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At least 883 records · Page 49Linked to original sources
PubMed1986

Activation of cytotoxic T cells and effector cells in experimental autoimmune thyroiditis by shared determinants of mouse and human thyroglobulins.

Previous studies have shown that T cells from genetically susceptible mice developing experimental autoimmune thyroiditis (EAT) proliferate in response to restimulation with mouse thyroglobulin (MTg) in vitro and differentiate into cells cytotoxic for syngeneic thyroid monolayers. To examine further the effector cells involved in pathogenesis and the determinants on MTg responsible for their activation, spleen cells (SC) and lymph node cells (LNC) from mice immunized with MTg or human (H) Tg, and adjuvant (complete Freund's adjuvant (CFA) or lipopolysaccharide (LPS] were cultured in vitro with MTg or HTg. Control cultures were incubated with concanavalin A (Con A) or purified protein derivative (PPD). The in vitro-activated cells which proliferated in response to MTg, HTg, or Con A adoptively transferred thyroiditis to normal recipients, whereas cells transferred directly without in vitro culture were very ineffective. The capacity to transfer EAT was abrogated by irradiation (1500 R), and SC from CFA-immunized control mice which responded in vitro to PPD stimulation did not transfer thyroiditis. The serum titers of MTg autoantibodies were uniformly low and were not correlated with severity of disease. The localization of EAT-effector (precursor) cells depended upon the site of immunization; they were found in the spleens after inguinal (subcutaneous) or systemic (intravenous) immunizations, but were present in the popliteal lymph nodes after hind footpad injections. Both homologous MTg and heterologous HTg functioned as in vivo sensitizing antigen and in vitro activating antigen for each other; such cultured cells transferred thyroiditis in vivo and became cytotoxic for thyroid monolayers in vitro. These findings show that shared determinants are autoantigenic and thyroiditogenic, and support the hypothesis that EAT-effector cells responsible for initiating thyroid damage include cytotoxic cells.

Adjuvants, Immunologic↗
PubMed1985

Rapid changes in specificity within single clones of cytolytic effector cells.

We find rapid changes in the specificity of the cytolytic effector cells in a mixed lymphocyte culture. The lysis patterns produced by cytolytic effector cells generated near limiting dilution in murine mixed lymphocyte reactions of three types, F1 anti-parent (F1(A X B) anti-A), allogeneic (C anti-F1(A X B)), and F1 antimodified parent (F1(A X B) anti-A-TNP), were investigated. Cultures were characterized by their ability or inability to lyse a panel of target cells (e.g., A, B, F1). When individual cultures were tested at two different times, changes in lytic pattern were routinely seen, with some patterns reproducibly increasing in frequency and others reproducibly decreasing (e.g., patterns involving lysis of F1 decreased in an F1 anti-A response but increased in a C anti-F1 response). X-linked isoenzyme analysis showed that changes can occur within a single clone of effector cells. These results imply that the T cell specificity repertoire continues to evolve during an ongoing immune response, a conclusion incompatible with clonal selection theory.

Animals↗
PubMed1979

Antibody dependent cell-mediated cytotoxicity to herpes simplex virus in man: the influence of drugs on polymorphonuclear leucocyte and mononuclear effector cells.

We have shown that the function of the effector cells in antibody mediated cell dependent cytotoxicity (ADCC) can be reduced by the use of a number of drugs and prostaglandins. Both polymorphonuclear leucocyte and mononuclear effector cells were studied. Aminophylline and isoproterenol markedly reduced this activity. All the prostaglandins tested--PGA1, A2, E1 and E2 had a similar but more profound effect. At a dose of 100 mg/ml hydrocortisone had relatively little influence and neither ASA nor indomethacin had any effect on the effector cells tested. It is suggested that the effect of PGE1 in stimulating a recrudescent herpes simplex infection may be by reducing the efficacy of ADCC in host defence.

Aminophylline↗
PubMed1992

Role of inter-heavy and light chain disulfide bonds in the effector functions of human immunoglobulin IgG1.

