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PubMed1992

Peripheral blood leukocytes of patients with Argentine hemorrhagic fever as effectors of antibody-dependent cell-cytotoxicity.

Peripheral blood mononuclear cells (PBMC) and polymorphonuclear leukocytes (PMNL) of patients with Argentine hemorrhagic fever (AHF) were tested as effectors (E) of antibody-dependent cell cytotoxicity (ADCC). 51Cr labeled chicken red blood cells (CRBC) coated with anti-CRBC or normal rabbit serum were used as targets (T). Three ADCC assays were performed with both effectors from patients: on admission (I), 4 days after the transfusion of immune plasma (II), and 30 days after the clinical onset (III). The ADCC values obtained displayed high variation between individuals. From the linear portions in the curves representing specific 51Cr release vs. E:T ratio plots, extrapolations were made to determine lytic units (LU), defined here as effector concentrations required to lyse 50% of the targets. The results were expressed as LU in 10(6) effector cells. The killing activity ranges of patients' PMNL (I = 1.04 +/- 0.34; II = 2.22 +/- 0.66; and III = 2.08 +/- 1.18) were not significantly different from that of 21 normal controls (1.19 +/- 0.36), except for range II (P less than 0.01). ADCC activity ranges of patients' PBMC (I = 3.40 +/- 1.06; II = 3.16 +/- 1.60; and III = 1.93 +/- 0.42) were not significantly different from that determined in 12 healthy subjects (1.86 +/- 0.40). These results demonstrate that patients' PBMC and PMNL can perform ADCC with efficiency comparable to normal effector cells, during the acute period of AHF, and in early convalescence. Consequently, ADCC can be a relevant mechanism in the clearance of Junin virus-infected cells.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1998

The effector component of the cytotoxic T-lymphocyte response has a biphasic pattern after burn injury.

INTRODUCTION: Burn injury delays allograft rejection and impairs the host defense against infection. These functions are mediated via the cytotoxic T-lymphocyte (CTL) response. The CTL response is divided into antigen recognition/processing and effector phases. Presensitization allows selective analysis of changes, induced by burn injury, in the effector limb of the CTL response in relation to time and burn size. METHODS: Anesthetized CBA mice were primed with either a flank allograft from C57BL/6 (B6) mice or an autograft (negative control). Five weeks after grafting, animals were anesthetized and received either a 0, 20, or 40% burn. Spleens were harvested 3, 7, 10, and 14 days after burn injury (n = 96), cocultured with B6 stimulator splenocytes, and assessed for CTL response to radiolabeled allogeneic targets in a 51Cr release assay. In experiment 2, spleens were harvested from unburned and 40% burned animals on Postburn Days 3 and 14. After triple staining, cells were analyzed by flow cytometry for CD4, CD8, and CD25 antigens. In experiment 3, splenocytes from 0 and 40% burned animals on Postburn Days 3 and 14, were cocultured with B6 stimulators for 5 days. Supernatants were evaluated for interleukin (IL)-2, IL-5, and interferon-gamma (IFN-gamma) using ELISA: RESULTS: The CTL response for 20 and 40% burned animals decreased 3 days postburn (-11.9 and -30.1%, P < 0.05), returned to baseline in 7-10 days, and was increased by 14 days postburn (15.8 and 22.6%, P < 0.05). The T-helper lymphocyte population (CD4) from 40% burn animals was significantly decreased on Postburn Days 3 and 14 (10.12 +/- 0.45% vs 11.78 +/- 0.29% and 10.19 +/- 0.24% vs 14.21 +/- 0.97%, respectively, P < 0.05). The CTL effector (CD8) splenocyte population was significantly higher in the burned animals on Postburn Day 14 (4.55% vs 3.71%, P < 0.05). On Postburn Day 3, average IL-5 production was higher in the burned animals (1.80 pg/ml vs 0.59 pg/ml, respectively, P < 0.05). The burn group, on Postburn Days 3 and 14, showed a decrease in mean IL-2 production (212.81 pg/ml vs 263.6 pg/ml and 342.7 pg/ml vs 421.4 pg/ml, respectively, P < 0.05). Mean IFN-gamma production on Postburn Days 3 and 14 was decreased in burned mice (263.75 pg/ml vs 285.57 pg/ml and 218.16 pg/ml vs 263.42 pg/ml, P < 0.05). CONCLUSIONS: Burn injury impairs the effector limb of the CTL response as a function of burn size in the immediate postburn period. CTL activity returns to baseline within 7-10 days postburn and has a rebound increase by Day 14. Early CTL suppression, after burn injury, may be due to a decrease in the T-helper subpopulation. The late increase in cytotoxicity may be secondary to an increase in the effector CTL population in the late postburn period. Burn injury causes a T-helper-2 phenotype as demonstrated by depressed IL-2 and IFN-gamma production and increased IL-5 production.

