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Biomedical subjects

J G Bekesi

Publications and source records attributed to J G Bekesi.

At least 37 records · Page 2Linked to original sources
PubMed1991

Human immunodeficiency virus type 1 (HIV-1) genomic sequences and distinct changes in CD8+ lymphocytes precede detectable levels of HIV-1 antibodies in high-risk homosexuals.

Polymerase chain reaction (PCR) identified regions of the gag, LTR, and env genes of human immunodeficiency virus type 1 (HIV-1) in 5 (13%) of 38 high-risk homosexual men who were negative for HIV-1 antibodies by Western blot (WB). Significant increases in CD8+ cells, particularly those bearing activation CD8+CD38+ and CD8+Ia+ antigens, and marked reductions in CD4+ cells were detected in WB-PCR+ subjects compared with 33 WB-PCR- homosexuals. WB-PCR+ subjects had impaired B cell but not T cell functions. Immunologic characteristics of WB-PCR+ homosexuals were indistinguishable from those of 17 WB+PCR+ subjects. Subjects progressing from WB-PCR- to WB-PCR+ to WB+PCR+ showed sequential phenotypic and functional alterations in their B and T cell compartments. These changes and the presence of HIV-1 genomic sequences were the first indications of HIV-1 infection and together with p24 antigenemia signified an inevitable progression to AIDS.

Adult↗
PubMed1991

Immunotherapy with IL2 by constant infusion and weekly doxorubicin.

Twelve women and 7 men, median age 58 (range 17-74), with a diagnosis of non-small-cell lung cancer (11 patients), inflammatory breast cancer (5 patients), osteosarcoma (2 patients), and colon carcinoma (1 patient) were studied. Treatment consisted of four consecutive 6-day courses of infusional interleukin-2 (IL2); 9 patients were treated with 20 X 10(6) IU/m2/day and 10 patients received weekly dose increments of 50% until the maximally tolerated dose was reached. One day after each course was completed patients received doxorubicin, 30 mg/m2; infusional IL2 was resumed 24 h after receiving doxorubicin. Rebounds of lymphocytes with high spontaneous synthetic rates of DNA occurred one day after stopping the infusion, despite doxorubicin administration. The kinetics were not different from earlier trials using IL2 alone. Sequential lymphocyte analysis showed that helper (CD4) and suppressor (CD8) T-cell subsets increased after the first week of treatment and declined thereafter, whereas the proliferation of natural killer (NK) cells (CD16) progressed through the 4-week treatment unaffected by doxorubicin. Mean cytolytic ability induced by IL2 against NK-resistant tumors in vitro was higher in patients who had evidence of clinical tumor regression and therefore is prognostically valuable (p = .02). Three patients left the study prematurely. Five partial remissions and 2 minimal responses were seen in the remaining 16 patients, but they were short-lived. Of the responding patients, only one had failed prior doxorubicin-containing chemotherapy. Toxicities attributable to IL2 and doxorubicin were encountered, and were manageable at these doses. Our data suggest that doxorubicin did not have cytotoxic or suppressive effects on lymphokine-induced lymphocyte functions and that both treatment modalities in combination are worthy of further investigation since they exert distinct and compatible cytotoxic mechanisms and induced tumor regressions with acceptable toxicity in a group of patients with poorly responsive cancers.

Adolescent↗
PubMed1990

Evaluation of p-F-Phe-m-bis-(2-chloroethyl)amino-L-Phe-Met-ethoxy HCl against transplantable and spontaneous murine neoplasia.

