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PubMed1994

Antibodies to the HIV-1 V3 loop in serum from infected persons contribute a major proportion of immune effector functions including complement activation, antibody binding, and neutralization.

Previous studies have shown that the V3 region of the HIV envelope is both critical to viral functions and immunogenic. However, the relative contribution of anti-V3 antibodies in the sera of infected individuals in mediating immune effector functions directed at whole intact virus and infected cells has not been determined. This study used peptides corresponding to several regions of the HIV envelope as inhibitors of antibody binding and antibody effector functions directed at virions and virus-infected cells in order to assess the relative importance of V3-specific antibodies in sera from infected persons. Approximately 40% of the antibody in serum which could bind to native viral proteins on HIVMN-infected cells was blocked by a peptide corresponding to the central 15 amino acids of the V3 loop. In contrast, little if any blocking of serum antibody binding was observed with peptides corresponding to flanking regions of HIVMN V3 or three regions of gp41. Since antiviral antibody can also activate immune effector functions, we determined whether peptides could block antibody-dependent activation of the complement system by HIV-infected cells or free virus. Surprisingly, the V3 loop peptide blocked 75-95% of complement activation on HIV-infected cells. While the V3 loop peptide also blocked a substantial portion of the neutralizing activity in serum from infected persons for free virus it was again more effective in inhibiting complement-mediated effects on free virus. Accordingly, antibody-dependent, complement-mediated virolysis was inhibited by 61-79%. The results of these experiments indicate that (1) a substantial portion (30-40%) of the antibody in sera from infected persons that is capable of binding to HIV-infected cells and HIV virions is V3-specific, and (2) these V3-specific antibodies are particularly important for complement activation on infected cells and virions. This indicates that the central portion of the V3 loop, while constituting less than 3% of the amino acid sequence of the HIV envelope, apparently provides a major gp160 site for immune effector functions, especially complement activation.

Acquired Immunodeficiency Syndrome↗
PubMed1985

The effect of indomethacin on the activation and effector function of suppressor cells from tumor-bearing mice.

The spleens of mice with large M-1 fibrosarcomas contain two populations of suppressor cells with the properties of macrophages and T cells. In this study, we tested the effect of indomethacin on suppressor cell activation and effector function. Neither the activation nor the effector function of the suppressor macrophages was inhibited by indomethacin, and the activity of suppressor macrophages correlated with the tumor size. In contrast, the treatment of tumor-bearing mice with indomethacin from the day of injection of tumor cells completely blocked the in vivo activation of suppressor T cells. Indomethacin did not, however, depress suppressor T cell activity if mice were treated only during the third week of tumor growth. The effector function of the suppressor T cells, as assessed in mixing assays, was partially blocked by indomethacin, while selective suppression by low-molecular-weight factors was completely blocked if indomethacin was present in the cultures. Furthermore, the in vitro activation of suppressor cells by soluble factors secreted by tumor-bearer spleen cells was completely blocked by indomethacin, and this inhibition was reversed by prostaglandin E1. These data are consistent with the hypothesis that prostaglandins are involved in the activation, but not the effector function, of tumor-activated suppressor T cells.

Animals↗
PubMed1988

Cytolytic antitumor effector cells in long-term cultures of human tumor-infiltrating lymphocytes in recombinant interleukin 2.

