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Biomedical subjects

L A Falk

Publications and source records attributed to L A Falk.

At least 37 records · Page 2Linked to original sources
PubMed1990

Synergy between transforming growth factor-beta and tumor necrosis factor-alpha in the induction of monocytic differentiation of human leukemic cell lines.

We examined the effect of transforming growth factor-beta (TGF-beta) alone and in combinations with other factors on the growth and differentiation of the human promyelocytic cell line HL60 and the human monoblastic cell line U937. Treatment with TGF-beta alone did not significantly affect growth or differentiation of HL60 cells, while it significantly inhibited proliferation and induced monocytic differentiation of a small percentage of U937 cells. Combinations of TGF-beta and tumor necrosis factor-alpha (TNF-alpha) acted in synergy to inhibit cell proliferation and to induce monocytic differentiation of both HL60 and U937 cells. In contrast, no synergy was observed when HL60 cells were treated with TGF-beta in various combinations with interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma), and retinoic acid. Examination of TNF-alpha receptor expression on HL60 and U937 cells showed that these cell lines expressed comparable levels of high-affinity TNF-alpha binding sites. Treatment of HL60 and U937 cells with TGF-beta did not induce significant changes in TNF-alpha receptor expression in either cell line. In contrast, HL60 cells expressed much lower levels of TGF-beta receptors than did U937 cells. Treatment of both HL60 and U937 cells with TNF-alpha induced a dose-dependent increase in expression of TGF-beta receptors, suggesting that the synergy between TNF-alpha and TGF-beta may result, at least in part, from upregulation of TGF-beta receptor expression by TNF-alpha.

Cell Differentiation↗
PubMed1990

Differential production of IFN-alpha/beta by CSF-1- and GM-CSF-derived macrophages.

Mature macrophages, derived in vitro from bone marrow progenitors under the influence of either macrophage colony stimulating factor (CSF-1) or granulocyte-macrophage (GM)-CSF, have been shown to differ morphologically and functionally. The data presented in this report demonstrate that macrophages derived from bone marrow progenitors under the influence of CSF-1 are highly resistant to infection with vesicular stomatitis virus (VSV), and that this refractoriness can be reversed by treatment of cells with anti-IFN-alpha/beta antibody. In contrast, macrophages derived from bone marrow progenitors under the influence of GM-CSF are highly susceptible to the cytopathic effects of VSV, but can be protected by very low concentrations of exogenous IFN-alpha/beta. These findings suggest that CSF-1 derived macrophages have a greater capacity for the production and/or utilization of IFN-alpha/beta than GM-CSF-derived macrophages, which may account for many of the differentiative differences reported previously.

Animals↗
PubMed1988

Analysis of Ia antigen expression in macrophages derived from bone marrow cells cultured in granulocyte-macrophage colony-stimulating factor or macrophage colony-stimulating factor.

