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Biomedical subjects

A Novogrodsky

Publications and source records attributed to A Novogrodsky.

At least 91 records · Page 5Linked to original sources
PubMed1984

Expression of receptors for interleukin 2: Role in the commitment of T lymphocytes to proliferate.

We examined the role of IL 2 and IL 2 receptors in human T lymphocyte proliferation induced by neuraminidase and galactose oxidase (NAGO)-treated autologous macrophages. T lymphocytes cultured with these aldehyde-bearing macrophages developed responsiveness to IL 2 after as few as 2 to 4 hr of activation and exhibited maximal responsiveness to IL 2 after 18 to 24 hr of activation. This early expression of IL 2 receptors was also shown by the direct binding of a monoclonal anti-IL 2 receptor antibody (anti-Tac) to the activated T lymphocytes. The production of IL 2 by T lymphocytes cultured with NAGO-treated macrophages closely paralleled the induction of IL 2 receptors on the T lymphocytes. IL 2 production began after 4 to 8 hr of activation and peaked at approximately 18 hr. Although the production of IL 2 is strictly dependent upon accessory cell function, the expression of receptors for IL 2 seems to be relatively independent of accessory cells. Despite early expression of receptors for IL 2 and early production of IL 2 by T lymphocytes during activation, T lymphocytes were not committed to proliferate in the absence of IL 2 until more than 24 hr of incubation with NAGO-treated macrophages had elapsed. The commitment to proliferate increased after 24 hr of activation until, after more than 40 hr of activation, the cells proliferated equally well in the presence or absence of IL 2. Proliferation of uncommitted, IL 2 receptor-bearing T lymphocytes was inhibited by interfering with IL 2 binding to its receptor by IL 2 receptor blockade with the anti-Tac antibody. In contrast, proliferation of T lymphocytes committed to proliferate was not affected by IL 2 receptor blockade with the anti-Tac antibody. Taken together, these data suggest three phases of T lymphocyte activation. The first phase requires mitogen (or antigen) to induce expression of IL 2 receptors and production of IL 2 by the T lymphocytes. Accessory cells are strictly required for IL 2 production during this activation phase, but they may not be necessary for expression of IL 2 receptors. The second phase is an IL 2-dependent phase that requires the interaction of IL 2 with the newly expressed IL 2 receptors. The third phase is a commitment of the activated T lymphocytes to proliferate that is independent of both mitogen and IL 2.

Adult↗
PubMed1983

Agents that increase cellular cAMP inhibit production of interleukin-2, but not its activity.

Proliferation of lectin-treated mouse thymocytes induced by the tumor promoter, 12-0-tetradecanoyl-13-acetate, is markedly inhibited by cAMP analogues, prostaglandin E and methylisobutylxanthine. Proliferation induced by interleukin-2 is resistant to inhibition by these compounds. The tumor promoter induces interleukin-2 production in a subpopulation of lectin-treated thymocytes, and production of this lymphokine is inhibited by agents that increase cellular cAMP.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Effect of polar organic compounds on leukemic cells. Butyrate-induced partial remission of acute myelogenous leukemia in a child.

Polar organic compounds, such as dimethylsulfoxide and butyric acid, are known to induce differentiation in Friend erythroleukemia cells as well as in other cell types. It has been found that many of the compounds that induce cellular differentiation, inhibit 3H-thymidine incorporation and induce cell damage when incubated with leukemic cells from patients with acute or chronic myelogenous or acute lymphocytic leukemia. These effects are time and dose dependent. Among the compounds tested, butyrate was the most potent. Parenteral administration of butyrate (500 mg/kg/day) for ten days to a child with acute myelogenous leukemia in relapse, and resistant to conventional therapy, resulted in elimination of myeloblasts from the peripheral blood, an increase in mature myeloid cells and a reduction in 3H-thymidine uptake by the patient's peripheral blood cells. Bone marrow myeloblasts were reduced from 70-80% to 20% following the course of intravenous butyrate. No impairment of liver or renal function and no coagulation abnormalities were observed during butyrate treatment. Organic agents that induce cell differentiation may provide additional reagents for the clinical management of selected cases of leukemia.

Adult↗
PubMed1983

12-0-tetradecanoylphorbol-13-acetate and concanavalin A enhance glucose uptake in thymocytes by different mechanisms.