Animals↗
PubMed2000

Purification and identification of novel Rab effectors using affinity chromatography.

Rab GTPases are central regulatory elements of the intracellular transport machinery of eukaryotic cells. To regulate vesicle docking and fusion as well as organelle dynamics Rab proteins interact with effector molecules in the GTP-bound active state. The identification of Rab effectors is, therefore, of primary importance for the mechanistic understanding of intracellular transport. Here we describe the experimental system we have developed to biochemically purify and identify effectors of the small GTPase Rab5. The method, which is based on an affinity chromatography procedure, results in the large-scale purification of Rab effectors in amounts sufficient for both their identification by microsequencing techniques and their functional characterization. In the case of Rab5, the procedure allows a comprehensive analysis of the downstream effectors and regulators of this GTPase. We expect this strategy to provide fundamental insights into the molecular mechanism of membrane transport but also to be applicable to several other GTPase-dependent biological functions.

Animals↗
PubMed1998

OX-40: life beyond the effector T cell stage.

The OX-40 receptor (OX-40R) is a transmembrane protein found on the surface of activated CD4(+) T cells. When engaged by an agonist such as anti-OX-40 antibody or the OX-40 ligand (OX-40L) during antigen presentation to T cell lines, the OX-40R generates a costimulatory signal that is as potent as CD28 costimulation. Engagement of OX-40R enhances effector and memory-effector T cell function by up-regulating IL-2 production and increasing the life-span of effector T cells. We hypothesize that the signal generated by the OX-40R inhibits activation-induced T cell death (AICD) and thereby increases the number of cells differentiating from the effector to memory T cell stage. In experimental autoimmune encephalomyelitis (EAE) OX-40R+ T cells are found only within the inflammatory site [central nervous system (CNS)]. Sorting OX-40R+ T cells from the CNS of animals with EAE revealed that they are autoantigen-specific T cells. Therefore, OX-40R-specific therapies were devised to eliminate or inhibit autoreactive T cells, while sparing the remainder of the T cell repertoire. In contrast, in vivo costimulation through the OX-40R in animals with cancer generated enhanced tumor-specific immunity leading to improved tumor-free survival. Thus, manipulation of the OX-40R during inflammatory responses can alter effector CD4(+) T cell function by enhancing or limiting T cell activation and survival.

Animals↗
PubMed1989

Serum and effector-cell antibody-dependent cellular cytotoxicity (ADCC) activity remains high during human immunodeficiency virus (HIV) disease progression.