Bone marrow cells from C3H/HeJ mice were cultured in recombinant granulocyte-macrophage-CSF (rGM-CSF) or recombinant or purified (natural) preparations of macrophage-CSF (CSF-1) for 7 days, the adherent macrophages removed enzymatically, recultured in the absence of growth factor, and examined for their differentiative and functional characteristics. Expression of Ia Ag differed markedly in these two populations. Antibody plus complement-mediated cytotoxicity indicated that the percent of Ia-positive macrophages was low (approximately 15 to 20%) in both populations. Treatment of cultures with rIFN-gamma increased the percentage of Ia-positive cells in both populations; however, more CSF-1-derived macrophages were induced to become Ia positive than rGM-CSF-derived macrophages. In contrast, total Ia expression and Ia density per cell, as measured by ELISA and quantitative immunofluorescence, respectively, showed that medium-treated rGM-CSF-derived macrophages exhibited greater total Ia expression and higher Ia density per cell than CSF-1-derived macrophages. Treatment of CSF-1-derived macrophages with rIFN-gamma increased total Ia expression per culture to the levels exhibited by rGM-CSF-derived cells, although the density of Ia Ag per cell remained lower than in rGM-CSF-derived cells (medium or rIFN-gamma-treated). Northern blot and slot blot analysis of cytoplasmic RNA extracted from freshly harvested rGM-CSF- or CSF-1-derived cells indicated that the differences seen in basal Ia expression were also reflected at the level of steady-state, Ia-specific mRNA. The functional capacity of these two macrophage populations to stimulate Ag-specific T cell proliferation was also assessed. rGM-CSF- or CSF-1-derived macrophages were first cultured in the absence or presence of rIFN-gamma, Ag-pulsed, and irradiated before co-culture with Ag-primed, purified T cells. Ag-induced T cell proliferation was significantly greater in rGM-CSF- than in CSF-1-derived macrophages. Treatment of either population with rIFN-gamma had only a minimal effect on the ability of either macrophage population to stimulate Ag-specific T cell proliferation. These findings suggest that the development of mature macrophages from bone marrow progenitors under the influence of either GM-CSF or CSF-1 may, in part, underlie the functional heterogeneity of different macrophage populations.

Animals↗
PubMed1988

Comparison of bone marrow progenitors responsive to granulocyte-macrophage colony stimulating factor and macrophage colony stimulating factor-1.

The responsiveness of bone marrow progenitors (BMP) from C3H mice to highly purified or recombinant preparations of Macrophage Colony-Stimulating Factor-1 (CSF-1) and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) was compared by counting the number of colonies (greater than or equal to 50 cells) after 10 days in culture with CSF. Cells responsive to CSF-1 or GM-CSF exhibited maximum colony formation over a wide dose range, although GM-CSF supported colony formation at lower concentrations. The response of BMP to optimal concentrations of CSF-1 was greater than or equal to 5 times greater than the response of BMP to GM-CSF. Analysis of the kinetics of colony formation revealed that, at day 5, the number of BMP responsive to GM-CSF or CSF-1 was approximately equal; the number of CSF-1 colonies increased significantly through day 10, while those cultured in GM-CSF did not. The response of BMP to CSF-1 and GM-CSF was also studied in liquid culture; the differences in yield of mature macrophages was consistent with the differences observed in agar culture. Although both cell populations were shown to be 100% mononuclear by day 7, Coulter Channelyzer analysis of these mature macrophages showed marked differences in cell size distribution. By day 7, cells grown in CSF-1 resulted in a homogeneous population of large cells, whereas GM-CSF cultures showed a heterogeneous distribution. Finally, CSF-1-derived cells possessed increased nonspecific and specific phagocytic capabilities when compared to GM-CSF-derived macrophages. These findings indicate that the actions of GM-CSF and CSF-1 upon the bone marrow compartment results in the generation of mature macrophages which differ morphologically and functionally and may account for the heterogeneity in macrophage populations.

Animals↗
PubMed1988

Bone marrow progenitors cultured in the presence of granulocyte-macrophage colony-stimulating factor versus macrophage colony-stimulating factor differentiate into macrophages with distinct tumoricidal capacities.

