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PubMed1986

Effector cell sensitivity to sugar moieties. III. Inhibition by monosaccharides of interleukin-2 enhanced natural killing against viral and nonviral tumor target cells.

Human NK cells recognize multiple target antigens. The ligands (antigens) involved in this interaction have not been clearly identified. Previously, we have shown that some monosaccharides inhibit NK mediated cytolysis in a concentration-dependent fashion and that NK cell activity involves recognition of carbohydrate structures on target cells via receptors on the effector cell surface. Using human IL-2 or recombinant IL-2, we have found that monosaccharides inhibit IL-2 enhanced functional activity in a concentration-dependent fashion; that increased expression of endogenous monosaccharide binding receptors on effector cells occurs after treatment with IL-2; and that greater quantities of monosaccharide were required to obtain equivalent inhibition of IL-2 enhanced NK activity. Our data reinforces the growing belief that effector cells express receptors with different sugar specificities and that quantitative differences in sugar specificities is a likely reason for NK cells having heterogeneous polyclonal activity.

Arabinose↗

PubMed1986

K562 killing by K, IL 2-responsive NK, and T cells involves different effector cell post-binding trigger mechanisms.

The monoclonal antibody 13.3 specifically blocks the trigger process of the NK-K562 cytolytic sequence at a post-binding effector cell level. This antibody was used to define differences in the lytic trigger processes of NK and other mechanisms of K562 lysis. Monoclonal antibody 13.3 inhibited lysis of K562 target cells by freshly isolated peripheral blood lymphocytes (PBL) and purified large granular lymphocytes (LGL), but had no inhibitory effect on antibody-dependent cell-mediated cytotoxicity to K562 by these effectors. Lectin-dependent cellular cytotoxicity (LDCC) to this target cell was also unresponsive to 13.3. The 13.3-induced inhibition of NK-K562 lytic activity persisted when PBL were activated in culture with interleukin 2 (IL 2) for periods up to 48 hr. After 48 hr of culture, the degree of inhibition diminished progressively in medium containing fetal calf serum but not in medium containing autologous serum. This 13.3-unresponsive lytic activity in cultured PBL could be attributed to more than one cell type and was present in both the LGL and Fc gamma receptor-depleted T cell fraction. Thus, K562 lysis by freshly isolated human lymphocytes via NK, K, and LDCC mechanisms is characterized by heterogeneity of the post-binding effector cell trigger mechanism. K562 lysis by lymphocytes cultured with IL 2 is similarly heterogeneous.

Antibodies, Monoclonal↗

PubMed1987

[The role of major histocompatibility complex genes in the reaction of macrophages and thymocytes during induction of T-effectors of the graft vs host reaction. III. Effect of antisera against H-2 complex antigens on the realization of the process].

The data are presented on the influence of antisera to different products of the histocompatibility gene complex on the interaction between macrophages and thymocytes during the formation of T-cell GVH effectors. The intensity of the local GVH reaction was evaluated by the index of the lymph nodes enlargement. The close physical contact between cells was necessary for the induction of T-effectors GVH. Treatment of macrophages or thymocytes with anti-H-2 and anti-H-2K antibodies, prior to the beginning of combined incubation, or addition of these antisera to the cultural media suppressed the formation of T-cell inducing GVH. Anti-H-2 I and anti-H-2 D sera did not affect the formation of GVH T-effectors.

Animals↗

PubMed1986

Monocyte-mediated augmentation of human natural killer cell activity: conditions, monocyte and effector cell characteristics.

