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PubMed1980

The antibody-dependent cell-mediated cytotoxic reaction. II. The effect of the concentration of anti-target cell antibodies on the identity of the human effector cells.

The circulating leucocytes of normal adults (lymphocytes, monocyte-lymphocyte mixtures and neutrophils) were investigated for their capacity to induce antibody-dependent cell-mediated cytotoxicity (ADCC). The target cell was the rabbit antibody-sensitized chicken erythrocyte. Under conditions of optimal target cell sensitization by anti-target cell antibodies, ADCC cytotoxic activity was exhibited by the neutrophils and lyphocytes to the apparent exclusion of the monocytes. The lymphocytes exhibit activity more rapidly than do the neutrophils and they are more active on an equal cell basis. However, when the effector cells were investigated using target cells sensitized with the anti-target cell antiserum in a threshold concentration, the monocyte and not the lymphocyte or neutrophil displayed ADCC cytotoxic activity. It was concluded that the effector cells in the circulation are heterogeneous and include subclasses of lymphocytes, monocytes and neutrophils and that the identity of the cytotoxic effector cells appears to vary with the concentration of anti-target cell antibodies.

Antibodies↗
PubMed1995

Conjugate formation between effector and target as a function of cytotoxicity in antibody-dependent killing of AK-5 tumor.

The present study was carried out to mechanistically view a possible correlation between the process of, conjugate formation and its relation to target cell death. AK-5 killing is mediated by CD8+ natural killer cells through ADCC. Immune effectors on exposure to antibody primed AK-5 tumor cells formed tight conjugates. Ability of various cell types (NK, T, monocytes and macrophages) to form conjugates was evaluated. Marked increase in the number of NK cells binding to the target as compared to the other cell types was observed. Cytotoxicity of free and bound effectors against antibody tagged AK-5 cells demonstrated a reduced cytotoxic ability of the former in contrast to a significantly high lytic potential of the bound effectors. The results highlight the requirement for priming of NK cells which mediate killing of AK-5 tumor and provide additional evidence that formation of stable conjugates acts as the first signal for triggering lymphocyte activation and effective target cell lysis.

Animals↗
PubMedDate not supplied

Renaissance of the effector role of the mast cell in bronchial asthma.

The mast cell, by virtue of its capacity to release a wide range of pro-inflammatory mediators, its abundant expression of the high-affinity receptor for immunoglobulin E and its strategic location in proximity to blood vessels, mucosal surfaces and smooth muscle, had long been considered as the central effector cell in asthma and other allergic diseases. In recent years there has been a tendency for less importance to be attached to this cell as a central effector in asthma. New findings, however, have led to a resurgence of interest in the mast cell and supported a reevaluation of its role. In particular the discovery that mast cells are a potential source of cytokines has suggested new ways in which mast cell activation could also participate in more persistent and even chronic inflammatory responses which we know are central to the pathophysiology of asthma. This review will address: 1) the main aspects of mast cell biology which are relevant to asthma with particular reference to mediators produced and their biological functions; 2) the evidence implicating the mast cell as an effector cell in both the immediate and delayed airway responses to allergen exposure; 3) how acknowledgement that mast cells act as a source of cytokines permits speculation on their involvement in the chronic inflammatory response of asthma.

Adenosine↗
PubMed1995

Muscarinic acetylcholine receptors: signal transduction through multiple effectors.

Muscarinic receptors regulate a number of important basic physiologic functions including heart rate and motor and sensory control as well as more complex behaviors including arousal, memory, and learning. Loss of muscarinic receptor number or function has been implicated in the etiology of several neurological disorders including Alzheimer's dementia, Down's syndrome, and Parkinson's disease. Muscarinic receptors transduce their signals by coupling with G-proteins, which then modulate the activity of a number of effector enzymes and ion channels. Five subtypes of muscarinic receptors (m1-m5) have been identified by molecular cloning and much has been learned about their distribution, pharmacology, and structure. Less is known about the molecular mechanisms of receptor-effector coupling and the biological role of each receptor subtype. The ectopic expression of genes encoding a single muscarinic receptor subtype in mammalian cell lines has provided an important model system in which to investigate receptor subtype-specific pharmacology and signal transduction. Expression models have revealed that single muscarinic receptor m1, m3, or m5 subtypes can activate multiple signaling effectors simultaneously including phospholipases A2, C, and D, as well as tyrosine kinase and a novel class of voltage-insensitive calcium channels. The m2 or m4 receptors have been shown to augment phospholipase A2 in addition to their established role as inhibitory receptors acting through the attenuation of adenylate cyclase. In addition to allowing investigations of the regulatory mechanisms of muscarinic receptors, expression models provide an excellent tool to investigate receptor-subtype specific physiology and pharmacology.