The therapeutic efficacy of PTT.119, p-F-Phe-m-bis-(2-chloroethyl)amino-L-Phe-Met-ethoxy HCl, was evaluated using the transplantable L1210 leukemia and Ridgway osteogenic sarcoma tumor lines and the spontaneous C3H/StRos mammary tumor and AKR leukemia tumor models. Given in a single i.p. dose at 5-10 mg/kg on day 2 or in two injections of 5-7 mg each on days 2 and 9 to BDf1 mice with peritoneal L1210 leukemia grafts, PTT.119 increased the life spans (ILS) of the population dying of tumor by 94%-313%. In addition, 10% of the mice receiving 7 mg PTT.119 on days 2 and 9 were free of L1210 leukemic grafts when autopsied at the end of the 70-day observation period. The average life span of AKR mice with Ridgway osteogenic sarcoma grafts was significantly increased from 36-40 days to greater than 79 days following one or two s.c. injections of 5, 7, or 12.5 mg/kg PTT.119. Administration of PTT.119 at 14 or 14 and 21 days after tumor graft not only induced regression of palpable tumors but resulted in the absence of grafts in 60%-70% of the mice in several of the treated groups on autopsy at 180 days. In contrast, spontaneous mammary tumors were less susceptible to PTT.119; an ILS of only 15%-38% was observed in C3H/StRos mice, which eventually succumbed to tumor. Nevertheless, the total regression of initial tumors and the absence of further tumor incidence (greater than 180 days) was confirmed by autopsy in 5%-10% of the C3H/StRos mice receiving multiple i.p. injections of 5 or 7.5 mg/kg PTT.119. The drug was highly effective against spontaneous AKR leukemia; multiple s.c. or i.p. injections for a total of 15-40 mg/kg PTT.119 increased the average 25-day life span up to 723% and sustained remission in 9%-40% of the animals for greater than 6 months.

Adenocarcinoma↗
PubMed1990

Characterization of human B cell (DK) and promonocyte (U937) clones after HIV-1 exposure: accumulation of viral reverse transcriptase activity in cells and early syncytia induction against SupT1 cells.

The kinetics of HIV-1 infection were compared among human B (DK), promonocyte (U937), T-B hybrid (CEMX174), and T (H9) cell lines. Just like H9 cells, CEMX174 cells exhibited strong syncytia induction capacity against highly HIV-1-sensitive CD4+ T cells (SupT1) and had high reverse transcriptase (RT) release in the supernatant. DK and U937 cells showed syncytia induction capacity by 72 hr, but RT activity in the culture supernatant (extracellular RT) increased much later. RT activity in cell lysates (intracellular RT) became detectable at 12-15 days. The inverted extracellular/intracellular RT ratio and syncytia induction capacity were also observed in chronically infected DK (DK-IIIB) and U937 (U937-IIIB) cell lines and subclones from U937-IIIB. Further, the coculture of H9 with DK-IIIB (which indicates no detectable extracellular RT release) showed remarkable amplification of extracellular RT with significant increase of T-B double marker hybrids (H9-DK-IIIB). Our results suggest that B cells and/or monocytes/macrophages may acquire fusing capacity against CD4+ T cells in early stages of the infection and that these cell-to-cell interactions may also lead to a reduction in the number of CD4+ T cells. Further, these T-B and T monocyte hybrids may serve as temporal sites for viral replication. These in vitro studies may provide clues to the possible immunopathological roles of HIV-1-infected B cells and monocytes/macrophages and may help in understanding the mechanisms of viral burden on an infected host.

B-Lymphocytes↗
PubMed1990

Involvement of lymphocyte function-associated antigen-1 (LFA-1) but not ICAM-1 in a radioactive leukocyte cell-mediated immunity (LA-CMI) assay.

A number of monoclonal antibodies (Mab) specific to human leukocyte adherence molecules were investigated for their possible function in LA-CMI assay. These data indicate that LFA-1 appears to be directly involved in LA-CMI of human peripheral blood leukocytes since both MAb H52, specific to LFA-1 beta and MAb MHM24, specific to LA-1 alpha inhibited LA-CMI that retained distinct functional characteristics normally exhibited in LFA-1-dependent adhesion steps. That is, binding of cells onto tube wall required the presence of bivalent cations and metabolic energy production; it could be stimulated by phytohemagglutinin (PHA) and was partially dependent on intact cytoskeleton and temperature. MAbs specific to other adherence molecules such as ICAM-1, CD2, CD58, CD4, CD8, CD11b and LAM-1 did not affect leukocyte adherence in this model.

Adult↗
PubMed1989

Inverse relationship between HIV-1 p24 antigenemia, anti-p24 antibody and neutralizing antibody response in all stages of HIV-1 infection.

