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Biomedical subjects

M B Sztein

Publications and source records attributed to M B Sztein.

At least 91 records · Page 5Linked to original sources
PubMed1986

Phase I/II trial of thymosin fraction 5 and thymosin alpha one in HTLV-III seropositive subjects.

Forty-two male homosexuals and/or hemophiliacs with depressed helper/suppressor T-cell ratios were treated with one of three different doses of thymosin fraction 5 (TF5, 30, 60, and 120 mg), or a single dose of thymosin Alpha One (TA1, 600 micrograms), by daily subcutaneous (SQ) administration for 10 weeks, followed twice weekly for 4 weeks. No major toxicity was noted for any of the preparations tested, although three subjects treated with TF5 had to discontinue therapy because of severe local skin reactions. Of the doses and preparations tested, only 60 mg TF5 was capable of significantly improving (p less than 0.02) mean T-cell lymphoproliferative responses to alloantigens (MLR) for six HTLV-III seropositive subjects who were abnormal prior to therapy. Peripheral blood lymphocytes from subjects treated with 60 mg TF5 also exhibited a transient restoration of mean mitogen-induced interleukin-2 (IL-2) production to normal. No effects were observed with any of the four treatment regimens on absolute helper T-cell numbers, NK activity, antibody titers to HTLV-III, or in the expression of a variety of surrogate markers for acquired immunodeficiency syndrome (AIDS). Four of the six seropositive subjects treated with 60 mg TF5 exhibited a return to depressed baseline MLR, after switching to twice weekly injections. With a median follow-up time of 20 months, six cases of AIDS developed. However, none of the five subjects whose MLR improved following treatment progressed to AIDS. We recommend daily subcutaneous (SQ) administration of 60 mg (40 mg/m2) TF5 for use in combined modality trials, along with drugs capable of suppressing replication of HTLV-III.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Multifocal damage of the testis induced in rats by passive transfer of antibodies prepared against non-collagenous fraction of basement membrane.

Multifocal damage of the testis was induced in 70% of the rats injected with an antiserum against a non-collagenous fraction (D-STBM) obtained from a preparation enriched in basement membranes of seminiferous tubules. The damaged areas were characterized by perivascular and peritubular cell infiltrates, changes in the walls of small vessels and seminiferous tubules, and sloughing of the germinal epithelium. By electron microscopy, the most frequent changes observed in basement membrane of the seminiferous tubules were folding, focal thickening, and delamination. By immunofluorescence, discontinuous linear deposits of rabbit IgG were observed along the walls of the seminiferous tubules. In the same localization, faint immunofluorescence showing the presence of rat IgG was also detected. The same pattern was obtained when rabbit and rat IgG eluted from the testes of these rats were layered on sections of normal rat testis. Moreover, by immunoelectron microscopy, discontinuous deposits of rabbit IgG were detected along the basement membranes of the seminiferous tubules. Neither C3 deposits nor changes in the serum CH 50 were observed. By leucocyte migration inhibition reaction (LMIR) a cellular immune response to basement membrane antigens was detected. In the control group, 12% of the rats injected with normal rabbit serum presented mild interstitial cell infiltrates and occasional sloughing of the germinal epithelium. Neither deposits of rat IgG or rabbit IgG nor a cellular immune response were observed.

Animals↗
PubMed1985

Interferon regulation of DR antigen expression and alloantigen-presenting capabilities of the promyelocytic cell line HL60.

Our research suggests that interferon may have an immunoregulatory role in the initiation phase of immune responses. Recent evidence has demonstrated that lymphokines regulate monocyte cell surface expression of DR antigens and, consequently, the ability of monocytes to activate T lymphocytes in an antigen-specific manner. In this report cloned interferons and a homogeneous cell line were used to demonstrate that interferon possesses these immunoregulatory functions. Cells of the promyelocytic cell line HL60, when incubated in vitro with recombinant gamma (IFN-gamma) and with alpha interferons (IFN-alpha), expressed enhanced levels of DR antigen as determined by both cytotoxicity and fluorescence-activated cell sorter analyses. Lower concentrations of IFN-gamma than IFN-alpha were needed to induce DR expression, and a higher percentage of monocytes were induced to express DR antigen by IFN-gamma than IFN-alpha. HL60 cells preincubated with lymphocyte-derived lymphokines or IFN-alpha also stimulated a significantly better in vitro allogeneic response in the mixed leukocyte reaction than untreated HL60 cells. Thus, interferon both the phenotypic expression of DR antigens of HL60 cells and their functional ability to initiate T-lymphocyte responses to an alloantigen.