The activity of both serum and effector cell antibody-dependent cellular cytotoxicity (ADCC) against human immunodeficiency virus (HIV-1, HIV) was assessed in HIV-infected individuals. The goal was to relate ADCC levels with the stage or progression of HIV disease. Serial serum samples, usually collected at 6-month intervals, from individuals at defined stages of HIV disease (seroconversion, the HIV-seropositive period before AIDS, and around the time of clinical AIDS diagnosis) were tested. HIV-coated CEM tumor cells were used as targets. Effector-cell ADCC activity was evaluated using fresh peripheral blood mononuclear cells (PBMC) from HIV-infected individuals at different stages of HIV disease. Samples were obtained from male homosexual participants in the Multicenter AIDS Cohort Study (MACS). In seroconverters, ADCC-inducing HIV-specific antibodies were detected at the time that the ELISA antibody test was first positive. Within several months, serum ADCC activity stabilized in each individual. In 29 HIV-seroprevalent individuals (HIV seropositive on their first visit), serum ADCC activity remained constant regardless of whether the individual's HIV disease was stable (high stable CD4; n = 9) or rapidly deteriorating (sharply declining CD4, n = 10; AIDS progressors, n = 10). With respect to effector-cell activity, PBMC from HIV-infected individuals with or without AIDS were capable of mediating ADCC with heterologous and usually with autologous sera. Although the level of NK cytotoxic activity and the level of antibody-armed effector cell activity have been reported to decline as disease progresses, our results support previous observations that ADCC effector-cell activity against antibody-coated targets does not decline in HIV infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1994

Phenotypic analysis of nylon-wool-adherent suppressor cells that inhibit the effector process of tumour cell lysis by lymphokine-activated killer cells in patients with advanced gastric carcinoma.

The causes of down-regulation of cytotoxic immune responses in cancer patients have not been fully evaluated. We previously demonstrated that T-cell-growth-factor-activated peripheral blood lymphocytes (PBL) with the surface phenotype CD8+ CD11b-, from patients with widespread metastasis of gastric carcinoma, inhibited the effector process of lymphokine-activated-killer(LAK)-cell-mediated cytolysis. In this study, we examined suppressor cell activity in freshly prepared PBL from 18 patients with advanced gastric carcinoma, and 10 normal healthy individuals. The suppressor cell activity was assayed by recording whether or not PBL inhibited directly the effector process of LAK cell cytotoxicity. Most of the PBL suspensions from cancer patients showed that they contained a population of cells that can directly inhibit the effector phase of tumor cell lysis of the cytotoxic cells. To analyze further the PBL responsible for the suppression, the cells were passed over a nylon-wool column. Nylon-wool-adherent cells significantly augmented the suppression, while the cells passing through abrogated the suppressive effect. Most nylon-wool-adherent cells from 10 normal healthy controls did not inhibit the cytotoxic reaction. To determine further the suppressor-effector population in nylon-wool-adherent cells, negative-selection studies using CD8-, CD4- or CD11b-coated magnetic beads, and positive-selection studies using CD8- or CD4-coated magnetic beads were performed. Finally the results suggest that the suppressor-effector cells comprise at least two different surface phenotypes: CD8+ T and CD8-CD11b+ cells. The possible role of CD4+ T cells and HLA-DR+ LeuM3+ macrophages as suppressor cells was ruled out in nylon-wool-adherent cells. CD8+ T and possibly CD8-CD11b+ cells apparently suppressed the efferent limb of the antitumor immunity. The selective immune suppression mediated by these cells may partly be concerned with escape mechanisms of gastric carcinoma from the host immune surveillance system.

Adult↗
PubMed1988

[Guanidine nucleotide binding proteins as membrane signal transduction components and regulators of enzymatic effectors].