Bone marrow-derived cells from C3H/HeJ mice were cultured in the presence of recombinant murine granulocyte-macrophage colony-stimulating factor (rGM-CSF) or highly purified murine macrophage colony-stimulating factor (CSF-1) for 7 days. Following this 7-day culture period, mature macrophages were harvested and replated at precise densities in the absence of exogenous rGM-CSF or CSF-1, and assayed in a two-signal tumoricidal assay. Cultures were stimulated with medium only or with combinations of recombinant interferon-gamma (rIFN-gamma) as the "priming" signal, and/or butanol-extracted lipopolysaccharide (But-LPS) as the "triggering" signal for 24 hr. At this time, 51Cr-labeled, P815 tumor target cells were added, and the percent tumor cell cytotoxicity was determined after 16 hr. Macrophages derived under the influence of rGM-CSF exhibited significant tumoricidal capacity with medium alone (16 +/- 5%). The addition of "priming" signal only (i.e., rIFN-gamma, 10.0 U/ml) significantly increased tumoricidal capacity to 31 +/- 9%. Treatment with But-LPS alone did not alter the basal tumoricidal activity of rGM-CSF-derived macrophages. Combinations of rIFN-gamma (10.0 U/ml) and But-LPS (0.5-5.0 micrograms/ml) generated highly tumoricidal macrophages (50-60% tumor cell cytotoxicity). In contrast, medium-treated CSF-1-derived macrophages exhibited a significantly lower basal level of tumor cytotoxicity (6 +/- 3%). Unlike rGM-CSF-derived macrophages, treatment of CSF-1-derived macrophages with high concentrations of rIFN-gamma alone did not increase significantly the level of cytotoxicity above that of medium-treated cultures. However, CSF-1-derived macrophages responded to the highest concentrations of But-LPS (5.0 micrograms/ml) to increase tumoricidal activity from 6 +/- 3% to 17 +/- 5%. Optimal tumoricidal activity (44 +/- 17%) was observed when CSF-1-derived macrophages were treated simultaneously with high concentrations of both rIFN-gamma and But-LPS. Thus, macrophages derived from bone marrow progenitors in either rGM-CSF or CSF-1 exhibited tumoricidal capacities that differed in basal activity as well as in their requirements for and sensitivities to "priming" and "triggering" signals.

Animals↗
PubMed1988

Granulocyte-macrophage colony stimulating factor (GM-CSF) and macrophage colony stimulating factor (CSF-1) synergize to stimulate progenitor cells with high proliferative potential.

The ability to expand a population of bone marrow progenitors capable of forming macrophage colonies of high proliferative potential (HPP-CFC) was achieved using a culture system and signal requirements not previously shown to support the growth of HPP-CFC. Using bone marrow cells from untreated animals (not 5-FU-treated), culture conditions designed primarily for the detection of GM-CFC or M-CFC progenitors, and a more stringent criteria for HPP-CFC colony size (greater than or equal to 2 mm diameter), HPP-CFC progenitor expansion was demonstrated following simultaneous addition of rGM-CSF and CSF-1 to bone marrow cultures. Examination of the sequence and temporal requirements for rGM-CSF and CSF-1 addition necessary for the development of HPP-CFC-like colonies revealed that addition of the second factor could be delayed for up to 5 days and still result in the development of significant numbers of HPP-CFC colonies. Based on a comparison with human spleen cell conditioned medium (HSCM) and interleukin 1 (rIL 1), as sources of "synergistic activity" (SA) for the development of HPP-CFC-like colonies in combination with CSF-1, the combination of GM-CSF and CSF-1 appears to represent a novel pathway for stimulating the expansion of HPP-CFC progenitors with high proliferative potential.

Animals↗
PubMed1988

Human immunodeficiency virus (HIV) antigenemia (p24) in the acquired immunodeficiency syndrome (AIDS) and the effect of treatment with zidovudine (AZT).

Infection with human immunodeficiency virus (HIV) may cause viral antigenemia, detected primarily as p24 viral core protein. Among 16 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex studied serially, 12 had or developed antigenemia ranging from 16 to 3006 pg/mL in plasma. The level could be categorized as high (greater than 100 pg/mL) or low (15 to 65 pg/mL). Three patients with anti-p24 antibody had no antigenemia. Zidovudine (AZT), 200 or 250 mg every 4 hours, reduced antigenemia by about 90%; other regimens were less effective. Leukocyte cultures were positive for HIV from patients with antigenemia, and in one third of samples in the absence of antigenemia. High levels of antigenemia correlated with symptoms, CD4 cell count, and prognosis. Drug toxicity requiring a lower dose was followed by increased antigenemia, recurrent symptoms, and decreased CD4 cells, suggesting lymphocyte toxicity. Monitoring antigenemia can be useful in evaluating patients with HIV infection and in evaluating the effect of antiviral chemotherapy.