Lymphocytes infiltrating human solid tumors (TIL) and autologous peripheral blood lymphocytes (A-PBL) were cultured with 1000 units/ml of recombinant interleukin 2 (rIL2) in long-term cultures. TIL isolated from 26 primary squamous cell carcinomas of the head and neck expanded better (P less than 0.01) and achieved higher total lytic units of activity against fresh tumor cell targets (P less than 0.05) than A-PBL. TIL obtained from primary hepatocellular carcinomas (n = 7) showed a higher degree of expansion than those from metastatic liver tumors (n = 7). Further, TIL from metastatic tumors of the head and neck, liver, and ovary were delayed up to 50 days in their proliferative response to rIL2. Long-term mass cultures in rIL2 of TIL, A-PBL, or normal PBL were serially monitored for cytotoxicity with different cultured and fresh tumor cell targets and for phenotypic markers of the predominating cell populations. Antitumor cytotoxicity was found in cultures enriched in CD3+Leu19+ and/or CD3-Leu19+ cells. Two-color sorting of such cultures followed by cytotoxicity assays confirmed that the human antitumor effectors expressed either the CD3+Leu19+ or CD3-Leu19+ phenotype. CD3+Leu19- cells had little or no antitumor cytotoxicity. The two types of Leu19+ effector cells were present in low numbers in fresh TIL, A-PBL, or normal PBL; in contrast, in some rIL2-expanded long-term cultures, they represented a majority of proliferating cells. This study identifies for the first time two types of antitumor effector cells in rIL2 cultures of human TIL, one of which may represent activated natural killer cells on the basis of the absence of the CD3 and expression of the Leu19 antigen. These antitumor effector cells mediate non-MHC-restricted cytotoxicity of fresh or cultured tumor cell targets of different histologic types.

Cells, Cultured↗
PubMed1981

Differential behavior of cytotoxic effector cells against HLA antigens in strong genetic linkage disequilibrium.

Five sets of cytotoxic effector cells were generated, using haplo-identical, first degree relatives in five different families, against the HLA-A3; B7 serological determinants combined with different DR antigens. When tested against a panel of cells bearing combinations of the HLA-A, -B and -DR antigens it was shown that the HLA-B7 antigen was as strong a CML target determinant alone as it was in the presence of HLA-A3. The strength of the HLA-A3 antigen as target determinant varied. With effector cells primed to the HLA-A3; B7; DR2 haplotype, the A3 antigen alone behaved as a weak target determinant. When the same target cells were tested with the effector cells generated against HLA-A3; B7 without DR2, the A3 antigen behaved as a strong target determinant. A number of target cells lacking the serologically detectable HLA determinants present on the sensitizing HLA haplotype were identified as being killed by specific effector cells. These data suggest either a number of new CML target determinants controlled by different loci or the presence of a single, new locus with multiple alleles controlling CML targets.

Cytotoxicity, Immunologic↗
PubMed1990

A strategy for evaluating lymphokine activation and novel monoclonal antibodies in antibody-dependent cell-mediated cytotoxicity and effector cell retargeting assays.

As novel antibody therapeutics are developed for different malignancies and require evaluation with cells previously uncharacterized as antibody-dependent cell-mediated cytotoxicity (ADCC) targets, efficient description of key parameters of the assay system expedites the preclinical assessment. A strategy is presented to define the behavior of cell lines or cell cultures as targets in ADCC assays, with emphasis on cytokine activation of effectors and attention to contributions of natural killer cells. Features of the target cell, the effector cell, and the assay itself are separately assessed. Target cells are evaluated for the kinetics of chromium labelling and release, and positive and negative control antibodies are selected. Effector cells are evaluated in ADCC for the impact of different donor sources, storage conditions, lymphokine concentration and duration of activation. The assay itself is assessed for the impact of the type of liquid medium, incubation duration, and effector-to-target ratio. Representative data are presented with a model human malignant T cell line, HuT102.

Antibodies, Monoclonal↗
PubMed1991

In vivo distribution and cytokine gene expression by enriched mouse LAK effector cells.