The role of inter-heavy and light chain disulfide bonds in the effector functions of human IgG1 was investigated. This was accomplished by mutating appropriate sites in IgG1 such that the disulfide bond pattern now resembled that of IgG4. The effector functions of the mutant antibody were then compared to native IgG1 and IgG4. The antibody-dependent cell cytotoxicity activity was completely abolished in the mutant and the complement-dependent cytotoxicity assay was reduced fifteen-fold. The results suggest that the inter-heavy and light chain disulfide bond pattern of an antibody molecule play a role in its effector functions.

Animals↗
PubMed1983

Effects of 3-deazaadenosine on antibody-dependent cellular cytoxicity and phagocytosis: reciprocal inhibition and augmentation of these functions in various effector cell populations.

3-Deazaadenosine (3-DAA), an inhibitor of S-adenosyl-L-homocysteine hydrolase, caused a dose-dependent inhibition of antibody-dependent cellular cytotoxicity (ADCC) against erythrocyte target cells of mouse spleen effector cells and complete Freund's adjuvant-induced peritoneal exudate cells. Inhibition of ADCC was accompanied by a proportional augmentation of antibody-dependent phagocytosis (ADø). When resident peritoneal cells were used as the source of effectors, ADø was inhibited by 3-DAA without augmentation of ADCC. Long-term (overnight) preincubation studies showed that the effect of 3-DAA on peritoneal ADø increased with time and was irreversible. Peritoneal exudate cells elicited by sodium caseinate mediated both antibody-dependent and -independent (spontaneous) phagocytosis. 3-DAA was shown as a potent and irreversible inhibitor of spontaneous phagocytosis. Inhibition of phagocytosis in these cell preparations resulted in augmentation of ADCC. In most of these effector cell populations, effects of 3-DAA were potentiated by the presence of L-homocysteine thiolactone.

Animals↗
PubMed1984

Comparison of the effects of quercetin with those of other flavonoids on the generation and effector function of cytotoxic T lymphocytes.

In previous studies (Schwartz et al., 1982) we showed that the naturally occurring plant flavonoid quercetin can inhibit both the in vitro generation and effector function of alloantigen specific cytotoxic T lymphocytes (CTL). In the present studies, several additional flavonoids of different chemical classes were tested similarly to determine whether structure-function relationships exist. We have found that some other flavonoids, e.g. apigenin , fisetin , hesperetin and chalcone also can inhibit both CTL generation and effector function, with the effective concentration varying with the specific flavonoid tested. On the other hand, flavonoids such as rutin, naringin and catechin were inactive in both systems. Taxifolin ( dihydroquercetin ) differed from all the other flavonoids in that it was a relatively active inhibitor of CTL generation, but was essentially unable to inhibit CTL effector function. The presence of a double bond at position C-2-3 in the flavone and flavonol aglycones, a keto group at C-4, B ring hydroxylation and/or a free hydroxyl group at C-3 may be associated with activity. We also show that the effects of some, but not all, of the flavonoids active in our systems can be blocked by Cu2+ ions. Therefore, chelation of divalent cations such as Cu2+ cannot explain the function of all flavonoids in these systems.

Animals↗
PubMed1984

Exposure of neonatal female mice to diethylstilbestrol persistently impairs NK activity through reduction of effector cells at the bone marrow level.

Female NMRI mice neonatally treated with diethylstilbestrol (DES) show persistent impairment of various immune parameters, including NK activity. The present study demonstrated that NK activity was reduced in all lymphoid compartments and thus is not due to a simple redistribution of effector cells. Poly I:C was unable to augment NK activity in DES treated animals in vitro and in vivo. This defect was not attributable to inability to produce interferon in response to poly I:C since interferon-beta was also unsuccessful in augmenting NK activity in vitro. Moreover, the lack of response was not dependent on alterations in macrophage function, as evident from experiments showing that macrophages from DES-exposed animals resulted in a normal enhancement of NK activity in response to poly I:C when mixed with lymphocytes from control animals. Studies at the single cell level revealed that the reduced NK activity was the result of a reduced number of target-binding effector cells, and that the individual cells actually binding a target killed the target in an apparently normal fashion. Adoptive transfer of bone marrow cells between control and neonatally DES-treated animals showed that the reduced number of effector cells was determined at the bone marrow level.