The effects of the tumor promoter 12-0-tetradecanoylphorbol-13-acetate (TPA) and the plant lectin concanavalin A (Con A) on glucose uptake in murine thymocytes were studied. TPA induces a rapid dose-dependent increase in the uptake of 2-deoxyglucose and in the transport of 3-0-methylglucose. Con A also elicits a time- and dose-dependent enhancement of 2-deoxyglucose uptake. The effect of Con A, however, is less pronounced. The effect of combined treatment of thymocytes with Con A and TPA is not additive. Cytochalasin B completely inhibits the basal, as well as TPA- and Con A-enhanced, 2-deoxyglucose uptake. Dexamethasone markedly inhibits basal 2-deoxyglucose uptake, but is less inhibitory to enhanced 2-deoxyglucose uptake induced by TPA and Con A. The effect of TPA on 2-deoxyglucose uptake and 3-0-methylglucose transport is refractory to inhibition by isobutyl methyl xanthine, dibutyryl cyclic AMP, and ethyleneglycol tetraacetic acid. These agents markedly inhibit the enhancement of 2-deoxyglucose (2-DOG) uptake by Con A. p-Bromophenacyl bromide, an inhibitor of phospholipase A2, also selectively inhibits Con A enhancement of 2-DOG uptake. Taken together, the results suggest that Con A and TPA exert their stimulatory effect on glucose uptake by different activating mechanisms, but they may share a final common transport pathway.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Decreased macrophage-mediated suppression of lymphocyte activation in chronic renal failure.

Prostaglandin-dependent adherent cell suppressor activity was assessed in patients with end-stage renal insufficiency. Proliferative responses of uremic peripheral blood mononuclear cells to optimal concentrations of phytohemagglutinin and concanavalin A were impaired. Responses to the galactosyl-directed lectins, soybean agglutinin and peanut agglutinin, were, however, normal or supranormal. The addition of 1 microgram/ml of indomethacin, to cell cultures resulted in relatively less potentiation of blastogenic responses to the galactosyl-directed lectins in cells from uremic patients (soybean agglutinin, p less than 0.02; peanut agglutinin, p less than 0.05). Similarly, depletion of adherent cells markedly enhanced blastogenesis induced by the galactosyl-directed lectins in normal cell cultures, whereas the effect was much less pronounced (soybean agglutinin, p less than 0.02; peanut agglutinin, p less than 0.02) in uremic cells. Reduced activity of the adherent cell suppressor system in patients with renal failure might be associated with altered sensitivity of uremic lymphocytes to soluble mediators of suppression. The lymphocytes of uremic patients, depleted of adherent cells, were relatively resistant to the inhibitory action of prostaglandin E1 (0.001 microgram/ml, p less than 0.05, and 0.01 microgram/ml, p less than 0.02) on galactosyl-directed, lectin-induced mitogenesis. In contrast, dibutyryl cyclic AMP (10(-4) M), 8-bromo cyclic AMP (10(-5) M), and 3-isobutyl-1-methyl xanthine (20 micrograms/ml) inhibited both control subject and patient cultures to the same extent. Prostaglandin E1 in combination with methyl isobutyl xanthine produced, in adherent-cell-depleted control subjects, levels of cyclic AMP that were significantly higher than in cells from uremic patients (p less than 0.05). Thus, depressed adherent cell suppressor activity in patients with renal failure may result in part from impaired generation of cyclic AMP by lymphocytes.

Adult↗
PubMed1983

On the mechanisms of inhibition of lymphocyte mitogenesis by high conA concentrations.

ConA at high concentrations inhibits lymphocyte mitogenesis. Previous studies have shown that inhibitory conA concentrations do not inhibit the acquisition of responsiveness to interleukin-2 (IL-2) when excessive conA is removed. To analyse further the problem of high-dose inhibition by conA, we determined whether inhibition of mitogenesis is related to inhibition of IL-2 production or, alternatively, whether factor production is intact, but the cells are rendered incapable of responding to the factor. ConA stimulates IL2 production at concentrations that are inhibitory to mitogenesis of human lymphocytes. IL-2 was assayed both in a murine cytotoxic T cell line and human memory cells. The response of IL-2-dependent cells to Il-2-containing medium was, on the other hand, inhibited by conA in a dose-dependent fashion. One mechanism whereby high conA concentrations inhibit mitogenesis is by rendering cells resistant to IL-2, possibly via extensive cross-linking of cell surface sites.

Animals↗
PubMed1983

Cellular and growth factor requirements for activation of human T lymphocytes by neuraminidase and galactose oxidase-treated lymphoid cells.