A double blind cohort study was conducted on 149 homosexual males and 36 patients with AIDS to investigate the relationship between HIV-1 antigenemia, the presence of neutralizing antibody (NA) activity and specific anti-viral core protein (p24) antibody (Ab) in the sera of HIV infected individuals during their progression to AIDS. All AIDS patients and 68% (101/149) of the homosexual males were HIV seropositive upon entering the study. Of those 48 (32%) homosexuals who were HIV negative at the onset, three seroconverted during the two year observation period. Retrospective studies of the HIV(-) subjects' sequentially stored serum samples demonstrated an early transient appearance of gag encoded p24 antigen (Ag) which preceded their production of NA and specific anti-p24 Ab. Following their seroconversion, no more circulating p24 Ag could be detected. Among the 101 HIV positive homosexuals, 16% rapidly progressed to AIDS and seven of these 16 (44%) subjects eventually died during the two year observation period. In this group of individuals with poor prognosis, presence of NA and anti-p24 Ab commenced at the onset reaching peak levels just prior to developing AIDS and began to decline as the clinical course worsened. Their circulating level of p24 Ag remained undetectable as long as there was quantifiable NA and anti-p24 Ab in their sera. Reappearance of circulatory p24 Ag, on the other hand, was associated with high risk for progression to AIDS.2+hus, while only 11

Acquired Immunodeficiency Syndrome↗
PubMed1988

Evaluation of 3-(p-fluorophenyl)-L-alanyl-3-[m-bis-(2-chloroethyl) aminophenyl]-L-alanyl-L-methionine ethyl ester HCl (PTT.119) against xenografts of human rhabdomyosarcoma.

PTT.119 [p-F-phe-m-bis(2-chloroethyl)amino-L-phe-met ethoxy HCl], a synthetic tripeptide mustard, was evaluated for therapeutic efficacy against a spectrum of childhood rhabdomyosarcomas (RMS) maintained as xenografts in immune-deprived mice. These xenografts were established from previously untreated tumors, and sublines were selected in mice for resistance to L-phenylalanine mustard (L-PAM). PTT.119 caused regression of four of six RMS lines established from untreated tumors, and demonstrated activity similar to that of L-PAM in this model. Against tumors Rh18/L-PAM and Rh28/L-PAM, selected in situ for L-PAM resistance, PTT.119 had no significant activity. Rh28/L-PAM was cross-resistant also to oxazophosphorine mustards (ifosfamide, cyclophosphamide), and both tumors were cross-resistant to adriamycin and vincristine. PTT.119 caused hematologic toxicity similar to that of L-PAM, characterized by a marked decrease in white blood cells and thrombocytopenia.

Animals↗
PubMed1988

Neutralizing antibodies as a prognostic indicator in the progression of acquired immune deficiency syndrome (AIDS)-related disorders: a double-blind study.

A double-blind longitudinal study for the presence of human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies (NAb) in the sera of 36 patients with acquired immune deficiency syndrome (AIDS), 149 prodromal homosexual subjects, and 33 heterosexual subjects has been carried out. All AIDS patients and 68% of prodromal homosexual subjects (101/149) were found to be HIV-1 antibody positive by Western blot assay. All heterosexual subjects were HIV-1 antibody negative. Neutralizing antibody(s) was determined by testing the protective activity of sera against HIV-1 infection of human T-cell line H9. Study subjects were divided into NAb(+) (antibody titer, greater than 1:40) and NAb(-) (antibody titer, less than 1:40) groups. During the 24-month observation period 2 of 80 (3%) HIV-1(+) NAb(+) individuals progressed to AIDS and died, as compared to 5 of 21 (24%) of HIV-1(+) NAb(-) subjects who progressed to AIDS. Similarly, among the NAb(+) AIDS patients 8 of 23 (35%) died, while 10 of 13 (77%) of the NAb(-) patients died during the course of the study. In addition, the absence or reduction of HIV-1 p17 and p24 antibodies directed against HIV-1 antigens as well as the low titer or absence of NAb appears to be closely related to the clinical progression of the disease. These studies suggest that a decrease in the virus neutralization capacity of the sera and a decrease or complete loss of HIV-1 p17 and p24 antibodies may be useful as prognostic indicators for the progression of disease in HIV-1-seropositive patients.

AIDS-Related Complex↗
PubMed1988

Effector lymphocyte response to homologous tumor antigens in various stages of malignant disease as monitored by leukocyte adherence inhibition--cell mediated immunity (LAI-CMI).

