in vitro capability of peripheral blood leukocytes (PBL) of apparently healthy adults to produce IFN-alpha. In this report, we have studied the effects of prostaglandins, indomethacin and pentoxifylline upon IFN-alpha production by the PBL of normal healthy donors. The donors were divided into two groups: "normal producers" - donors that consistently produced greater than 2,000 ref. units IFN-alpha per 10(7) PBL and "low producers" - donors that consistently produced less than 2,000 ref. units IFN-alpha per 10(7) PBL. Addition of exogenous PGE1 or PGE2 into interferon production media significantly inhibited IFN-alpha yield by the PBL of both normal and low producers. The inhibition was dose dependent. A significant rise in the IFN-alpha yield was seen when PBL of "low producers" were exposed individually to either pentoxifylline or indomethacin. However, no increase in titer of IFN-alpha was seen when PBL of "normal producers" were exposed to either of these two agents during interferon production periods. With regard to PBL of "low producers", the enhancement of IFN-alpha yield was further potentiated when both indomethacin and pentoxifylline were utilized concurrently at their optimal concentrations. These results suggest that enhancement of IFN-alpha production by PBL of apparently healthy adults who are low producers may be possible and may have preventive value.

Alprostadil↗
PubMed1986

Human peripheral blood mononuclear cells (PBM) cultured in serum-free medium. III. Morphological study of an in vitro microcytotoxicity model.

An in vitro tumor immunity model is suggested. Interactions between lymphocytes and macrophages in serum-free medium are being studied as well as the effect induced upon these interactions by the addition of heterologous and homologous tumor cells. In our model, the tumor cells seem to be approached by the lymphocytes before any contact with the macrophages and then presented to the latter. The macrophages may then acquire an "activated" structure and display cytotoxic properties. A pattern of in vitro cellular immunity is obtained. This description may serve as a model for further study and understanding of the process of tumor immunity. It is suggested that in contrast to generally accepted models of cellular immunology, lymphocytes can interact directly with antigen complexes and present them to macrophages. The latter would in turn be activated, become cytotoxic and produce or accumulate immune globulins. These cells seem to be an in vitro analog of the recently described tumor infiltrating lymphocytes (TIL) which reside in vivo within spontaneous tumors.

Cell Communication↗
PubMed1985

Purification to homogeneity of a high molecular weight human B cell growth factor; demonstration of specific binding to activated B cells; and development of a monoclonal antibody to the factor.

High molecular weight B cell growth factor (HMW-BCGF) produced by a T cell line was purified to homogeneity and demonstrated to bind specifically to activated human B cells. A monoclonal antibody to HMW-BCGF was developed that (a) specifically inhibited the activity of HMW-BCGF in enhancing B cell proliferation, (b) specifically bound to HMW-BCGF in Western blots, (c) specifically absorbed HMW-BCGF activity from culture supernatants, and (d) specifically absorbed an internally labeled protein from T-ALL supernatant which comigrates with HMW-BCGF on sodium dodecyl sulfate-polyacrylamide gels. This antibody should help in cloning the gene for HMW-BCGF and further exploring the physiologic roles of HMW-BCGF.

Animals↗
PubMed1985

Human T cell leukemia/lymphoma virus I infection and subsequent cloning of normal human B cells. Direct responsiveness of cloned cells to recombinant interleukin 2 by differentiation in the absence of enhanced proliferation.

A human T cell leukemia/lymphoma virus (HTLV)-I-infected B cell clone expressed Tac antigen on its cell surface and responded to recombinant interleukin 2 (IL-2) by increased production of IgM without any increase in proliferation. Anti-Tac antibody completely inhibited the IL-2-induced differentiation of this HTLV-I-infected B cell clone. This study demonstrates that HTLV-I can directly infect normal mature human B cells, and that the Tac antigen, which may be induced by infection with HTLV-I, is the functional receptor for IL-2-induced B cell differentiation. The availability of such cell lines and clones should provide useful tools to delineate precisely the differentiation step in the human B cell cycle.

Antigens, Surface↗
PubMed1985

Synthesis and properties of bis(2,2-dimethylaziridinyl)phosphinic amides: a series of new antineoplastic agents.