Proliferation of peripheral blood mononuclear leukocytes (PBL) can be stimulated by irradiated autologous PBL that have been treated with neuraminidase and galactose oxidase (NAGO). We determined the types of cells that stimulate and respond by isolating populations of cells enriched for macrophages, B lymphocytes, and T lymphocytes. With PBL as responding cells, proliferation was stimulated by irradiated, NAGO-treated cells with the following hierarchy: macrophage greater than PBL greater than B cells greater than T cells. Irradiated NAGO-treated macrophages and PBL induced proliferation of isolated T cells greater than or equal to the proliferation they stimulated in PBL, indicating that T cells are the predominant responding cell type. Irradiated, NAGO-treated B cells or T cells were weak stimulators of isolated T cell proliferation when compared to their ability to stimulate PBL. The ability of irradiated NAGO-treated B cells or T cells to stimulate isolated T cell proliferation was greatly enhanced by the addition of untreated macrophages or by the addition of conditioned media from mitogen-activated PBL. Biologic, biochemical, and biophysical characterization of the conditioned media revealed it contained both lymphocyte polypeptide growth factors, interleukin 1 and interleukin 2. Semipurified preparations of either of these growth factors were capable of enhancing T cell proliferation stimulated by irradiated NAGO-treated B or T cells. These data indicate T cell proliferation induced by irradiated, NAGO-treated cells requires the aldehyde-bearing cells for the induction of soluble growth factor production and for the induction of putative membrane receptors for these growth factors.

Adult↗
PubMed1983

Inhibition of phorbol ester-mediated interleukin-2 production by cellular differentiating agents.

Lymphocyte proliferation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is inhibited by agents known to induce differentiation in murine erythroleukemia cells and other cell lines. In the present study, we determined the cellular targets for the action of TPA among murine thymocyte subpopulations, the phase of blastogenesis that is activated by the tumor promoter, and the phase that is inhibited by the differentiating agents. Mouse thymocytes were fractionated into populations bearing receptors for peanut agglutinin (PNA; PNA-positive cells) and populations lacking such receptors (PNA-negative cells). TPA is comitogenic for lectin-treated, unfractionated thymocytes and PNA-negative thymocytes but not for PNA-positive thymocytes. PNA-negative cells, a minor population in unfractionated thymocytes, are therefore the cellular targets for the comitogenic activity of TPA. TPA induces the production of interleukin-2 (IL-2) in lectin-treated PNA-negative populations but not in PNA-positive cells. The differentiating agents inhibit TPA-mediated proliferation of unfractionated and PNA-negative, lectin-treated thymocytes. In contrast, IL-2-mediated proliferation of lectin-treated thymocyte subpopulations is resistant to inhibition by these agents. Inhibition appears to be related to decreased production of IL-2, since the differentiating agents inhibit IL-2 production by both PNA-negative thymocytes and by a human leukemic cell line.

Animals↗
PubMed1982

Hydroxyl radical scavengers inhibit lymphocyte mitogenesis.

Agents that are known to be scavengers of hydroxyl radicals inhibit lymphocyte mitogenesis induced by phorbol myristate acetate (PMA) to a greater extent than they inhibit mitogenesis induced by concanavalin A or phytohemagglutinin. These agents include dimethyl sulfoxide, benzoate, thiourea, dimethylurea, tetramethylurea, L-tryptophan, mannitol, and several other alcohols. Their inhibitory effect is not associated with cytotoxicity. The hydroxyl radical scavengers do not inhibit PMA-dependent amino acid transport in T cells or PMA-induced superoxide production by monocytes. Thus, they do not inhibit the primary interaction of PMA with responding cells. Treatment of peripheral blood mononuclear cells with PMA increased cellular guanylate cyclase in most experiments, and dimethyl sulfoxide tended to inhibit this increase. In addition to inhibition of PMA-induced mitogenesis, hydroxyl radical scavengers markedly inhibited the activity of lymphocyte activating factor (interleukin 1). The differential inhibition of lymphocyte mitogenesis induced by different mitogens appears to be related to the differential macrophage requirements of the mitogens. The data suggest that hydroxyl radicals may be involved in mediating the triggering signal for lymphocyte activation. Some of the hydroxyl radical scavengers are inducers of cellular differentiation,. nd it is possible that their differentiating activity is related to their ability to scavenge free radicals.