AIDS-Related Complex↗
PubMed1987

Diagnosis of human immunodeficiency virus infection in seronegative homosexuals presenting with an acute viral syndrome.

Early diagnosis of acute human immunodeficiency virus (HIV) infection is difficult because patients may be seronegative for HIV at the time of presentation. We have used a serum HIV antigen (HIV-Ag) enzyme immunoassay (EIA) to diagnose acute HIV infection in four high-risk patients. The clinical syndrome in these four patients was characterized by fever (four), rash (three), myalgias-arthralgias (three), and pharyngitis (two). All patients had spontaneous resolution of their symptoms within eight to 12 days. Serum HIV antibody, as measured by a commercially available screening EIA and by Western blot analysis, was negative in all patients at time of presentation and all seroconverted on subsequent testing. Human immunodeficiency virus was isolated from two of two patients during the acute illness. Initial serum samples from all four patients were positive for HIV-Ag. Serum samples of three of four patients became negative for HIV-Ag and positive for HIV antibody. These data suggest that serum HIV-Ag detection by EIA may be useful in the diagnosis of the acute syndrome caused by HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Correlation of serum HIV antigen and antibody with clinical status in HIV-infected patients.

An enzyme immunoassay (EIA) has been developed which detects antigen(s) (Ag) of the human immunodeficiency virus (HIV) in the serum of patients with the acquired immunodeficiency syndrome (AIDS), AIDS-related complex (ARC), and patients at high risk for HIV infection. The test has a sensitivity of approximately 50 pg/ml of HIV protein. The specificity of the assay was determined with various virus infected cell lines, normal human sera/plasma, and serum from patients not known to be at risk for HIV infection. No false-positive HIV-Ag results were seen. Sera from 69% of patients with AIDS were positive for HIV-Ag as were 46% of patients with ARC and 19% of asymptomatic, HIV-antibody-positive individuals. There were significant associations between the stage of HIV infection--ie, AIDS vs ARC vs asymptomatic--and the detection of HIV-Ag in serum (p less than 0.0001) and the lack of detection of antibody to HIV core Ag (p less than 0.0001). HIV-Ag was also found in the serum of two asymptomatic antibody-negative individuals who were at high risk for AIDS and who later developed HIV antibody. The presence of HIV-Ag in sera was confirmed by an inhibition procedure. Thus, HIV-Ag can be detected in the serum of infected individuals prior to antibody production and correlates with the clinical stage of HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Correlation of enzyme-linked immunosorbent assays for serum human immunodeficiency virus antigen and antibodies to recombinant viral proteins with subsequent clinical outcomes in a cohort of asymptomatic homosexual men.

A cohort of asymptomatic homosexual men at a Boston community health center was screened for the presence of human immunodeficiency virus (HIV) serum antigen and antibodies to recombinant proteins containing portions of the envelope and the gag (core) gene products. Of 196 asymptomatic men screened, 149 were antigen-negative/antibody-negative, 41 were antigen-negative/antibody-positive, and six were antigen-positive/antibody-positive. All three men in whom the acquired immune deficiency syndrome (AIDS) developed over the next year were antigen-positive at enrollment. Although a larger portion of the men who were antigen-positive and did not demonstrate progression to AIDS after one year had thrush, zoster, or generalized lymphadenopathy, the associations were not statistically significant. Whereas all of the seropositive men had antibody to viral envelope antigens, about a quarter did not have detectable antibodies to recombinant core antigens. However, all of these men had detectable antibody to core antigens by Western blot. Titers to recombinant core and envelope antigens tended to be lower in the men with AIDS. HIV-infected persons who are more likely to have enhanced immuno-compromise may be identified by these newer tests, but further longitudinal studies will be necessary to fully understand their prognostic value.

AIDS-Related Complex↗
PubMed1985

A region of the Herpesvirus saimiri genome required for oncogenicity.