Adenylyl Cyclases↗
PubMed1994

Heterotrimeric G proteins containing G alpha i3 regulate multiple effector enzymes in the same cell. Activation of phospholipases C and A2 and inhibition of adenylyl cyclase.

Previous studies have shown that a single type of transmembrane receptor is able to regulate multiple effectors through the activation of heterotrimeric G proteins. For example, the m2 muscarinic acetylcholine receptor (mAChR) expressed in Chinese hamster ovary (CHO) cells inhibits adenylyl cyclase, stimulates phospholipase C-dependent intracellular Ca2+ release, and activates phospholipase A2 through pertussis toxin-sensitive G proteins. However, it is unclear whether multiple effector enzymes can be regulated by one type of heterotrimeric G protein within a single cell. To investigate this question, we constructed a derivative of G alpha i3 (termed G alpha i3 C > S) in which the carboxyl-terminal cysteine residue, the site for pertussis toxin modification, was changed to a serine. Following pertussis toxin treatment of transfected CHO cells expressing the m2 mAChR, we found that the G alpha i3 C > S protein underwent guanine nucleotide exchange in response to the muscarinic agonist carbachol, while the m2 mAChR failed to activate the endogenous G alpha i2 and G alpha i3 proteins. Moreover, coupling of heterotrimeric G proteins containing G alpha i3 C > S to the m2 mAChR resulted in pertussis toxin-resistant inhibition of adenylyl cyclase, stimulation of phospholipase C-induced intracellular Ca2+ release, and phospholipase A2-mediated arachidonic acid release. Therefore, these studies provide conclusive evidence that heterotrimeric G proteins containing just G alpha i3 can regulate multiple effector enzymes within the same cell type.

Adenylate Cyclase Toxin↗
PubMed1994

Commonality of the gene programs induced by effectors of apoptosis in androgen-dependent and -independent prostate cells.

Prostate tissue is composed of both androgen-dependent and -independent cells. To identify the gene program induced by effectors of apoptosis in both of these cell types, we performed differential hybridization on a complementary DNA library prepared from an androgen-independent prostate cancer cell line, AT-3, exposed to ionomycin. Five distinct complementary DNAs representing ionomycin-inducible genes, designated prostate apoptosis response (par) -1, -2, -3, -4, and -5, were identified. Nucleotide sequencing identified par-1 as the rat homologue of a serum- and oxidative stress-inducible gene, 3CH134/erp/CL100; par-2 as the injury-inducible gene HB-EGF encoding a heparin-binding epidermal growth factor-like growth factor; par-3 as the serum-inducible gene cyr-61; whereas par-4 and par-5 were novel, as judged by a GenBank search. par-1, -3, -4, and -5 were also induced in rat ventral prostate following castration, which causes androgen ablation, leading to apoptosis of androgen-dependent prostate cells. Pretreatment of rats with nifedipine prior to castration abrogated inducible expression of the par genes, indicating that their expression was downstream to Ca2+ elevation. Further characterization of these genes revealed that induction of par-4 is apoptosis specific: it is not induced by effectors of growth stimulation, oxidative stress and necrosis, or growth arrest in prostate cells. Together, par-1, -3, -4, and -5 represent an apoptosis response gene program common to both androgen-dependent and -independent prostate cells. Thus, cell death programs in prostate cells are comprised of genes specifically associated with apoptosis as well as those with multifunctional roles in growth regulation. Since elevation of intracellular Ca2+ is central to apoptosis in many cell types, we predict that par genes will be important components of diverse effector-driven apoptotic pathways.