Benzoates↗
PubMed1982

Immunosuppressive properties of polar organic compounds that induce cellular differentiation in Friend erythroleukemia cells.

We studied the effect of several polar organic compounds, known to induce erythroid differentiation in Friend leukemia (FL) cells, on in vitro human lymphocyte responses and on skin graft survival in mice. The short chain fatty acids, butyric acid (BA), propionic acid (PA), valeric acid, and the polar organic solvents, dimethyl sulfoxide, dimethylformamide, and dimethylacetamide, all mediated significant inhibition of alloantigen-induced proliferation and generation of cytotoxic T lymphocytes (CTLs) in human primary and secondary mixed lymphocyte culture (MLC) reactions. Hexamethylenebisacetemide, another potent inducer of differentiation in FL cells, also mediated significant suppression. Inhibition of MLC with polar organic compounds was accomplished at concentrations known to induce differentiation in FL cells and that are not cytotoxic to peripheral blood mononuclear cells. In distinct contrast, agents that are structurally related to BA, but that do not induce differentiation in FL cells, such as caproic acid, beta-OHBA, gamma-amino BA, and isobutyric acid, did not exhibit immunosuppressive properties. Pokeweed mitogen-driven polyclonal B cell activation was also suppressed by agents that induce erythroid differentiation in FL cells. In addition to potent in vitro immunosuppressive properties, supplementation of drinking water with BA or PA resulted in prolongation of full-thickness skin grafts in DBA/2 (H-2d) to C57BL/6 (H-2b) donor-recipient combinations. Our findings indicate that polar organic compounds that induce differentiation in FL cells are potent immunosuppressive agents.

3-Hydroxybutyric Acid↗
PubMed1982

Abrogation of proliferation and generation of cytotoxic T cells in human mixed lymphocyte culture reactions by modification of the cell surface with mitogenic oxidizing agents.

Multiple lectins with specificity for cell surface glyco-proteins inhibit cellular and humoral immune responses and induce transplantation tolerance. Because cell surface glycoproteins play a significant role in various immune events involving cell to cell interactions and because the mixed lymphocyte culture (MLC) reaction is a prototype of immune phenomenon involving cell to cell interactions as well as an in vitro analogue of graft-destructive immune events, the effect of modification of the cell surface with oxidizing mitogens was investigated. Treatment of responder or stimulator cells with neuraminidase and galactose oxidase (NAGO) or with sodium periodate (IO-4) resulted in marked suppression of alloantigen-induced proliferation and in vitro generation of primary cytotoxic T cells (CTLs) in human MLCs. A prominent coupling of mitogen-induced proliferation to abrogation of MLC was consistently observed with modification of stimulator or responder cell surface with either NAGO or IO-4. The possibility that destruction of receptor sites and/or stimulatory units was responsible for the suppression of MLCs was excluded by restoring both proliferation and generation of primary CTLs by reduction of mitogen-oxidized cell surfaces with sodium borohydride. The ability of polyclonal activators to inhibit antigen-specific responses might be useful in abrogating unfavorable alloimmune responses.

Adult↗
PubMed1981

Mitogenic and co-mitogenic properties of hemin.

We report here that hemin, an agent known to induce cellular differentiation in Friend erythroleukemia cells, induces mitogenesis in human T cells and enhances mitogenic responses to supraoptimal concentrations of Con A. Mitogenesis induced by suboptimal or optimal concentrations of Con A is not affected by concentrations of hemin that markedly potentiate responses to supraoptimal amounts of Con A. Maximum mitogenic responses are reached 4 to 5 days after initiation of the cultures. The mitogenic response is macrophage dependent, whereas enhancement of responses to supraoptimal concentrations of Con A is not. Indeed, a greater degree of enhancement is observed after removal of adherent cells. Responses to other mitogens (phytohemagglutinin, wheat germ agglutinin, and sodium periodate) are also enhanced by hemin. Compounds that are metabolically or structurally related to hemin are neither mitogenic nor co-mitogenic. Protoporphyrin IX, which is nonmitogenic, is rendered mitogenic by the chemical insertion of iron to form hemin. Hemin does not affect Con A binding to lymphocytes. These findings indicate that hemin is a macrophage-dependent T cell mitogen with the unusual and remarkable property of overcoming the inhibition of mitogenesis induced by high concentrations of Con A. Since hemin has a limited number of metabolic effects, it provides a useful probe for determination of molecular events associated with lymphocyte activation.

Adult↗