Animals↗
PubMedDate not supplied

Drug-mediated increase of susceptibility of human lung cancer to NK or LAK effector cells.

Previous studies in murine models have shown that in vivo or in vitro treatment of tumor cells with mutagenic triazene compounds (TZC) lead to the appearance of novel drug-mediated tumor antigens (DMTA) capable of eliciting graft resistance in syngeneic hosts. This phenomenon, defined as 'chemical xenogenization' (CX), could be of potential value for immunochemotherapy of human neoplasias. It was also shown that TZC modulate NK sensitivity of murine tumor cells. Therefore, experiments were conducted to evaluate whether susceptibility of a human lung adenocarcinoma cell line (H125) to natural cytotoxic effectors could be affected by treatment with an in vitro active TZC. The results showed that drug treatment of H125 line leads to heritable increase of susceptibility to NK and LAK cells. Moreover, increased binding between effector and drug-treated target cells was observed. Additional studies on HLA antigens showed that changes in HLA-ABC molecule expression were probably not involved in TZC-induced increase of NK/LAK susceptibility. These results suggest that TZC treatment of a human tumor could result in increased expression of membrane structures recognized by natural cytotoxic effector cells. Further studies are required to explore whether these changes are generated by mutational events correlated with TZC-induced CX of human cancer cells.

Antigens, Neoplasm↗
PubMed1996

Hormonal secretion patterns but not autonomic effector responses elicited by hypothalamic heating and cooling are altered in febrile rabbits.

The effects of hypothalamic heating and cooling on thermoregulatory effector activities, lipid and carbohydrate metabolism, insulin, glucagon, thyroxine, arginine vasopressin (AVP) and cortisol were investigated in conscious rabbits and compared with those obtained in the febrile state. The study shows that under control conditions hypothalamic heating lowers, and cooling raises core temperature. Core temperature always rose to similar degrees in response to bacterial lipopolysaccharide (LPS) during an observation time of 150 min, but it started to rise from lower and higher levels, respectively, during hypothalamic heating and cooling. The effects of hypothalamic thermal stimulation on specific thermoregulatory effector activities support the conclusion that, within 60 min after LPS, the hypothalamic warm signal input is reduced relative to the cold signal input. The increase of thyroxine levels following LPS suggests that the elevation of the thermoregulatory setpoint was caused by an increased input of hypothalamic TRH neurons, known to induce the full autonomic pattern of cold defense also in response to non-thermal stimuli. With the exception of an increase of glucagon during hypothalamic cooling at control conditions, hypothalamic thermal stimulation alone did not alter lipid and carbohydrate metabolism, insulin, thyroid hormone, AVP and cortisol secretion. A spontaneous heat loss effector response separated the first from the second fever phase 60 min after LPS. Subsequently AVP and cortisol plasma levels rose in febrile animals, irrespective of hypothalamic heating and cooling, presumably as a consequence of pyrogenic activation of corticotropin releasing factor (CRF) producing neurons and their reciprocal interaction with TRH neurons on the one hand, and by a reciprocal interaction of the latter with AVP neurons on the other.

Animals↗
PubMed1983

Involvement of transferrin and transferrin receptors in human natural killer effector:target interaction.