The vast majority of extracellular signals alters cell function by activating cell surface receptors. The transmembranous signalling process initiated by an activated receptor leads to the generation of an intracellular signal and eventually to a cellular response. In contrast to receptors that are permanently coupled to an enzyme or an ion channel representing the effector, a large number of surface receptors for hormones, neurotransmitters and receptors for exogenous chemical or physical stimuli reversibly interacts with membranous signal transduction components which, in turn, regulate intracellular messenger-generating effectors. The transducer molecules isolated so far form a family of guanine nucleotide-binding proteins (G- or N-proteins). All isolated G-proteins are composed of three different subunits (alpha, beta, gamma). The alpha-subunit, which is specific for the individual G-protein, binds and hydrolyzes GTP and is target of ADP-ribosylating bacterial toxins. Hormone-induced activation of a receptor causes interaction with the alpha-subunit of a G-protein and the exchange of bound GDP with GTP. The GTP-bound form of the alpha-subunit represents the active form of the G-protein, which is capable of stimulating or inhibiting the respective effector. The active state of the alpha-subunit is terminated by its inherent GTPase activity causing hydrolysis of bound GTP. The beta gamma-complexes of G-proteins are structurally very similar and functionally interchangeable; they appear to dissociate from the alpha-subunits during receptor activation of the G-protein. Possible functions of the beta gamma-complex are to anchor the non-activated G-protein in the membrane, to facilitate G-protein-receptor interaction, and to promote the inactive state of the alpha-subunit. G-protein-regulated effectors include enzymes, ion channels and probably transporters. The best studied G-protein-regulated enzyme is the retinal cyclic GMP-phosphodiesterase which is activated by bleached rhodopsin via the tissue-specific G-protein, termed transducin. The ubiquitously occurring membrane-bound adenylate cyclase is under dual control by families of stimulatory and inhibitory receptors, acting via G-proteins called Gs and Gi, respectively. Moreover, the receptor control of phospholipases A2 and C and probably of phospholipase D most likely involves G-proteins which have not yet been identified. Finally, the activity of NADPH oxidase of neutrophils and that of cyclic AMP phosphodiesterases in liver and fat cells may be regulated via G-proteins. Modulations of non-enzymatic effectors are reviewed elsewhere.

Animals↗
PubMed1994

The relationship between receptor-effector unit heterogeneity and the shape of the concentration-effect profile: pharmacodynamic implications.

The apparent concentration-effect relationship is the ensemble of many effector units (such as individual cells or channels) that do not always exhibit a uniform stimulus-effect relationship. This concept is substantiated by many observations of heterogeneity in receptor-effector populations including hormone secreting cells, response to hormonal stimuli, activity pattern of second messengers, stimulus-evoked synaptic currents, and single ion channels. The relationship between drug concentration and magnitude of pharmacologic response is commonly described by the sigmoidal Emax model which was derived from the Hill equation. The sigmoidicity factor (N) in this model is assumed to be a pure mathematical parameter without physiological connotations. This work demonstrates that the numerical value of N (measured empirically) is the product of two factors: (i) the degree of heterogeneity of the effector subunits, i.e., the elemental component that upon drug stimulus contributes its pharmacological effect independently and does not interact with other subunits (it could range from a single receptor up to a whole tissue), and (ii) value of N*--the shape factor of the subunits' concentration-effect relationship. A special case of this approach occurs when N* > 5, which is an on-off case. Here N is determined by the distribution (density equation) of the subunit values. In case of heterogeneity of the microparameters of the effector subunits the apparent N will always have a lower value than N*. According to this theory it can be concluded that without knowledge of the distribution of the microparameters no mechanistic interpretation can be deduced from the apparent N value. If in the future N* can be determined by theoretical or experimental methods, the distribution function relating N* to N can be calculated. The relevance of this theory is increased in view of the progress being made in advanced research techniques which may enable us to determine the concentration-effect relationship at the level of the individual effector unit.

Hormones↗
PubMed2004

Crosstalk and differential response to abiotic and biotic stressors reflected at the transcriptional level of effector genes from secondary metabolism.

Plant secondary metabolism significantly contributes to defensive measures against adverse abiotic and biotic cues. To investigate stress-induced, transcriptional alterations of underlying effector gene families, which encode enzymes acting consecutively in secondary metabolism and defense reactions, a DNA array (MetArray) harboring gene-specific probes was established. It comprised complete sets of genes encoding 109 secondary product glycosyltransferases and 63 glutathione-utilizing enzymes along with 62 cytochrome P450 monooxygenases and 26 ABC transporters. Their transcriptome was monitored in different organs of unstressed plants and in shoots in response to herbicides, UV-B radiation, endogenous stress hormones, and pathogen infection. A principal component analysis based on the transcription of these effector gene families defined distinct responses and crosstalk. Methyl jasmonate and ethylene treatments were separated from a group combining reactions towards two sulfonylurea herbicides, salicylate and an avirulent strain of Pseudomonas syringae pv. tomato . The responses to the herbicide bromoxynil and UV-B radiation were distinct from both groups. In addition, these analyses pinpointed individual effector genes indicating their role in these stress responses. A small group of genes was diagnostic in differentiating the response to two herbicide classes used. Interestingly, a subset of genes induced by P. syringae was not responsive to the applied stress hormones. Small groups of comprehensively induced effector genes indicate common defense strategies. Furthermore, homologous members within branches of these effector gene families displayed differential expression patterns either in both organs or during stress responses arguing for their non-redundant functions.