In continuation of efforts to improve the antitumor selectivity of the 2,2-dimethylaziridine class of alkylating agents, a series of N-substituted bis(2,2-dimethyl-1-aziridinyl)phosphinic amides has been synthesized and evaluated. All of these compounds (3-15) were tested in vivo against leukemia P-388 in mice, where most of them caused significant increase of survival time at nontoxic dose levels. Some of the most active compounds were also tested against leukemia L1210, B16 melanoma, and colon 26 carcinoma; in the latter tests, the parent unsubstituted amide 3 appeared to show the highest antitumor activity. Since the dose-limiting toxicity of the clinically tested prototypes of this class of anticancer agents AB-132 (1) and AB-163 (2) had been found to be CNS toxicity attributable mainly to the inhibition of cholinesterase, the compounds were tested in vitro against the cholinesterases from horse serum, electric eel, and bovine erythrocytes, as well as in vivo for the inhibition of the cholinesterase present in the whole blood of mice. In all of these assays, the various members of the present series showed a wide range of anticholinesterase activities, ranging from almost zero (for 3) to even higher potency than that of the prototype 2. A similarly wide range of stability was observed toward hydrolytic ring opening of the 2,2-dimethylaziridine moieties. Several of the compounds, particularly 3, deserve further study.

Animals↗
PubMed1985

Human B lymphoma cell line producing B cell growth factor.

Namalva, a human B cell lymphoma line, produced a factor with a molecular weight of approximately 60,000 which enhanced the proliferation of normal activated human B lymphocytes. The factor also enhanced the proliferation of certain B cell lines. It can be distinguished physiologically and biochemically from other lymphokines known to enhance B cell proliferation, namely, interleukin (IL) 1, IL 2, and interferon. The production of B cell growth factor by B cell tumor lines may contribute to their ability to grow autonomously and may reflect an important component of the neoplastic potential of the cell. B cell growth factor produced by tumors may also affect normal cells in vivo.

B-Lymphocytes↗
PubMed1985

Human peripheral blood mononuclear cells (PBM's) cultured in serum free medium (II): Lymphocyte-macrophage interaction and related morphological changes.

Morphological descriptions of the attachments between lymphocytes and macrophages are made in serum free cultures. Dynamic morphological processes related to these attachments are explored in live cells using an inverted microscope and the phase technique. The May Grunwald-Giemsa stain and scanning and transmission electron microscopy are also described for the same population of cells. Immunoglobulins were detected in the cells by the immunoflourescence technique. Following lymphocyte-macrophage attachments, the macrophages shrink and round up and subsequently, their cytoplasm becomes laden with immunoglobulin. The membrance surface of interacting macrophages gradually changes from the ruffled appearance characteristic of a monocyte to a blebbed structure. The blebs seem to be related to an exocytotic process, which is most probably immunoglobulin secretion.

Cell Communication↗
PubMed1985

Characterization of a T4+/Leu-8+ T cell clone that directly helps B cell Ig production by secreting B cell differentiation factor.

A human T4+/Leu-8+ T cell clone (YA2) was established by phytohemagglutinin activation and interleukin 2 (IL 2) propagation. Functional characterization of this clone demonstrated that it provided potent help towards Ig production by pokeweed mitogen-stimulated B cells in the presence of small numbers of autologous T cells or by Staphylococcus aureus Cowan I (SAC)-activated B cells in the presence of B cell growth factor (BCGF). YA2 provided no help to resting B cells and minimal help to either unactivated B cells cultured with BCGF or SAC-activated B cells. Supernatant generated from clone YA2 by IL 2 stimulation had significant B cell differentiation activity but no BCGF or IL 2 activity. Thus, YA2 is a T4+/Leu-8+ potent direct helper only to B cells that are activated and proliferating due to its selective secretion of a differentiation factor, and not an activation and growth factor. The availability of phenotypically defined cloned populations of T cells with restricted functional helper activity related to the secretion of selected B cell tropic factors should prove useful in the dissection of the role of individual T cell subsets in the regulation of the human B cell cycle.

Antigens, Differentiation, T-Lymphocyte↗