In this current study one of the determinants of natural killer cell specificity in immunosurveillance against cancer, may be the recognition of transferrin receptors on neoplastic cells by the NK effectors. Human transferrin, when saturated with iron (FeTf), was found to inhibit human natural killer (NK) activity against K562 tumor cells, if included in assay mixtures at physiologically relevant levels. Whereas both FeTf and iron-free transferrin (ApoTf) inhibited initial conjugate formation at the level of the target cell, only FeTf inhibited NK cytolytic activity, as judged by release of chromium from the targets. This suggested a functional role for FeTf on either NK or tumor cells. When either targets or effector lymphocytes were pre-incubated with FeTf, inhibition of killing was strongest when the targets were first exposed to FeTf. The evidence suggested that NK-associated transferrin mediated the interaction with target cells through free target-associated transferrin receptors. The finding that rabbit anti-human transferrin antibody (RaHTf) inhibited killing, when reacted with effector lymphocytes but not with target cells, supported this hypothesis.

Humans↗
PubMed1987

Effector or target cell selection mediated by C3 bridges.

Potential effector cells (including stimulated lymphocytes and cultured monocytes) and potential target cells of NK and AK type cytotoxic reactions (including several lymphoblastoid cell lines) cleave the third complement component (C3). As a result of expression of C3bA sites such cells are able to bind covalently the activated C3b through its metastable binding site and thereby become "armed" by the C3b. This permits C3b-bridge formation between these cells and CR1-bearing cells. The "effector selection" (i.e. when C3b is bound covalently to potential target cells) or "target selection" (when C3b is covalently bound to C3bA sites on potential effector cells) mediated by C3b bridges results in enhanced killing capacity. Macrophages activate and bind C3b as well; but the covalent binding of C3b by these cells inhibits Fc receptor mediated ADCC type killing.

Animals↗
PubMed1995

Generation of effector T cells in Hymenolepis nana-infected, FK-506-treated BALB/c mice.

FK-506 administered into mice daily at a dose of 10.0 mg/kg (but not 1.0 and 5.0 mg/kg) caused suppression of protective immunity to Hymenolepis nana, when the agent was injected intraperitoneally during the induction phase of protective immunity. Daily administration of 10.0 mg/kg FK-506, during the course of larval development from challenge, also suppressed protective immunity. Inhibition of protective immunity was only observed in mice that received FK-506 for 6 days at a daily dose of 10.0 mg/kg and were challenged 24 h after the final FK-506 injection. FK-506 did not inhibit formation of effector cells that mediate delayed-type hypersensitivity (DTH) to H. nana egg antigen when the agent was administered intraperitoneally at a dose of 10.0 mg/kg/day for 6 days before cell preparation. However, FK-506 did inhibit DTH effector cell activation when cells prepared from infected, saline-injected mice were transferred into 10.0 mg/kg FK-506-treated recipient mice. These results strongly indicate that FK-506 cannot inhibit the generation of effector cells but will suppress their function in vivo.

Animals↗
PubMed1994

Transforming growth factor-beta 1 inhibits tumor necrosis factor-alpha/lymphotoxin production and adoptive transfer of disease by effector cells of autoimmune encephalomyelitis.

We previously reported that the CD4+ suppressor cells (Ts) that regulate recovery of Lewis rats from experimental autoimmune encephalomyelitis (EAE) produce transforming growth factor-beta (TGF-beta). We also reported that TGF-beta downregulates interferon-gamma (IFN-gamma), but not interleukin-2 (IL-2) production, by the CD4+ effector T cells (Te) that mediate EAE. We now report that TGF-beta also inhibits the production of tumor necrosis factor/lymphotoxin (TNF/LT) by EAE effector cells. When activated in vitro with myelin basic protein (MBP), Te produced TNF/LT, as measured using a WEHI 164 cytotoxicity assay. The specificity of cytokine action was demonstrated using neutralizing antibodies to TNF/LT. When added to the Te+MBP cultures, TGF-beta inhibited TNF/LT production in a dose-dependent fashion. Moreover, neutralizing anti-TGF-beta antibodies augmented TNF/LT production in the Te+MBP cultures. We also confirm that TGF-beta inhibits adoptive transfer of EAE. In contrast, murine IL-10 only partially inhibited TNF/LT and IFN-gamma production by Te. We conclude that TGF-beta production by Ts plays a major role in recovery from EAE in the Lewis rat by inhibiting TNF/LT and IFN-gamma production by the effector cells that mediate EAE.