Acetates↗
PubMed1975

Glucocerebrosidase: stoichiometry of association between effector and catalytic proteins.

1. The effector and catalytic proteins of glucocerebrosidase associated in the presence of acidic phospholipid to give active enzyme. 2. At optimum concentrations of acidic phospholipid (about 0.15 mM), the association reached equilibrium instantaneously. 3. From the experimental data, a tentative model of the association was deduced. This involved a two-step complex formation. When the effector concentration was limiting, a simple binary complex was formed between one molecule each of effector and catalytic proteins; the reaction proceeded rapidly to completion. When the effector was in excess, a ternary complex was formed by the addition of another molecule of effector; this reaction did not go to completion and was characterised by a finite equilibrium constant. 4. The experimental data were curve fitted to an equation derived from the model

Cell Membrane↗
PubMed1983

Cross-reactive recognition of alloantigens and certain B6 mutant antigens by antigen-specific and polyclonally activated cytotoxic effector cells.

Various B6 cytotoxic T lymphocyte (CTL) effector populations were tested for cross-reactive lysis (CRL) of unmodified third-party allogeneic as well as of various Kbm and Dbm mutant target cells. The effector cells were generated by in vitro stimulation of B6 spleen cells either from unprimed mice against alloantigen, Con A, or a pool of different allogeneic stimulators, or from in vivo hapten-self primed mice against trinitrophenyl (TNP)-self or N-(5-sulfonic-1-naphthyl)ethylenediame (AED)-self antigens. Except for AED-primed effector cells all CTL populations exhibited significant CRL on third-party allogeneic target cells. More importantly, these alloreactive and H-2-restricted effectors also lysed some of the Kb mutants, but not others. Thus, unmodified bm1 and bm11 mutants were lysed by all of the B6 wild-type effectors, whereas bm6 and bm9 were only weakly lysed by alloreactive CTL. None of the B6 CTL populations lysed bm13 and bm 14 target cells. These data indicate that (a) alloreactive and self-restricted CTL can recognize the same molecular structure of Class I antigens although the epitopes may be different; (b) CTL discriminate between a few amino acid substitutions in certain positions of the H-2 molecule, and (c) the newly generated antigenic determinants of the bm mutants allow them to be divided into three categories in terms of their allogenicity for these cross-reactive CTL populations.

Animals↗
PubMed1985

Monoclonal anti-human tumor antibodies of six isotypes in cytotoxic reactions with human and murine effector cells.

Eighty-seven murine monoclonal antibodies (MAb) produced against human tumors of various origins and representing six different immunoglobulin classes were tested for antitumor reactivity in antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays. Mouse splenocytes, thioglycolate-elicited mouse peritoneal macrophages, freshly obtained nonadherent human peripheral blood lymphocytes, and human monocytes were used as effector cells, and human or rabbit serum as the source of complement. Of all four effector cell types tested, mouse macrophages showed the highest cytotoxic activity, based on net cytotoxicity, minimum requirement for Mab concentration, and effector cell number. Different immunoglobulin classes were associated with characteristic patterns of reactivity with the various effector cells or complement, independent of the target cell type used. MAb able to mediate ADCC were found among all IgG subclasses, with IgG2a and IgG3 MAb inducing lysis with all effector cell types. IgM and IgA MAb were nonreactive in the various ADCC assays, but IgM MAb were highly cytotoxic with complement.