Lymphokine activated killer (LAK) cells administered in combination with interleukin 2 (IL2) can mediate antitumor activity in tumor-bearing mice and advanced cancer patients. Relatively little is known about the mechanism by which adoptively transferred LAK cells plus IL2 mediate these antitumor effects in vivo, and it remains unclear to what extent the actual LAK effector cells can accumulate in tumors. In the present study, enriched cytolytic LAK effector cells were obtained by fractionation of bulk LAK cell cultures on Percoll density gradients. About 95% of the total lytic activity was recovered from the 55% of cells isolated in fraction 2 (Fr2). The cells recovered in Fr2 are mostly large, proliferating lymphoblasts that express either the NK-associated surface markers NK1.1 (38%) or LGL-1 (31%), or the cytotoxic T cell phenotype, Lyt2 (39%). The cytolytic lymphoblasts obtained from Fr2 were radiolabelled with either 111Indium-Oxine (111InOx) which labels all cells in the population, or with 125Iododeoxyuridine (125IUdR) which labels only proliferating cells, and injected iv into mice bearing murine renal cancer (Renca). 111InOx-labeled Fr2 cells migrated mostly to spleen (28%) and liver (35%), with approximately 5% of the injected label detectable in the Renca-bearing kidney by 24 hrs. In contrast, Fr2 cells labeled with 125IUdR, which labels only the proliferating blasts thought to include the actual effector cells, exhibited a very different localization pattern. 125IUdR-Fr2 cells were retained in the lungs at higher levels than were 111InOx-Fr2 cells and very little label was detectable in liver (6%), spleen (3%), or tumor bearing kidney (2%) at 24 hrs. These results suggest that most of the large, proliferating lymphoblasts are cleared from the body by 24 hrs and very few localize into even large tumors. Subsequently, Northern blot analyses performed on bulk LAK cells revealed a potent induction of mRNA for TNF alpha by 6 hrs and for IFN gamma by 48 hrs. The intensity of gene expression for both cytokines was increased in Fr2 as compared to the unfractionated bulk LAK cells or to non-cytolytic cells obtained from Fr3. Overall, these results suggest that at least some of the antitumor effects mediated by LAK cells occur by the release of cytokines that synergize with exogenous IL2 for the activation of host effector cells.

Animals↗
PubMed1978

A mechanism for indirect allosteric action of charged effectors.

A mechanism for indirect allosteric action of charged effectors on substrate binding to a macromolecule is proposed. It is accounted for by electrostatic interaction among effectors in the solution, away from their receptors. The possibility of the mechanism proposed is tested in the allosteric action of univalent salt and 2,3-diphosphoglycerate on oxygen binding to hemoglobin. A model for electrostatic interaction between these two effectors in the solution and for their overall effect on oxygen binding is introduced. The 2,3-diphosphoglycerate binding constant to deoxygenated hemoglobin as a function of univalent salt concentration and the median ligand activity as a function of the concentration of univalent salt and 2,3-diphoshoglycerate are calculated and compared with experimental data. The obtained results indicate that electrostatic interaction in the solution may significantly contribute to indirect allosteric action of charged effectors.

Allosteric Regulation↗
PubMed2005

Effector-dependent and response location learning of probabilistic sequences in serial reaction time tasks.

We investigated the contributions of the sequences of effectors and response locations to probabilistic sequence learning in the serial reaction time task by means of bimanual transfer. Participants, trained with the dominant hand, were either required to maintain responding with the dominant hand after transfer or to switch to the nondominant hand. For both groups, half of the participants were transferred to the originally trained sequence, whereas the other half was transferred to a mirror-ordered sequence. This way, the sequence of effectors varied independently of the sequence of response locations. Sequence learning was assessed with probabilistic sequences, composed of either first-order or second-order probabilities. Transfer of sequence knowledge to the nondominant hand was equally good for the originally trained sequence as for the mirrored sequence. This suggests that probabilistic sequence learning can be based on either the sequence of effectors or response locations. However, when participants responded with the dominant hand to a mirrored sequence, transfer performance was disturbed. This indicates that changing both the sequences of effectors and response locations has a disruptive effect on the learning performance.

Adult↗
PubMed2005

Action observation supports effector-dependent learning of finger movement sequences.

Practising a motor skill can result in effector-dependent learning (learning that does not transfer from the set of muscles used in training to a new set of muscles). Proceeding from neurophysiological evidence of motor activation during action observation, this study asked whether observational learning, learning through observation of skilled performance, can also be effector-dependent. Adult human participants observed a model's right hand as the model responded to an eight-item sequence in a serial reaction time (SRT) task. Their sequence learning was then compared in two tests with that of controls who had observed the model's right hand responding to random targets during training. All participants performed the SRT task with their right hand in the first test and with their left hand in the second. Evidence of observational learning was obtained in the right hand test but not in the left hand test. This implies that sequence learning based on observation of right hand performance did not transfer to the left hand, and therefore that observational learning can support effector-dependent learning of finger movement sequences. A second experiment used the same procedure to assess learning by a group of participants who observed a sequence of response locations only. This group did not observe the model's responses. Results suggested that action observation was necessary for the effector-dependent observational learning demonstrated in Experiment 1.