The characteristics of the effector cells and monocytes, and conditions required for the monocyte-mediated augmentation of human natural killer (NK) cell activity were investigated. Enriched null cell populations were further fractionated by Percoll centrifugation and used as effector cells. The LGL-enriched fraction was less susceptible than either the unfractionated cells or the other Percoll fractions to the monocyte augmentation when mixed with monocytes in the chromium-release assay and when precultured with monocytes for 12 hr, retrieved by carbonyl iron treatment, and tested for NK activity against K562. This differential susceptibility was reflected at the single cell level. The LGL-enriched Percoll fraction did not display the increase in target-binding cells with lytic activity that was exhibited by the other effector cell preparations after culture with monocytes. No differences in Leu-7 and Leu-11 phenotypes were detected between enriched null cells that had been cultured with and without monocytes for 12 hr. At the monocyte level, it was shown that pretreatment of the monocytes with LPS did not alter their NK-augmenting activity appreciably. Glutaraldehyde-fixed monocytes were not effective, and actinomycin D-treated monocytes were less effective than untreated or irradiated monocytes when mixed with enriched null cells in the assay. Actinomycin D-treated monocytes did not augment and possibly suppressed NK activity tested after 12-hr culture, and irradiated monocytes were less effective for augmenting NK activity than untreated cells. Monocyte-mediated augmentation could be detected when the medium used for null cell-monocyte coculture was supplemented with a) different lots of fetal bovine serum, b) human AB serum, c) autologous serum, or d) no serum. Polymyxin B and indomethacin did not alter the monocyte effect. Finally, the monocyte-mediated augmentation of human NK was not MHC restricted, since allogeneic combinations were also effective. These results suggest that 1) lymphocytes other than LGL participate in the monocyte-mediated augmentation of NK activity, 2) the augmentation is probably activational rather than maturational, 3) the monocytes must be viable to be effective when mixed with null cells during the assay, 4) de novo RNA and/or protein synthesis by the monocytes is required for the monocytes to induce augmented activity in null cells after 12-hr coculture, 5) prostaglandin synthesis and endotoxin are probably not involved in the augmentation, 6) the phenomenon is not MHC restricted, and 7) monocytes may express augmentative and suppressive activities concurrently.

Adult↗

PubMed1979

Correlation between natural and antibody-dependent cell-mediated cytotoxicity against tumor targets in the mouse. II. Characterization of the effector cells.

Direct comparison of the effector cells mediating natural killer (NK) activity against mouse tumor cells and antibody-dependent cell-mediated cytotoxicity (ADCC) against mouse tumor target cells coated with alloantisera indicated that NK cells and K-cells (effector cells mediating ADCC) may belong to the same subpopulation of lymphocytes, but they have a different mechanism of killing. Effector cells mediating NK activity and ADCC were nonadherent, nonphagocytic Fc receptor-bearing cells that sediment at 3.5-4.5 mm/hour. Treatment with anti-Thy 1.2 serum in the absence of complement resulted in an increase of NK activity, whereas this treatment caused a substantial loss in ADCC. Both NK activity and ADCC were equally sensitive to the in vivo or in vitro effects of X-irridiation. In vivo inoculations of high doses of hydrocortisone resulted in a reduction of NK activity, but ADCC was not affected. NK cells were trypsin-sensitive, with a profound decrease in the cytolytic activity being observed in a 4-hour 51Cr release assay. The activity, however, could be recovered after overnight incubation at 37 degrees C. Trypsin treatment did not inhibit ADCC as measured by the 18-hour assay.

Animals↗

PubMed1985

Immunologic control of a retrovirus-associated murine adenocarcinoma. VIII. Corynebacterium parvum-activated natural killer cells as potent antibody-dependent cell-mediated cytotoxicity effectors.