Animals↗
PubMed1989

An [35S]methionine cytotoxicity assay requiring small numbers of effector and target cells.

This communication describes an assay to detect polyclonal cytotoxic activity of small numbers of effector cells. 200 tumor target cells, radiolabelled with 10,000-20,000 cpm [35S]methionine, are incubated with proportionately few effector lymphocytes in microtiter wells. The targets are sufficiently well labelled to permit detection of cytolysis caused by greater than or equal to 1000 cytotoxic cells, at effector:target ratios as low as 5:1. This method permits the rapid assay of limited numbers of effector cells, avoids lengthy culture of effector cells in order to acquire sufficient numbers, and is useful for limiting dilution analysis of cytotoxic T lymphocytes or their precursors.

Animals↗
PubMed1992

Effector-target interactions: saturability, affinity and binding isotherms. A study of such interactions in the human NK cell-K562 tumour cell system.

Effector-target interactions at the cell-to-cell level have been studied. This has revealed that saturability, i.e., the existence of a finite number of specific receptor sites, applies to both the effector and target cell populations and plays a key role in the formation of conjugates. As a result, two maximum conjugate frequencies, alpha max and beta max, are recognised for the effector and target cell populations, respectively. The dissociation constant of the conjugates formed, KD, characterizes effector-target affinity. This constant, together with the maximum conjugate frequencies, are the three parameters which make it possible to describe the binding process quantitatively. The existence of binding isotherms for effector-target interactions has been demonstrated. These isotherms contain all the relevant information necessary to interpret quantitatively the formation of conjugates. Quantitative procedures to determine the three binding parameters are described together with the modifications necessary to use Scatchard plots in the analysis of conjugate frequencies in these kinds of cell-to-cell interactions. A quantitative study of these interactions in the NK-K562 tumour cell system has been performed. For this purpose, nine different cell source donors were used to test the model proposed. Relationships with related phenomena--CMC and the adhesion process--are also discussed.

Adult↗
PubMed1992

Identification of effector-activating residues of Gs alpha.

The heterotrimeric G proteins transduce extracellular signals by interacting with specific intracellular effectors. We have used a scanning mutagenesis approach to identify amino acids of alpha S, the alpha subunit of Gs, that determine the specificity of its interaction with its effector, adenylyl cyclase. In alpha subunit chimeras, residues 236-356 of alpha S comprise the shortest linear stretch that is required for activation of adenylyl cyclase. Within these 121 residues, we identified four clusters of residues in which substitutions prevented effector activation. Mutations in three of these regions did not affect alpha subunit expression or the GTP-induced conformational change. The identified alpha S residues in the NH2-terminal half of the 121-residue region endowed the cognate alpha i2 segment with the ability to activate effector, while those in the COOH-terminal half did not. In a three-dimensional G alpha model, based on the structure of p21ras, the effector-activating residues of alpha S form a surface on the membrane-facing side of the molecule; this surface includes a region that changes conformation upon binding GTP.

Amino Acid Sequence↗
PubMed1983

The role of non-immune IgG in controlling IgG-mediated effector functions.

The majority of evidence supports the conclusion that IgG-dependent effectors respond to antibodies which have been polymerized artificially or by polyvalent antigens, but not to monomeric IgG antibodies. Effectors can distinguish polymerized IgG antibodies from monomeric IgG because they contain multiple receptor units and can interact multivalently with polymerized IgG. However, monomeric IgG is present at very high concns in plasma and interstitial fluids and will inhibit multivalent interactions in vivo between polymerized antibody and effectors. Such inhibition raises the question of how IgG-mediated effector responses could function in vivo. In this review we present a mathematical model which quantitatively predicts how polyvalent ligands interact multivalently with receptors in the presence of excess monovalent ligand. We then show that results from experiments in vitro using such diverse systems as the binding and endocytosis of immune complexes by macrophages, complement-mediated lysis of antibody-coated target cells, and ADCC can be explained qualitatively by the model. We conclude that monomeric IgG does not totally inhibit IgG-mediated effector functions but, rather, raises the threshold of antibody binding which is required to elicit a response. We then consider how non-immune IgG may serve as a homeostatic regulator of IgG-dependent responses, in vivo, perhaps for the purpose of inhibiting responses to low levels of cell-bound IgG autoantibodies.