Adult↗
PubMed2003

Recombinant immunotoxins and retargeted killer cells: employing engineered antibody fragments for tumor-specific targeting of cytotoxic effectors.

Over the past years, monoclonal antibodies have attracted enormous interest as targeted therapeutics, and a number of such reagents are in clinical use. However, responses could not be achieved in all patients with tumors expressing high levels of the respective target antigens, suggesting that other factors such as limited recruitment of endogenous immune effector mechanisms can also influence treatment outcome. This justifies the search for alternative, potentially more effective reagents. Antibody-toxins and cytolytic effector cells genetically modified to carry antibody-based receptors on the surface, represent such tailor-made targeting vehicles with the potential of improved tumor localization and enhanced efficacy. In this way, advances in recombinant antibody technology have made it possible to circumvent problems inherent in chemical coupling of antibodies and toxins, and have allowed construction via gene fusion of recombinant molecules which combine antibody-mediated recognition of tumor cells with specific delivery of potent protein toxins of bacterial or plant origin. Likewise, recombinant antibody fragments provide the basis for the construction of chimeric antigen receptors that, upon expression in cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells, link antibody-mediated recognition of tumor antigens with these effector cells' potent cytolytic activities, thereby making them promising cellular therapeutics for adoptive cancer therapy. Here, general principles for the derivation of cytotoxic proteins and effector cells with antibody-dependent tumor specificity are summarized, and current strategies to employ these molecules and cells for directed cancer therapy are discussed, focusing mainly on the tumor-associated antigens epidermal growth factor receptor (EGFR) and the closely related ErbB2 (HER2) as targets.

ErbB Receptors↗
PubMed2003

Dendritic cell and effector cell infiltration in soft tissue sarcomas with reactive lymphoid hyperplasia.

The lymph node is the site of antigen presentation, and dendritic cells are sentinels for anti-tumor immunity. However, little is known about the histological features of lymph nodes and dendritic cells in soft tissue sarcomas. The reactive lymph node and infiltration of dendritic cells or effector cells were studied histologically in 10 soft tissue sarcomas with reactive lymphoid hyperplasia. The cases included four malignant fibrous histiocytomas, two malignant peripheral nerve sheath tumors, one synovial sarcoma, one epithelioid sarcoma, one malignant granular cell tumor, and one liposarcoma. The proportions of the T zone, lymphoid follicle, and lymphoid sinus (which was occupied by cells immunopositive for antibodies against CD3, CD20, or CD68) were 33.4% +/- 11.0%, 6.1% +/- 4.9%, and 13.5% +/- 6.5%, respectively. T zone hyperplasia was observed in all cases, and sinus histiocytosis was found in four. The proportion of the T zone in regional lymph nodes of soft tissue sarcoma patients was significantly higher than that in adult autopsy cases without a cancer history. CD8-, TIA-1-, or granzyme B-positive effector cells were found in each sarcoma tissue. Whereas CD1a-positive dendritic cells were not detected, S-100 protein-positive or CD83-positive dendritic cells were observed in five sarcoma tissues. The coefficient correlation between the numbers of effector cells and dendritic cells positive for CD83 or S-100 protein were demonstrated. Although this is a preliminary report, the present study demonstrated that some soft tissue sarcoma patients showed reactive lymphoid hyperplasia. Furthermore, the association between the infiltration of dendritic cells and that of effector cells was observed in patients with soft tissue sarcomas.

Adolescent↗
PubMed2006

Apoptosis effector mechanisms: a requiem performed in different keys.