Herpesvirus saimiri naturally infects squirrel monkeys (Saimiri sciureus) without producing signs of disease; infection of other New World primates, however, results in a rapidly progressing, malignant, T-cell lymphoma. Results described in this report identify a region of the viral genome that is required for oncogenicity in owl monkeys (Aotus trivirgatus); this region is not required for replication of the virus. This is believed to be the first such genomic region identified in a herpesvirus system.

Animals↗
PubMed1984

Human T-cell leukemia virus: transformation in vitro of nonhuman primate T-lymphocytes and experimental inoculation of nonhuman primates.

T-lymphocytes from three species of New World monkeys were susceptible to transformation in vitro with human T-cell leukemia virus. Marmoset T-lymphocytes transformed in vitro with HVS or HVA, T-lymphotropic herpesviruses of New World monkeys, were also transformed with HTLV resulting in doubly transformed T-cells. This finding may provide a potential model for investigating the possible interaction between a herpesvirus and T-lymphotropic retroviruses in the clinical condition AIDS.

Animals↗
PubMed1983

Phenotypic analysis of new world primate mononuclear cell surface antigens.

We have applied a panel of monoclonal antibodies against antigens present on the surface of human mononuclear cells to the study of mononuclear cell surface antigens expressed by seven species of New World primates. Antibodies to the sheep erythrocyte receptor (OKT11a) to a thymocyte antigen (OKT10), to the I region of the major histocompatibility locus (OKIa), and to an antigen found on the surface of human monocytes (OKM1) cross-reacted with mononuclear cell surface antigens of most of the species studied. Antibodies to antigens which have been correlated with functional capabilities in the human system (OKT4, OKT5, OKT8, 3A1) were much less reactive with platyrrhine mononuclear cells. These reagents may be quite useful in studies of primate phylogeny and immunology.

Animals↗
PubMed1982

Herpesvirus saimiri strain variability.

Herpesvirus saimiri was isolated from 22 squirrel monkeys by cocultivation of peripheral lymphocytes with permissive owl monkey kidney monolayer cells. Comparison of virion DNA fragments produced from restriction endonuclease digestion was used as a sensitive measure of strain variability. Although all isolates contained similarities and common features, 19 of the 22 were readily distinguished. Three of the isolates, however, were indistinguishable and possibly were related epidemiologically. Distinct subtypes of H. saimiri were not evident by these criteria; Peruvian, Colombian, Guyanan, and Bolivian squirrel monkeys yielded isolates without characteristic features peculiar to the geographic region. Three of three colony-born squirrel monkeys that were tested yielded a strain of virus distinct from that obtained from the mother. In separate experiments, two of three animals chosen at random yielded a strain of virus different from that originally obtained 16 and 22 months previously; only one of the three animals examined yielded the same strain of virus 22 months after the original isolation. The degree of restriction endonuclease fragment variability among H. saimiri strains appeared to be greater than previously observed for other herpesviruses.

Animals↗
PubMed1981

Induction of target antigens and conversion to susceptible phenotype of NK-cell-resistant lymphoid cell line.

Two autologous Herpesvirus papio producer lymphoid cell lines and one autologous non-producer line were compared for susceptibility to natural killer (NK) cell-mediated lysis. The non-producer cell line, 26CB-1, was more resistant to NK cell killing compared to one viral producer counterpart 13CB-1, but equally resistant when compared to another, 8CB-1. Treatment with chemical agents that affect differentiation or activate the viral cycle, including n-butyrate, IuDR, 5-azacytidine and tunicamycin, increased the susceptibility to killing of the non-producer line but had less effect on the 13CB-1 producer line. The increase in susceptibility was due to induction of new target antigens: activated 26CB-1 cells were more effective at inhibiting NK-cell-mediated lysis and were bound by more NK cells than untreated control cells. The expression of NK target structures may be related to the differentiated state rather than to the viral production status to target cells.

Animals↗