Androgens↗
PubMed1993

Natural killer cells as effector cells of graft-versus-leukemia activity in a murine transplantation model.

The transfer of cytotoxic effector cells reduces the risk of relapse after allogeneic BMT. Two murine leukemia cell lines, A20 (B lymphocytic) and WEHI-3 (myelomonocytic), were used to investigate antileukemic effector mechanisms operating independently from graft-versus-host disease (GVHD). Different results were obtained with the two leukemia models. After injection of A20 cells, the majority of Balb/c recipients treated with syngeneic BMT died due to leukemia relapse (89%). The transplantation of MHC-matched DBA marrow resulted in chronic GvHD but did not reduce the risk of relapse (86%). Grafting of MHC-mismatched (but GvH-nonreactive) marrow cells from (C57xBalb)F1 hybrids, however, led to a significantly lower relapse rate (47%, p < 0.05). In vitro testing revealed that F1 cells but not Balb/c or DBA cells exert NK cell activity against A20. The elimination of NK 1.1-positive cells from the graft reduced the antileukemic activity of (C57xBalb)F1 marrow against A20 in vivo. After injection of WEHI-3 leukemia cells, syngeneic BMT cured most of the recipients (62%) and transplantation of (C57xBalb)F1 marrow provided no additional benefit. In contrast to unmanipulated Balb/c and (C57xBalb)F1 cells, which showed no NK activity against WEHI-3 in vitro, IL-2 treated effector cells were highly cytotoxic. Transfer of IL-2 preincubated grafts significantly decreased the relapse rate of WEHI-3 (19 vs. 38%) after syngeneic and allogeneic BMT. Our data indicate that GvL activity can be separated from GvHD. In our murine model, GvL activity appears to depend more on the donors NK/LAK cell activity than on the presence or absence of GvHD.

Animals↗
PubMed1993

Interleukin-2 antitumor and effector cell responses.

Based on the above considerations, there are a number of implications for the clinical development of rIL-2 that depend on the putative effector cell. If the effector cell responsible for rIL-2-mediated antitumor effects is the LAK cell, effective treatment regimens will likely continue to require extremely high doses of rIL-2. Based on preclinical models, one would also predict that LAK cell-mediated tumor killing against nonimmunogenic tumors would be most effective in low tumor burden states and could only be demonstrated clinically in large-scale, randomized, adjuvant trials. On the other hand, some weakly immunogenic tumors might be susceptible to CTL-mediated killing even when disease was further advanced. The antitumor activity of rIL-2 in patients with large tumors suggests that this might be the case for some patients with RCC. Treatment approaches that result in the generation of relevant effector cell populations would be expected to markedly enhance CTL-dependent rIL-2 antitumor activity. However, unless antigenic heterogeneity was minimal, multiple tumor antigen-specific T-cell populations would have to be generated for responses to be complete and durable.

Animals↗
PubMedDate not supplied

[The effect of new biologically active substances on effector T-lymphocytes in vitro].

Levamisole has been demonstrated to stimulate the activity of T effectors in patients with rheumatic arthritis directly and indirectly via production of the factors influencing effector functions. The organosilicon compound minval was beneficial both in patients and donors. Its activity was mediated by the production of factors in donors, whereas in patients it showed direct and indirect actions, being higher than that of levamisole. The bioflavonoid derived from the Rosa L. root was shown to exert no action on T-effector function.

Adjuvants, Immunologic↗
PubMed1993

Characterization of Ras effector mutant interactions with the NF1-GAP related domain.

The GTPase activating proteins Ras GAP and the neurofibromatosis-type 1 (NF1) gene product have been implicated as both potential mediators and regulators of the mitogenic effects of the ras proteins. In this study, the interactions of selected Ras effector mutants with the NF1-GAP related domain (NF1-GRD) were investigated. The NF1-GRD was unable to stimulate the GTPase of Ras[Asn33], Ras[Ser35] or Ras[Asn38], all transformation defective mutants. Each of these mutants had reduced but detectable binding to the NF1-GRD (apparent KD of 9 microM, 4 microM and 2 microM respectively, vs 0.5 microM for normal Ha-ras). The NF1-GRD was able to fully stimulate the intrinsic GTPase of the transformation-defective Ras[Gly26Ile27] and Ras[Glu45] mutants, each of which bound the NF1-GRD with wild type affinity or better (KD = 0.13 microM and 0.4 microM respectively). The transforming Ras[Glu30Lys31] protein showed no GTPase stimulation and bound most poorly to the NF1-GRD (apparent KD of 16 microM). The interaction of the NF1-GRD with these specific Ras effector mutations is similar to that observed for Ras GAP. When the relative transforming activity of the valine 12 form of each Ras mutant was plotted against the apparent KD for NF1-GRD binding, little correlation was observed. These results support the hypothesis that the NF1 gene product does not function as a downstream effector of Ras in the mitogenic pathway.