Animals↗
PubMed1992

Reduced sensitivity of O2 transport to allosteric effectors and temperature in loggerhead sea turtle hemoglobin: functional and spectroscopic study.

The functional and spectroscopic (EPR and absorbance) properties of the adult loggerhead sea turtle (Caretta caretta) hemoglobin have been studied with special reference to the action of allosteric effectors and temperature. Present results indicate that turtle Hb displays a very low O2 affinity and a very small sensitivity to allosteric effectors and temperature. Furthermore, the amplitude of the Bohr effect for O2 binding is strongly reduced. In parallel, EPR and absorbance spectroscopic properties of the nitrosylated derivative of turtle Hb suggest that the hemoprotein is in a low-affinity conformation, even in the absence of allosteric effectors. These findings suggest the existence of unusual molecular mechanisms modulating the basic reaction of Hb with O2, which may be linked to specific physiological needs related to the diving behavior of the turtle.

Allosteric Regulation↗
PubMed1989

Reduction of cytotoxic effector cell activity in colon 38 tumours following treatment with flavone acetic acid.

Host cells have been implicated as being involved in the antitumour effects of flavone acetic acid (FAA), an agent with selectivity towards solid tumours which is currently undergoing clinical trial. To determine whether tumour-associated host cells are affected by FAA treatment, tumour-infiltrating leukocytes (TIL) were isolated from subcutaneous Colon 38 tumours, which are known to be sensitive to FAA. 1-2 x 10(5) TIL were isolated per gram of tumour, comprising mainly small lymphocytes and macrophages. Spontaneous activity against YAC-1 and P815 tumour targets was tested in a 4 h 51Cr-release assay for lymphoid cytotoxic effector cells. High levels of activity were exhibited by TIL against both P815, which is resistant to natural killer (NK) cells, and to NK-sensitive YAC-1 cells. In contrast, splenic cell populations contained only NK cell activity. Within 1 h of intraperitoneal administration of FAA (330 mg/kg) the cytotoxic effector cell activity of the TIL population was dramatically depressed, remaining low during the time in which extensive tumour necrosis became evident. In contrast, splenic NK activity was unchanged at 1 h and elevated at 4 h. The decrease in lymphoid killer activity of the TIL population following treatment argues against the primary involvement of these effector cells in mediating the antitumour action of FAA.

Animals↗
PubMed1993

Pyruvate kinase from Lactobacillus bulgaricus: possible regulation by competition between strong and weak effectors.

The pyruvate kinase from Lactobacillus bulgaricus has been purified to homogeneity. The native enzyme is composed of four probably identical subunits of relative molecular mass M(r) 72,000 +/- 4,000. The unique N-terminal amino acid sequence is homologous to those of other pyruvate kinases, especially of type I and II enzymes from Escherichia coli. The saturation of the pyruvate kinase from Lactobacillus bulgaricus is hyperbolic for ADP and cooperative for the other substrate phospho-enol-pyruvate. The enzyme is strongly activated by glucose-6-phosphate, ribose-5-phosphate, and fructose-6-phosphate, which increase the affinity for phospho-enol-pyruvate. These activators seem to stabilize the same state of the enzyme, since their maximum activations are not additive, but their partial activations can be cumulated. Pyruvate kinase is also weakly activated by AMP and inhibited by fructose-1,6-bisphosphate. However, both AMP and fructose-1,6-bisphosphate act as strong inhibitors in the presence of a strong activator, because these weak effectors suppress the activation by glucose-6-phosphate, ribose-5-phosphate, or fructose-6-phosphate. This mutual exclusion of strong and weak effectors, which appears as an original regulatory mechanism, could reflect either the binding of different effectors to different interacting sites or their competition for a unique polyvalent regulatory site in the pyruvate kinase from Lactobacillus bulgaricus.