Apoptosis is the regulated form of cell death utilized by metazoans to remove unneeded, damaged, or potentially deleterious cells. Certain manifestations of apoptosis may be associated with the proteolytic activity of caspases. These changes are often held as hallmarks of apoptosis in dying cells. Consequently, many regard caspases as the central effectors or executioners of apoptosis. However, this "caspase-centric" paradigm of apoptotic cell death does not appear to be as universal as once believed. In fact, during apoptosis the efficacy of caspases may be highly dependent on the cytotoxic stimulus as well as genetic and epigenetic factors. An ever-increasing number of studies strongly suggest that there are effectors in addition to caspases, which are important in generating apoptotic signatures in dying cells. These seemingly caspase-independent effectors may represent evolutionarily redundant or failsafe mechanisms for apoptotic cell elimination. In this review, we will discuss the molecular regulation of caspases and various caspase-independent effectors of apoptosis, describe the potential context and/or limitations of these mechanisms, and explore why the understanding of these processes may have relevance in cancer where treatment is believed to engage apoptosis to destroy tumor cells.

Animals↗
PubMed1986

Stimulation of protein methylase II from Torpedo marmorata by cholinergic effectors.

The enzymatic transfer of methyl groups mediated by protein methylase II onto proteins of the electroplaque tissue of Torpedo marmorata is described. The protein methylase II resides to the extent of 80% in the cytosol and 20% in the acetylcholine receptor-rich membrane. The kinetics of the methyl-group transfer are characteristically different in the cytosol and membrane fractions. The reaction is inhibited by phosphate with IC50 = 450 microM. The cholinergic effectors carbamoylcholine, flaxedil and alpha-bungarotoxin applied to the outside of the acetylcholine receptor-rich membrane vesicles stimulated the protein methylase II which is exclusively located inside the vesicles. The stimulation is biphasic and transient, yielding an increased initial velocity and a peak of activity at 2 min after the addition of the effector. The stimulation by carbamoylcholine is qualitatively similar to that elicited by the antagonist. In addition, the protein methylase II is stimulated transiently by phospholipase A2 with a time-course clearly different from that of the cholinergic effectors. We conclude that the conformational change in the receptor-protein elicited by cholinergic effectors is efficiently transduced to the cytoplasmic methylation sites.

Animals↗
PubMed1984

Interaction of cardiac glycosides and Na,K-ATPase is regulated by effector-controlled equilibrium between two limit enzyme conformers.

The paper describes the dissociation parameters of the complexes between [3H]-digitoxin and Na,K-ATPase (Na+ + K+-activated, Mg2+-dependent ATP phosphohydrolase, E.C. 3.6.1.3) from pig cardiac muscle and brain cortex formed and dissociated in the presence of different combinations and concentrations of the enzyme effectors ATP, Mg2+, Na+ and K+. Systematic variation of effector-ligation of Na,K-ATPase allowed production of glycoside complexes with two enzyme conformers only, which showed either rapid or slow dissociation kinetics. Appropriate changes of enzyme ligation allowed the interconversion of the two conformer types. Biphasic, rapid and slow glycoside release was not bound with the presence of two Na,K-ATPase isozymes, but caused by the enzyme ligation-determined coexistence of the two conformers of Na,K-ATPase. The rate constants for the rapid and slow glycoside release were within the complexes of each dissociation type much alike indicating uniform isomerization kinetics of the two conformers even when differently liganded. Taken together, the observations indicated the effector-controlled isomerizations of two conformers of Na,K-ATPase possessing different geometries of the glycoside binding domain. Present findings and relevant literature data were integrated in a circular, consecutive and simultaneous model for induced conformation changes that accounted for the regulation of the interaction of cardiac glycosides and Na,K-ATPase through an effector-controlled equilibrium between two limit enzyme conformers.

Adenosine Triphosphate↗
PubMed1987

Glutamate suppression of feeding and the underlying output of effector neurons in Helisoma.

This study tested the consequences of 3 stress conditions on feeding consumption in the freshwater snail Helisoma. Two stresses (placement in a hypotonic environment and body wall incision) were without effect on food consumption. In contrast, placement of animals in a hypertonic environment (20% seawater) caused a transient suppression of feeding. Since the osmolarity and composition of molluscan blood is known to be altered under conditions of osmotic stress, we reasoned that a blood-borne agent might be responsible for the observed suppression of feeding. We tested this hypothesis by chromatographic analysis of blood and, based on this analysis, subsequent assay of putative neuromodulatory agents on the patterned motor activity (PMA) expressed by effector neurons of the buccal ganglion. Our analysis shows that a rise and fall of blood acidic amino acids corresponds to the suppression of feeding. Furthermore, bath application of glutamate at its elevated physiological level (100-150 microM) to buccal ganglia caused complete and prolonged suppression of PMA in effector neurons. This suppression is attributable to activation of chloride and potassium currents which shunt patterned synaptic inputs to the effector neurons. We conclude that glutamate, in an endocrine-like fashion, can exert a powerful neuromodulatory action on the feeding effector neurons of Helisoma.