Amino Acid Sequence↗
PubMed1993

Different structural organization of Ras and Rho effector domains.

Ras regulates proliferation and differentiation signals in cells, and activation of the protein can lead to malignant transformation. Activation of the related protein, Rho, affects cell morphology, and it has been suggested that it may also have some oncogenic potential. We show here that Rho does not induce a malignant phenotype in NIH3T3 cells but instead is a potent activator of actin stress fibre formation. The limited homology between Ras and Rho has enabled us to determine the amino acids specifying their different biological activities and GTPase-activating protein (GAP) protein sensitivities using chimeras. Rho substituted with amino acids 23-46 of Ras induces transformed foci in NIH3T3 monolayers, and we conclude that Ras has a single effector domain required for downstream signalling. Although mutational analysis of Rho has revealed that residues 32-42 are also essential for its biological activity, Ras substituted with amino acids 25-48 of Rho does not induce actin stress fibre formation. On the basis of these experiments, we propose that Rho may have two effector domains: one at amino acids 32-42 and corresponding to the effector region of Ras and the second located elsewhere in the carboxy-terminal two-thirds of the molecule.

3T3 Cells↗
PubMed1993

The influence of effectors and subunit interactions on Escherichia coli carbamoyl-phosphate synthetase studied by differential scanning calorimetry.

Differential scanning calorimetry of Escherichia coli carbamoyl-phosphate synthetase and its isolated large and small subunits reveals in each case an irreversible, kinetically controlled transition, at a temperature 14 degrees C higher for the holoenzyme than for the subunits, indicating dramatic stabilization of the subunits in the heterodimer. The deletion of the COOH-terminal 171 (mutant CarB'2373) or 385 (mutant CarB2177) residues of the large subunit results in more asymmetric transitions at a temperature 7 degrees C lower than for the wild type. The allosteric effectors IMP, UMP, and ornithine induce small reversible transitions at low temperature in the endotherm for the wild-type enzyme, but not for CarB'2373, as expected if the effectors bind in the 171-residue, COOH-terminal region. In contrast, two ligands that bind outside the deleted region, Ap5A (a ligand of both ATP sites) and glycine (an analog of glutamine) decrease and increase, respectively, the stability of the two mutants and of the wild type. The stabilization by glycine requires that the subunits are associated. The results support the implication of the 20-kDa COOH-terminal domain of the large subunit in the allosteric modulation by all the effectors and are consistent with the folding of the large subunit as a pseudohomodimer of its two homologous halves.

Allosteric Regulation↗
PubMed1995

[Interaction of derivatives of short oligonucleotides with nucleic acids. I. Effect of various types of effectors on alkylation of DNA-targets].

It was shown that the tandem of the derivatives of short oligonucleotides efficiently and site specifically interacts with target 20 base deoxyribonucleotide (M). It was demonstrated that the very low hybridization ability of tetranucleotide (D) and its 3'-cholesterol and 3'-estrone esters (D-ChS and D-EsS, respectively) increases significantly in the presence of the effectors: octanucleotides (E1 and E2), and their 5',3'-diphenazinium (Phn-E1-Phn and Phn-E2-Phn) and 5'-cholesteryl-3'-phenazinium (ChS-E1-Phn and ChS-E2-Phn) derivatives, which flank them on the target strand. The influence of the effectors on the interaction of the target M with tetranucleotide D or its alkylating derivatives (RCl-D) increases in a series E1 + E2 < ChS-E1-Phn + ChS-E2-Phn < Phn-E1-Phn + Phn-E2-Phn. For the steroid derivatives, D-ChS and D-EsS, and the reagents based on them (RCl-D-ChS and RCl-D-EsS), this series is E1 + E2 < Phn-E1-Phn + Phn-E2-Phn < ChS-E1-Phn + ChS-E2-Phn. The modification level of the target M with derivatives RCl-D-EsS in the presence of ChS-E1-Phn and ChS-E2-Phn reaches 40% even at 37 degrees C under conditions close to physiological. The possibility of using 5'-cholesteryl-3'-phenazinium-containing oligonucleotides as effectors of the interaction of target DNA with the derivatives of short oligonucleotides was demonstrated.