Antigen-Presenting Cells↗
PubMed1985

Comparison of the effects of thymosin and other thymic factors on modulation of interleukin-2 production.

Thymosin fraction 5 (TF5) enhances interleukin-2 (IL-2) production by human peripheral blood mononuclear leukocytes (PBL) when cocultured in the presence of phytohemagglutinin (PHA). This important biological activity of TF5 is not due to the presence of two previously well-characterized component peptides, thymosin alpha 1 and thymosin beta 4, but rather to a new, still to be identified component of TF5. Comparison of TF5 with other well-defined thymic preparations and peptides indicates that this biological activity is unique to TF5 and a closely related extract prepared from porcine thymus tissue. Using a standard human PBL cell population obtained by leukopheresis and cryopreservation, it should now be possible to establish a reproducible bioassay for the isolation and characterization of one or more components of TF5 with the property of enhancing PHA-induced IL-2 production by human PBL.

Animals↗
PubMed1984

Deficient DR antigen expression on human cord blood monocytes: reversal with lymphokines.

Expression of DR antigen on cord blood (neonatal) human monocytes using complement-mediated cytotoxicity with anti-DR alloantisera and fluorescent-activated cell sorting (FACS) utilizing a battery of anti-DR mouse monoclonal antibodies was assessed. Forty preparations of neonatal cord blood monocytes were purified by adherence and elution from plastic petri dishes: lymphocyte contamination was less than 5% as indicated by esterase and peroxidase stains and cell sizing. By cytotoxicity tests 22 +/- 5.5% (SD) of neonatal monocytes expressed DR compared to its expression on 78.6 +/- 3.1% of adult monocytes. By FACS analysis, the frequency of DR expression on neonatal monocytes was 19-33% compared to 71-82% for adult monocytes. Incubation of neonatal monocytes with concanavalin A (Con A) or phytohemagglutinin (PHA)-stimulated human peripheral blood mononuclear cell culture supernatants (lymphokine) or recombinant interferon-alpha (IFN-alpha) increased the expression of DR antigens in a dose- and time-dependent manner. A Con A-supplemented culture supernatant of unstimulated peripheral blood mononuclear cells had no effect on DR expression. Neonatal monocytes that were pretreated with anti-DR and complement in order to remove DR-positive cells were induced to express DR antigen after 2 days in culture with lymphokine. Thus DR-negative neonatal monocytes can be induced to express DR antigen. These results suggest a correctable maturational deficiency of neonatal monocytes. The inducibility of DR antigen expression by lymphokines and recombinant IFN-alpha suggests that they play an important role in the regulation of immune responses.

Concanavalin A↗
PubMed1984

Thymosin increases production of T-cell growth factor by normal human peripheral blood lymphocytes.

The in vitro incubation of phytohemagglutinin-stimulated peripheral blood lymphocytes with thymosin results in a marked and reproducible increase in production of T-cell growth factor, which is dose dependent and most pronounced in the first 24 hr of culture. Incubation of lymphocytes with thymosin alone failed to induce any production of T-cell growth factor. The biological activity of thymosin fraction 5 cannot be attributed to the activity of thymosin alpha 1, one of the well-characterized peptide components of fraction 5. These data provide the basis for (i) a potential mechanism for the in vivo immunorestorative effects of thymosin in primary and secondary immunodeficiencies and (ii) identification of an additional, but as yet undefined, immunoregulatory component of thymosin fraction 5.

Dose-Response Relationship, Drug↗
PubMed1984

Regulation of human peripheral blood monocyte DR antigen expression in vitro by lymphokines and recombinant interferons.