Adenosine Diphosphate↗
PubMed1985

Effectors of amino acid transport processes in animal cell membranes.

Various effectors, which act upon ion gradients, protein synthesis, membrane components or cellular functional groups, have been employed to provide insights into the nature of amino acid-membrane transport processes in animal cells. Such effectors, for example, include ions, hormones, metabolites and various organic reagents and their judicious use has allowed the following list of conclusions. Sodium ion has been found to stimulate amino acid transport in a wide variety of cell systems, although depending on the tissue and/or substrate, this ion may have no effect on such transport, or even inhibit it. Amino acid transport can be stimulated in some cell systems by other ions such as K+, Li+, H+ or Cl-. Both H+ and K+ have been found to be inhibitory in other systems. Amino acid transport is dependent in many cell systems upon an inwardly directed Na+ gradient and is stimulated by a membrane potential (negative cell interior). In some cell systems an inwardly directed Cl- and H+ gradient or an outwardly directed K+ gradient can energize transport. Structurally dissimilar effectors such as ouabain, Clostridium enterotoxin, aspirin and amiloride inhibit amino acid transport presumably through dissipation of the Na+ gradient. Inhibition by certain sugars or metabolic intermediates of the tricarboxylic acid cycle may compete with the substrate for the energy of the Na+ gradient or interact with the substrate at the carrier level either allosterically or at a common site. Stimulation of transport by other sugars or intermediates may result from their catabolism to furnish energy for transport. Insulin and glucagon stimulate transport of amino acids in a variety of cell systems by a mechanism which involves protein synthesis. Microtubules may be involved in the regulation of transport by insulin or glucagon. Some reports also suggest that insulin has a direct effect on membranes. In addition, a number of growth hormones and factors have stimulatory effects on amino acid transport which are also mediated by protein synthesis. Steroid hormones have been noted to enhance or diminish transport of amino acids depending on the nature of the hormone. These agents appear to function at the level of protein synthesis. While stimulation may involve increased carrier synthesis, inhibition probably involves synthesis of a labile protein which either decreases the rate of synthesis or increases the rate of degradation of a component of the transport system.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids↗
PubMed1995

Effect of BAY u3405, a thromboxane A2 receptor antagonist, on neuro-effector transmission in canine tracheal tissue.

Thromboxane A2 (TXA2) is reported to potentiate vagal nerve neuro-effector transmission in airway smooth muscle tissue. We investigated the effects of BAY u3405 (3(R)-[[4-fluorophenyl)sulfonyl]amino]-1,2,3,4,-tetrahydro-9H-carbazole - 9-propanoic acid), a potent and selective TXA2 receptor antagonist, on the increase in vagal nerve neuro-effector transmission induced by a TXA2 mimetic, U-46619, in the canine trachea. We measured the contractions of canine tracheal smooth muscle evoked by electrical field stimulation (EFS) and by acetylcholine (ACh) in the presence and absence of a subthreshold dose of U-46619 (the highest dose that did not induce any smooth muscle contraction). We then examined whether BAY u3405 inhibited the effect of U-46619 on tracheal smooth muscle. The following results were obtained: (i) subthreshold doses of U-46619 (10(-10) M and 10(-9) M) significantly increased the amplitude of the contractions evoked by EFS; (ii) by contrast, U-46619 had no effect on the contractile response of smooth muscle to exogenously applied ACh; (iii) the contraction evoked by EFS was completely abolished by the application of atropine (10(-6) M) or tetrodotoxin (10(-7) M), indicating that EFS caused the smooth muscle contraction through the release of ACh from vagal nerve terminals; and (iv) pretreatment with BAY u3405 (10(-6) M) abolished the excitatory action of U-46619 on the amplitude of twitch contraction evoked by EFS in the trachea. These results indicate that U-46619, at low concentrations, has a prejunctional action stimulating neuro-effector transmission, presumably increasing ACh release from vagal nerve terminals through TXA2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