Alkylation↗
PubMed1996

H-2Dp transgene alters natural killer cell specificity at the target and effector cell levels. Comparison with an H-2Dd transgene.

The expression of MHC class I molecules is an important determinate of natural killer (NK) cell specificity. The missing self hypothesis proposes that NK cells express receptors for self-MHC class I molecules so that target cells that share MHC class I alleles with the NK cells are not killed by those NK cells. However, some effector cells fail to kill some allogeneic target cells suggesting that shared motifs between different MHC class I alleles can interact with the effector cell class I receptors and prevent lysis. We have used transgenic mice to critically assess whether different MHC class I alleles can exert common influences on NK cell specificity at the host/effector and target cell levels. The specificity of NK cells have been compared between C57BL/6 (H-2b) mice and B6DP (H-2b, H-2Dp) and D8 (H-2b, H-2Dd) transgenic mice. The data indicate that H-2Dp and H-2Dd confer similar protection and specific lysis, such that NK cells from either of the H-2Dp or H-2Dd transgenic mice kill nontransgenic target cells yet they do not kill either of the transgenic target cells. The expression of an H-2Dp transgene also provides protection for C57BL/6 lymphoblasts from allogeneic BALB/c (H-2d) NK cells. Furthermore, H-2Dp and H-2Dd transgenic target cells are lysed to a similar extent by H-2k effector cells. These data suggest that H-2Dp and H-2Dd may be able to inhibit the same NK cell population. This may occur through a shared motif recognized by the same receptor, or different motifs recognized by different, but co-expressed receptors.

Animals↗
PubMed1977

[Mechanism of the regulatory influence of an effector cell on noradrenaline-H3 uptake by an adrenergic neuron].

In isolated organs of the white rat, activation of neuronal absorption of noradrenaline-H3 under action of alpha-adrenoblocking agent phentolamine (1-10(-6) M) was due to release of a humoral factor from the effector cell and its effect on the adrenergic neuron. Under influence of activating agent for alpha-adrenoreceptors mesatone (1-10(-5) M), formation and release of humoral factor inhibiting the neuronal absorption of noradrenaline-H3, occurrs. Formation of the humoral factors altering the intensity of amine absorption is associated with activation of the protein synthesis in effector cell and occurs on alteration of functional state (excitation and blockade) of postsynaptic adrenoreceptors. A possible way for the reverse transsynaptic control of neuronal absorption of noradrenaline via adrenoreceptors of effector cell, and the role of this regulatory mechanism in activity of adrenergic system, are discussed.

Animals↗
PubMed1996

Effector mechanisms in demyelinating neuropathies.

While the cause of the immune-mediated neuropathies (Guillain-Barr-e syndrome, GBS; CIDP; multi-focal motor neuropathy and paraproteinemic neuropathies) remains elusive considerable progress has been made in delineating the effector mechanisms that underlie myelin destruction. In GBS circulating antibodies to glycolipids possibly precipitated by an antecedent Campylobacter jejuni infection can be detected with high frequency. These antibodies may interfere with neuromuscular transmission and eventuate myelin damage by activating the complement system, providing for the generation of chemotactically active split products C3a and C5a, the opsonin C3b, and assembly of the membrane attack complex. Such antibodies may also, via binding to the Fc receptor, target macrophages to the myelin sheath. Corroborative evidence for a crucial pathogenic role of antibody-mediated complement activation is also available for the MAG-associated neuropathies. Macrophages as decisive effector cells of myelin damage may also act by releasing injurious molecules such as oxygen radicals, nitric oxide metabolites, proteases, eicosanoids and cytokines. Demyelinative as well as degenerative actions have been described for the cytokines TNF-alpha and lymphotoxin. Increased understanding of the effector mechanisms underlying demyelination may aid in developing more efficacious treatments for this group of neuropathies.