Leukocyte adherence inhibition-cell mediated immunity (LAI-CMI) studies were performed on leukocytes obtained from patients with various stages of breast cancer, colon carcinoma and lung cancer in order to monitor cell mediated immunity during tumor progression. In the presence of autologous serum, all patients with localized tumors showed positive LAI-CMI indexes (greater than 20%), while significant reduction of homologous tumor antigen recognition as measured by the LAI-CMI responses was observed in nearly all patients with Stage IV breast cancer, Duke C colon cancer and Stage III lung cancer. On substituting autologous serum with normal AB serum, leukocytes from patients with large tumor burdens responded to homologous tumor antigens. These results indicate the existence of organ-specific serum factor(s) which may mask the receptor sites on effector cells for tumor recognition. Patients with such serum blocking factor(s) showed significant increase of IgG immune complexes IgM, IgA and alpha-2-macroglobulins. Application of a protein A affinity column purification resulted in a major reduction of IgG and other immune globulins but not of alpha-2-macroglobulin. The blocking effects of autologous serum, however, were not completely abrogated by filtration on the protein A column, thus suggesting that SBF may be heterogeneous in nature and may occur in other serum protein fractions beside the immune globulins.

Adult↗
PubMed1988

Impairments in functional subsets of T-suppressor (CD8) lymphocytes, monocytes, and natural killer cells among asbestos-exposed workers.

Peripheral blood leukocytes from asbestos-exposed workers were analyzed by dual color flow cytometry using monoclonal antibodies that identify developmental (HLA-DR) and functional (Leu 8) subsets of T helper, suppressor lymphocytes, and monocytes. An increase in the number of T suppressor cells was closely associated with a decrease in T lymphocyte functions while numerical defects in activated monocytes (Leu M3+Ia+) and natural killer cells (Leu 7+) were correlated with a depressed Th/Ts ratio. Furthermore, among asbestos-exposed workers with depressed T cell functions we have demonstrated a significantly higher number of the effector Ts (Leu 2+ Leu 8-) subset which regulates both the Th/Ts lymphocyte system as well as B cells and NK cell activities. These findings identified changes in the T suppressor feedback regulatory loop as being responsible for the immunoregulatory imbalance among long-term asbestos workers. In double blind analyses of demographic and radiographic data these phenotypic changes were not correlated with age, smoking history, or duration of exposure but were associated with radiographic evidence of asbestos-associated effects. This correlation established a direct link between asbestos exposure and the subsequent development of immune dysfunction.

Adult↗
PubMed1988

Mammary tumor and melanoma cell transport of PTT.119, a bis-(2-chloroethyl)amino-L-phenylalanine derivative with carrier amino acids.

Uptake of the bifunctional alkylating agent, PTT.119, p-F-Phe-m-bis-(2-chloroethyl)amino-L-Phe-Met-ethoxy-HCl, by the MJY-alpha mammary tumor and B16 melanoma cell lines occurred via two natural pathways for amino acid transport. The primary route of PTT.119 entry was the classical L System, whereas, the ASC System carrier was inconsistently operational for uptake of the tripeptide accounting for 5-6% of PTT.119 transport in the B16 melanoma cells. Tripeptide uptake by MJY-alpha mammary tumor cells did not occur via ASC carriers indicating that the mechanism of drug transport was dissimilar among the tumor cells. In spite of these differences the results support the hypothesis that amino acid residues covalently linked to an alkylating moiety do serve as carriers to enhance drug delivery.

Amino Acids↗
PubMed1988

Multiple transport pathways for L1210 cells: uptake of PTT.119, a bifunctional alkylator with carrier amino acids.