The in vitro regulation of adult human monocyte DR antigen expression was studied. Normally about 75% of freshly obtained human peripheral blood monocytes express DR antigens as determined by anti-DR and complement-mediated cytotoxicity assays. DR expression on monocytes in unfractionated peripheral blood mononuclear cell cultures persisted to variable degrees for up to 5 d of incubation. However, when the mononuclear cells were thoroughly depleted of nonadherent cells, cultured monocytes consistently exhibited progressively decreased DR expression over 2-5 d of incubation. Readdition of nonadherent cells to the adherent cell population prevented or delayed this decrease in monocyte DR antigen expression. Thus, monocyte DR expression diminished markedly during in vitro incubation; however, the presence of nonadherent cells somehow interfered with this process. In other experiments, peripheral adherent monocytes, which had been cultured for 2-3 d to reduce their DR expression, could be induced to reexpress DR antigens after 2 d of incubation with unpurified lymphokine-containing culture supernatants, recombinant human interferon-alpha, or recombinant human gamma interferon (IFN-gamma). The reinduction of DR expression on human monocytes by lymphokines was abrogated by an antiserum produced to the synthetic N-terminal amino acids of human IFN-gamma, indicating that IFN-gamma is the active mediator in the lymphokine-containing preparations. Monocytes cultured with lymphokines or recombinant interferons also could initiate a significantly greater mixed lymphocyte response than control monocytes. Thus, IFN-gamma-containing lymphokines and recombinant interferons are required to induce human monocyte DR expression and accessory cell capacity in vitro, since in their absence monocytes become DR antigen-deficient. Finally, incubation of unfractionated human mononuclear cells with anti-human IFN-gamma also promoted the loss of monocyte DR expression. These findings suggest that resting lymphocytes are probably capable of producing sufficient IFN-gamma in vitro to result in the maintenance of the monocyte DR phenotype.

Cells, Cultured↗
PubMed1983

Characteristics of an epidermal cell thymocyte-activating factor (ETAF) produced by human epidermal cells and a human squamous cell carcinoma cell line.

In this study we show that both cultured normal human epidermal cells (EC) and a human squamous cell carcinoma (SCC) cell line produce a thymocyte-activating factor (ETAF). EC-ETAF and SCC-ETAF both have a Mr of 15,000 and were eluted from chromatofocusing at the same isoelectric points of 7.2, 5.8, and 5.0. Both activities were maintained at alkaline pH and were destroyed at temperatures above 60 degrees C. In addition to stimulating thymocyte proliferation, human ETAF exhibited a variety of other pertinent biologic activities. Although EC-ETAF or SCC-ETAF by themselves exhibited no T-cell growth factor activity, both ETAF preparations enhanced Interleukin 2 production by cultured human peripheral blood lymphocytes when stimulated with polyclonal T-cells stimulants (Concanavalin A and phorbol myristate acetate). Human ETAF also was chemotactic for rabbit polymorphonuclear leukocytes and was directly mitogenic for cultured human dermal fibroblasts. Injection of human ETAF into C3H/HeJ mice, resulted in inducing serum amyloid A (SAA) production by murine hepatocytes. The thymocyte growth-enhancing activity, the fibroblast-stimulating activity, and the SAA-inducing capacity of ETAF all coeluted off AcA54 gel. These biologic as well as biochemical properties of human keratinocyte-derived ETAF are identical with those of human macrophage-derived Interleukin 1. The ability of keratinocytes to release an immunomodulating factor with such diverse consequences may play an important role in normal wound healing and in diseases involving epithelial tissues.

Carcinoma, Squamous Cell↗
PubMed1983

A corneal cytokine triggers the in vivo synthesis of serum amyloid A by hepatocytes.

Recently a cytokine released by primary corneal epithelial cell cultures as well as by a rabbit corneal cell line (SIRC), corneal epithelial cell-derived thymocyte-activating factor (CETAF) has been described. The biological and biochemical properties of CETAF are similar to those of epidermal cell-derived factor (ETAF) and macrophage-derived interleukin 1 (IL 1). Like IL 1 or ETAF, SIRC supernatant, as well as partially purified CETAF (both molecular weight pools) significantly enhanced serum amyloid A production by hepatocytes, when injected intraperitoneally into C3H/HeJ mice. Therefore, corneal epithelial cells, by a nonspecific helper factor, CETAF, may exert immunoregulatory functions during chronic corneal inflammation.

Amyloid↗
PubMed1983

Properties of murine and human epidermal cell-derived thymocyte-activating factor.