Autoantibodies↗
PubMed1997

Differential expression of transcription directed by a discrete NF-AT binding element from the IL-4 promoter in naive and effector CD4 T cells.

Acquiring the ability to selectively produce IFN-gamma or IL-4 is a fundamental property of the immune system and enables T cell subsets (Th1, Th2) to deliver their effector functions. To create an experimental system to examine regulation of critical promoter elements within the IL-4 gene, we have prepared and analyzed transgenic mice expressing the luciferase gene under the control of the distal NF-AT binding site from the IL-4 promoter. This site is immediately adjacent to an AP-1 site, and this NF-AT/AP-1 composite site is termed either P1 or PubB. The distal NF-AT site we have used to prepare these reporter transgenic mice lacks the AP-1 binding site but contains the NF-AT binding site (P1(NF-AT)) These transgenic mice were also intercrossed with transgenic mice expressing a single MHC class II-restricted TCR. Expression of transcriptional activity under the control of P1(NF-AT) was observed only in effector T cells, and not naive T cells, after stimulation with Ag or polyclonal stimuli. By contrast, gel mobility shift assays showed that nuclear extracts from both naive and effector T cells contained NF-AT, which could effectively bind to the P1(NF-AT) element. IL-4-stimulated Th2 differentiation did not increase the TCR responsiveness of the P1(NF-AT) element by more than 2-fold but increased production of IL-4 protein by more than 10-fold. These data suggest that factors interacting with the P1(NF-AT) element regulate transcriptional activity in a naive/effector T cell-specific manner but not in a Th1/Th2-specific manner. Th1/Th2-specific regulation of the composite P1 element may result from regulation of transacting factors that bind to the AP-1 portion of this element.

Animals↗
PubMed1997

Bispecific antibody-dependent cellular cytotoxicity of HER2/neu-overexpressing tumor cells by Fc gamma receptor type I-expressing effector cells.

A bispecific antibody, MDX-H210, was developed to target cytotoxic effector cells expressing Fc gamma receptor type I (Fc gammaRI, CD64) to HER2/neu-overexpressing tumor cells. HER2/neu is an appropriate target for immunotherapy due to the high level of expression of this proto-oncogene in a variety of malignancies. The expression of Fc gammaRI is limited primarily to cytotoxic immune cells, including monocytes, macrophages, and cytokine-activated polymorphonuclear (PMN) cells. Therefore, tumor cells bound with MDX-H210 can be selectively recognized by effector cells with cytotoxic potential. MDX-H210 was prepared by chemical conjugation of Fab' fragments derived from the HER2/neu-specific monoclonal antibody, 520C9, and the Fc gammaRI-specific monoclonal antibody, H22. This bispecific molecule demonstrated specific, dose-dependent, and saturable binding to both HER2/neu- and Fc gammaRI-expressing cells. A solid-phase immunoassay that demonstrated simultaneous and specific binding to both antigens was used to confirm the bispecific nature of MDX-H210. Monocytes and PMN cells mediated MDX-H210-dependent lysis of HER2/neu-overexpressing cell lines derived from breast, ovarian, and lung carcinomas. IFN-gamma treatment of monocytes enhanced antibody-dependent cellular cytotoxicity, whereas IFN-gamma and granulocyte colony-stimulating factor were required for PMN cell-mediated tumor cell lysis. In addition, MDX-H210 elicited tumor necrosis factor-alpha secretion from monocytes when cultured in the presence of HER2/neu-positive target cells. These in vitro data suggest that targeting tumor cells to Fc gammaRI with MDX-H210 may be an effective treatment for malignancies that overexpress HER2/neu. The in vivo cytotoxic potential of MDX-H210 may be enhanced by combination therapy with the cytokines granulocyte colony-stimulating factor and IFN-gamma, which up-regulate Fc gammaRI expression on cytotoxic effector cells.

Antibodies, Bispecific↗