Adult↗
PubMed1993

Relative susceptibility of SJL/J and B10.S mice to experimental allergic encephalomyelitis (EAE) is determined by the ability of prethymic cells in bone marrow to develop into EAE effector T cells.

SJL/J mice are highly susceptible to actively induced experimental allergic encephalomyelitis (EAE), whereas B10.S mice are resistant. However, both strains share the H-2s haplotype. We have previously shown that the relative susceptibility of SJL/J and B10.S mice to acute EAE correlates, respectively, with high and low responsiveness to myelin basic protein (MBP), as determined by cloning and limiting dilution analysis of in vitro T cell proliferation. Here, we have investigated the ability of SJL/J and B10.S mice to generate EAE-effector T cells in vivo. We have developed a new mouse strain, B10.S Thy 1.1, that differs at the Thy 1 locus from SJL/J and B10.S mice (both Thy 1.2) but has the same MHC and resistance pattern to EAE as do B10.S mice. Using radiation bone marrow chimeras formed between SJL/J and B10.S Thy 1.1 mice, we have shown that a population of radiosensitive prethymic cells in SJL/J bone marrow has an intrinsic potential to generate EAE-effector T cells, whereas that in B10.S Thy 1.1 bone marrow does not. This lack of detectable EAE effector cells in B10.S Thy 1.1 mice does not appear to be due to the generation of suppressor T cells or to a defect in antigen-presenting cells. Moreover, the potential of SJL/J bone marrow to generate EAE-effector T cells is not inhibited by the concomitant presence of B10.S Thy 1.1 bone marrow cells, thymocytes or dendritic cells in mixed chimeras. Hence, the relative susceptibility of SJL/J and B10.S mice to EAE appears to be directly related to the respective responder status of their T cells to MBP, as evidenced by their ability (or inability) to generate EAE-effector T cells. This high and low responder status appears in turn to be linked to non-MHC background genes, although this has not been established formally.

Animals↗
PubMed1986

Mapping functional epitopes of the human LFA-1 glycoprotein: monoclonal antibody inhibition of NK and CTL effectors.

Anti-LFA-1 monoclonal antibody (MoAb) was originally identified by screening antibodies for their ability to inhibit cytolysis in the absence of complement. Anti-LFA-1 MoAb has been shown to inhibit both natural killer (NK) and cytolytic T lymphocyte (CTL) mediated cytolysis. To further define the utilization of this molecule in cell-mediated cytolysis, we used a panel of MoAb to functional epitopes on both the alpha and beta chains of the LFA-1 heterodimer. The panel was used to compare OKT3- NK effectors and OKT3+ CTL clones. As expected, function-associated MoAb to CTL antigens (T3, T8, LFA-2) and target cell antigens (HLA, LFA-3) blocked only CTL clones and not NK effectors. In contrast, anti-LFA-1 MoAb blocked both NK effectors and CTL clones. In addition, the panel of anti-LFA-1 MoAb demonstrated an identical hierarchy of functionally relevant LFA-1 epitopes. Given the similar utilization of LFA-1 in NK and CTL mediated cytotoxicity assays, we explored the ability of MoAb to different epitopes on LFA-1 to inhibit conjugate formation. Anti-LFA-1 MoAb inhibition of NK-target binding paralleled the inhibition of CTL-target binding. Thus, functional epitopes on the LFA-1 molecule have been defined for NK and CTL effectors. The identical hierarchy of functional epitopes indicates that the LFA-1 molecule is similarly utilized in NK and CTL mediated cytotoxicity and that the relevant epitopes are involved in effector-target conjugate formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