Delivery of the bifunctional alkylating agent, PTT.119 [p-F-L-Phe-m-bis-(2-chloroethyl)amino-L-Phe-Met-ethoxy-HCl], into tumor cells is significantly greater compared to L-phenylalanine mustard (L-PAM) as demonstrated by the 2-fold reduction in PTT.119 dosage required to reduce the viable L1210 cell fraction by 50% (TCD50). This increased uptake and consequent cytolytic efficacy observed in Dulbecco's phosphate buffer was more apparent in culture medium; under this physiologic condition the TCD50 concentration of PTT.119 was 5 times lower than L-PAM. PTT.119 entry into leukemia cells was examined using competition transport assays assessing the ability of the tripeptide to compete with various amino acids and nonmetabolizable substrates for carrier receptors of the L, A and ASC transport systems. A 1-min exposure to a 1- to 50-fold excess of PTT.119 prior to addition of radiolabeled substrates significantly reduced within 60 s both sodium-dependent and sodium-independent uptake of leucine, methionine, threonine and alpha-[1-14C]-aminoisobutyric acid (AIB), but not MeAIB. In complimentary studies, L1210 cells were protected from PTT.119 cytolysis by an 8,000-fold excess of AIB, whereas beta-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH) only abrogated tripeptide cytotoxicity by 95-97% even at BCH:PTT.119 ratios of 200,000. Leucine and methionine protection were significantly less effective; the TCD50 of leucine and methionine were 3.23 and 2.4 microM, respectively, compared to 11.41 microM for AIB and 7.96 microM for BCH. In addition, MeAIB and phenylalanine were totally unable to protect L1210 cells from PTT.119-induced cytolysis. The data indicate that L121 cells actively transport PTT.119 primarily by the BCH-sensitive, AIB-sensitive, MeAIB-insensitive L carrier system. A second, BCH-insensitive, AIB-sensitive and MeAIB-insensitive carrier which is also involved in tripeptide uptake is probably the ASC system.

Alkylating Agents↗
PubMed1987

Isoprinosine-induced modulation of T-helper-cell subsets and antigen-presenting monocytes (Leu M3 + Ia +) resulted in improvement of T- and B-lymphocyte functions, in vitro in ARC and AIDS patients.

Peripheral blood leukocytes from ARC and AIDS patients were analyzed following phytohemagglutinin- and pokeweed mitogen-induced lymphocyte transformation by dual-color flow cytometry using monoclonal antibodies that identify developmental (HLA-DR) and functional (Leu8) subsets of T cells and monocytes. Significant decreases in both the suppressor regulating helper T subset (Leu3+ Leu8+) and the reciprocal inducer helper T subset (Leu3+ Leu8-) responsible for inducing differentiation of B cells were observed. Simultaneously, the percentages of the effector suppressor T cells and the precursor suppressor T cells were increased, both of which were required for generation of suppression of cell-mediated immunity. There was also a progressive selection of Ia+ cells bearing the Leu2 (Ts) markers and a concurrent reduction of the percentage of antigen-presenting monocytes and activated helper T cells. These results suggest that the functional deficiencies in AIDS may be caused by defects in T-cell activation as well as antigen presentation by monocytes. Isoprinosine induced an increase in both regulator Th (Leu3+ Leu8+) and inducer Th (Leu3+ Leu8+) subsets of helper T cells while potentiating the expression of Ia antigen on helper T cells and monocytes during mitogen-driven DNA synthesis. These events initiated a cascade of cellular interactions leading to partial restoration of cell-mediated immune responses. These interferences with the defective helper/suppressor regulatory pathways may have important therapeutic implications.

AIDS-Related Complex↗
PubMed1987

Multiple dysfunctions in developmental and activational stages of T lymphocytes, B lymphocytes and monocytes in ARC and AIDS patients.

Peripheral blood leukocytes from ARC and AIDS patients were examined before and after phytohemagglutinin (PHA) stimulation by dual color flow cytometry and monoclonal antibodies which identify developmental and activational stages of T lymphocytes, B cells and monocytes. There was a persistent elevation in the total number of circulating Ia+ lymphocytes with progressive selection for B1+ Ia+ lymphocytes and T suppressor cells and a concurrent reduction in the antigen-presenting monocytes. Following PHA stimulation there was a marked decrease in all subsets of Ia+ lymphocytes and monocytes. These results indicate (a) multicellular dysfunctions in the immunosurveillance mechanisms in AIDS, and (b) that many functional subsets of circulating lymphocytes and monocytes were already activated and therefore poorly responsive to additional antigenic or mitogenic stimuli.