Amino Acids↗
PubMed1983

Adoptive transfer of experimental autoimmune thyroiditis (EAT) in guinea pigs: requirement for Ia-positive antigen-presenting cells for in vitro activation of effector T cells.

Lymph node T cells from guinea pigs sensitized in vivo with guinea pig thyroglobulin (GPTG) could transfer experimental autoimmune thyroiditis (EAT) to normal syngeneic recipients after in vitro culture with GPTG or GPTG-pulsed peritoneal exudate cells (PEC). Although EAT effector T cells have been shown previously to be Ia negative at the time of transfer, the addition of specific anti-Ia serum to the cultures inhibited effector cell activation. The inhibitory effect of anti-Ia on effector-T-cell activation was shown to be due to inhibition of the function of antigen-presenting PEC rather than to an effect on the sensitized T cell. Moreover, only Ia-positive PEC could present antigen in this system and Ia matching between the PEC and the T cell was required for effective T-cell activation. GPTG-pulsed Strain 2 (EAT susceptible) and Strain 13 (EAT resistant) PEC could both present antigen to T cells from 2 X 13 F1 guinea pigs although Strain 2 PEC were more effective, suggesting that defective antigen presentation by macrophages may at least partially explain the relative resistance to EAT of Strain 13 guinea pigs. These results indicate that interaction between Ia-positive PEC and sensitized T cells in vitro is necessary for the development of active effector T cells that can transfer EAT.

Animals↗
PubMed1988

Cloned cytotoxic T lymphocyte target cells fail to induce early activation events in effector cytotoxic T lymphocytes.

We have explored further the basis for resistance of cloned cytotoxic T lymphocytes (CTLs) to cell-mediated cytotoxicity. We find that most cloned CTLs recognized as specific target cells by other cloned CTLs used as effector cells fail to activate three early events that may be critical in triggering lysis in the effector CTLs: Ca2+ influx, microtubule organizing center (MTOC) reorientation, and serine esterase release. To the extent that any or all of these events are involved in activation or expression of the lytic pathway in effector CTLs, our results suggest that in addition to being inherently resistant to cytotoxic granule extracts, many CTLs are also unable to induce lytic function in other (effector) CTLs. We have found one CTL clone that can respond to recognizable cloned CTL target cells with at least MTOC reorientation and serine esterase release, although the target CTLs are still not lysed. In this case, the resistance of the target CTL to lysis may be due solely to its resistance to cytoplasmic granule contents.

Animals↗
PubMed1991

The principal tumor necrosis factor receptor in monocyte cytotoxicity is on the effector cell, not on the target cell.

Several tumor target cell lines, prototypically K562 cells, are resistant to lysis by recombinant tumor necrosis factor (TNF alpha) but are killed by monocytes expressing membrane-associated TNF, suggesting that membrane TNF could account for monocyte-mediated cytotoxicity. Formaldehyde-fixed monocytes or extracted monocyte membrane fragments are cytotoxic to K562 target cells. Treatment of monocytes with interferon-gamma (IFN-gamma) increases cytotoxicity by live and fixed cells or by extracted monocyte membranes. Both TNF and TNF receptors are detectable on monocyte membranes by FACS analysis, and the levels of each are modulated by treatment with IFN-gamma. Cytotoxicity can be inhibited by either anti-TNF or anti-TNF receptor antibodies. Incubation of effector cells with exogenous soluble TNF prior to fixation or membrane preparation increases their cytotoxicity. In contrast, incubation of the target cells with exogenous TNF neither increases nor decreases killing by effector cell membrane fragments or intact effector cells. The data suggest that the TNF receptors on the effector cell, but not on the target cell, play a crucial role in TNF-mediated cytotoxicity.

Cytotoxicity, Immunologic↗