Keratinocytes, the predominant cell within the epidermis, perform some macrophage-like functions, such as endocytosis and phagocytosis. We therefore investigated whether keratinocytes may also exert some nonspecific immunoregulatory functions through the secretion of mediators. Tissue cultures of freshly isolated murine and human keratinocytes as well as keratinocyte cell lines secrete a cytokine, epidermal cell-derived thymocyte-activating factor (ETAF), which augments in vitro lymphoproliferative responses. Keratinocyte cell line cells produce increased levels of ETAF activity after exposure to a variety of cell-damaging agents such as silica, endotoxin, phorbol myristate acetate, hydroxyurea, and mechanical disruption. Biochemical studies showed that murine and human ETAF, like interleukin 1 (IL 1), had a molecular weight between 12,000 and 20,000, interacted with hydrophobic phenyl-Sepharose, and was eluted from anion but not cation exchangers. Like IL 1, murine ETAF had a single isoelectric point whereas human ETAF eluted as three peaks of activity (pI 7.2, 5.8, and 5.0). Partially purified ETAF of either species also had the same biological properties of IL 1. That is, ETAF enhanced IL 2 production by T cells in culture, was chemotactic for polymorphonuclear leukocytes, and was directly mitogenic for fibroblasts. When injected into C3H/HeJ mice ETAF induced hepatocyte production of serum amyloid A, an acute phase protein. Furthermore, ETAF, like IL 1, may act as an endogenous pyrogen and induce fever when injected into rabbits. These findings indicate that production of IL 1-like molecules is not confined to cells of the immune system and that ETAF production by keratinocytes may have important implications in would healing, as well in the pathogenesis of inflammatory and neoplastic diseases.

Animals↗
PubMed1982

Antigens of the basement membranes of the seminiferous tubules induce autoimmunity in Wistar rats.

A preparation enriched in basement membranes from seminiferous tubules was isolated from rat testes (STBM) and injected with complete Freund's adjuvant into Wistar rats. In 60% of animals a mild multifocal orchitis was observed. In damaged areas, perivascular and peritubular mononuclear cell infiltrates and different degrees of cell sloughing of some seminiferous tubules were observed. Electron microscopy revealed focal thickenings and delamination of the basement membrane of the seminiferous tubules as well as vacuolization of Sertoli cell cytoplasm. Using immunofluorescence discontinuous linear deposits of IgG were detected along the seminiferous tubular wall. Moreover, the same pattern of immunofluorescence was observed when the IgG eluted from the testes of the immunized rats was layered on sections of normal rat testis. Circulating antibodies to STBM were detected using passive haemagglutination in approximately 45% of the immunized rats, with titers ranging from 1:20 to 1:80. Leukocyte migration was inhibited when the spleen cells of the immunized rats were incubated with antigens from the basement membrane of seminiferous tubules, whilst a negative reaction was obtained when the soluble fraction of testis homogenate was used.

Animals↗
PubMed1982

The role of interleukin 1 in acute phase serum amyloid A (SAA) and serum amyloid P (SAP) biosynthesis.

The acute phase SAA and SAP profiles have been compared for localized and endotoxin induced inflammation in LPS responder and nonresponder strains of mice. The SAP profile can reflect a delay with respect to the start of the increase. Its maximum is on the order of ten times the nonacute phase concentration and elevated concentrations are sustained 24 to 48 hours after SAA concentration is rapidly decreasing to normal. The role of Interleukin 1, known to have an essential role in SAA production, was investigated for SAP production. Purified mouse IL 1 and rabbit IL 1 produced a minimal elevation of SAP concentration above normal values, especially when compared with their effects on SAA concentration. BCG infection was shown to synergistically augment SAA induction by LPS and was shown to enhance IL 1 production by macrophages in response to LPS. Unlike SAA synthesis, BCG-preinfection fails to synergistically augment the LPS-induced SAP response. BCG infection alone produced highly elevated and sustained increases in SAP concentration, whereas, the effect on SAA concentration was minimal. Macrophages appear to play an important role in SAP acute phase elevation, but the mechanism in different from that of SAA elevation.

Acute Disease↗
PubMed1982

An epidermal cell-derived cytokine triggers the in vivo synthesis of serum amyloid A by hepatocytes.

Lipopolysaccharide (LPS) stimulates macrophages to produce a number of closely related soluble mediators, including interleukin 1 (IL 1), endogenous pyrogen (EP), and serum amyloid A (SAA) inducer, which are able to induce hepatocyte production of SAA, an acute-phase reactant. Keratinocytes also produce a soluble mediator, epidermal cell-derived thymocyte-activating factor (ETAF), which is very similar to IL 1. The experiments reported here show that unpurified ETAF-containing preparations, as well as ETAF after chromatography by gel filtration (Sephacryl S-200), anion-exchange on DEAE, phenyl-Sepharose, or isoelectrofocusing, were all able to induce the in vivo production of SAA by hepatocytes. Additionally, ETAF and SAA inducer exhibited the same pattern of temperature sensitivity. These observations add further support to the hypothesis that ETAF, IL 1, EP, and SAA inducer comprise a group of closely related mediators and that nonlymphoid cells can produce mediators that can regulate systemic inflammatory reactions.

Animals↗