AIDS-Related Complex↗
PubMed1987

Normalization of immunoregulatory T-helper T-suppressor sublineages and cell-mediated immunity by isoprinosine in vitro in the early stages of AIDS.

Applying flow cytometric analysis and a panel of monoclonal antibodies that define functional subsets and stages of lymphocyte differentiation, we found both inducer and suppressor regulating subsets of helper T cells to be depressed with concurrent increase in the functionally active effector suppressor T cells in prodromal homosexuals and patients with AIDS. Concomitantly a broad spectrum of aberrations in all stages of B cell developments were observed. Failure of isolated peripheral blood lymphocytes from these subjects to respond to formalin-fixed Staphylococcus aureus cowan 1 (SAC) indicated intrinsic defects in their resting B cells, while impairment in pokeweed mitogen (PWM)-induced blastogenesis coupled with increased levels of Ig secretion signified regulatory defects in their mature B cells, which may be related to helper-suppressor dysfunctions. Based on these findings, a multifactorial immunodysfunction in AIDS was proposed. The antiviral biological modulator drug isoprinosine was shown to enhance PWM-induced, T-cell dependent, B-cell blastogenesis and normalize the spontaneous secretion of Ig while showing no modulative effects on SAC-induced (resting B-cell) transformations. It also modified, in a selective fashion, the phenotypic coexpression of both HLA-DR and Leu8 antigen on helper and suppressor T cells. Among prodromal subjects at risk to develop AIDS, isoprinosine augmented the expression of both helper T-cell subsets while reducing the number of suppressor effector cells and activated suppressor cells. These interferences with the helper-suppressor regulatory loop may explain the therapeutic efficacy of this drug in the early stages of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Tumor necrosis factor enhances murine SL3-3 retrovirus replication.

Synthesis of extracellular virions from NIH 3T3 cells productively infected with the murine leukemogenic SL3-3 retrovirus, was significantly increased by exposure to recombinant human tumor necrosis factor (rHuTNF). Compared to control cells SL3-3 virus production was 7-10-fold greater in cultures treated for 24 hours with 100-400 units of rHuTNF/cm2 of cell layer. In contrast, identical treatment of these cells with natural murine interferon alpha/beta, recombinant murine interferon-gamma, or recombinant human IL-2 consistently reduced SL3-3 virion production. Although both interferon (IFN) preparations decreased virion production by 25-95% within a 24 hour period, increased SL3-3 replication was observed following simultaneous addition of rHuTNF and either IFN. Increases in SL3-3 virus production did not require the constant presence of rHuTNF; elevated viral synthesis was detected 2 days after short pulse exposures of 30 minutes to 2 hours. Infected NIH 3T3 cells exposed to 200 units rHuTNF/cm2 of cell layer for 48 hours also continued to produce increased levels of SLS-3 virions 2 weeks after treatment.

Animals↗
PubMed1987

Immunorestorative properties of isoprinosine in the treatment of patients at high risk of developing ARC or AIDS.

We have evaluated the immunomodulatory effects of isoprinosine in a double blind randomized clinical study on 63 immunosuppressed male homosexuals with persistent generalized lymphadenopathy (PGL) or ARC. The subjects received either placebo or isoprinosine at 1 or 3 g/day for 28 days. All subjects were monitored for performance for a one year period. In the 3 g/day treatment group clinical improvement was reported by 52% of the patients in contrast to 15% in the placebo group. Patients receiving 3 g/day isoprinosine showed significant increase in NK cells, a major subset of which bears the Leu 7 surface antigen, and in NK cell function as early as at the termination of treatment. This normalized NK cell property was still evident 5 months after cessation of therapy. Total T lymphocytes and T helper cells also increased in this group and a concomitant reduction was observed in activated T lymphocytes (HLA-DR+). As a direct result of the therapy an increase was found in the Th regulatory (Leu 3+ Leu 8+) cell population resulting in normalization of Th inducer/Th regulatory cell ratio. A concomitant reduction to normal range occurred in Ts effector (Leu 2+ Leu 8-) and functionally activated Ts (Leu 2+ HLA-DR+) cell populations. The kinetics of these effects suggest that isoprinosine stimulates the production of precursor lymphocytes and initiates a process of cell differentiation capable of producing long-term restoration of host immunity.

AIDS-Related Complex↗