The antibody-dependent lytic activity of Corynebacterium parvum-induced peritoneal exudate cells was examined in vitro by utilizing AD755a tumor targets and a homologous anti-AD755a hyperimmune serum. Maximum antibody-dependent cell-mediated cytolysis (ADCC) of tumor targets was achieved within 4 hours of incubation. ADCC activity was found primarily in the plastic nonadherent cell population and was greatly enriched following removal of phagocytic cells by carbonyl iron. Phenotypically, the cells active in short-term ADCC were Qa-5+, ASGM-1+, Thy 1.2+, and NK 1.1+ and were unaffected by treatment with Lyt 1.2, Lyt 2.2, MAC-1, or I-Ab antibodies plus complement. Cells active in antibody-independent lysis of AD755a targets were phenotypically identical to antibody-dependent effectors. Although indicative of a natural killer (NK) cell phenotype, C. parvum-induced effectors differed from "spontaneous" splenic NK cells in their relative sensitivity to anti-Thy 1.2 as well as to anti-NK 1.1 treatment. Unlike the IgG2a-dependent lysis of AD755a-derived cells by inflammatory macrophages, all IgG isotypes of antiAD755a serum were equally effective in ADCC mediated by C. parvum NK cells. Finally, treatment of C. parvum-inoculated animals with anti-ASGM-1 serum eliminated in vitro NK activity and abrogated the in vivo therapeutic effects of hyperimmune serum. These findings, together with other correlations detailed herein, strongly suggested that C. parvum-activated NK cells appeared to represent a unique subset of NK cells that can serve as potent effectors in the antibody-dependent killing of AD755a tumor cells.

Adenocarcinoma↗

PubMed1985

[Action of phospholipids and gangliosides on tumor cell sensitivity to the cytostatic and membrane-toxic action of splenic effectors].

The authors attempted to study which parts of the lipid molecules are most responsible for an increase in the sensitivity of the tumor cell to the cytostatic and membrano-toxic action of natural spleen effectors. Use was made of different combinations of egg phosphatidylcholine, phosphatidylethanolamine, cardiolipin, dipalmitoyl phosphatidylcholine and a mixture of bovine brain gangliosides. Introduction of phosphatidylethanolamine into the membrane of tumor cells increased, that of phosphatidylcholine and cardiolipin did not change whereas introduction of a mixture of brain gangliosides reduced their sensitivity to spleen effectors. Introduction of brain gangliosides together with egg phosphatidylcholine into the membrane of the target cell increased whereas that together with dipalmitoyl phosphatidylcholine reduced its sensitivity to spleen effectors. It is concluded that the increase in the sensitivity of the tumor cell primarily depends on changes in the lipid template of its membrane, induced by unsaturated fatty acids of egg phosphatidylcholine, and to a less degree on the properties of carbohydrate heads of gangliosides.

Animals↗

PubMed1979

Comparison of the effector mechanisms during endotoxin fever in the adult rabbit.

In unanaesthetized adult rabbits an intravenous dose of E. coli endotoxin evoked a febrile rise in colonic temperature at ambient temperatures of 9 to 31 degrees C. The rise in colonic temperature and oxygen consumption did not depend on the ambient temperature, while, among the heat loss effectors, in warmer environments only the depression of respiratory heat loss and in cooler environments only ear skin vasoconstriction contributed to the febrile rise in colonic temperature. In moderately warm environments the endotoxin first induced a maximum inhibition of respiratory frequency and this was followed by vasoconstriction. Later, a transient rise in oxygen consumption occurred. During defervescence the timing of the effectors was reversed. The results showed that a febrile response is not necessarily characterized by simultaneous changes in the thermoregulatory effector mechanisms.

Animals↗

PubMed1979

Studies on in vivo priming of the TNP-reactive cytotoxic effector cell system. I. Comparison of the effects of intravenous inoculation with TNP-conjugated cells on the development of contact sensitivity and cell-mediated lympholysis.

A comparison was made of the effects of i.v. inoculation of trinitrophenyl-(TNP) conjugated syngeneic cells on the subsequent in vitro generation of TNP-reactive effector cell activity and on the in vivo development of TNP-contact sensitivity. The administration of syngeneic TNP-conjugated spleen cells before 2,4,6-trinitro-1-chlorobenzene (TNCB) painting abolished the capability of animals to develop TNP-contact sensitivity. In contrast, the same treatment resulted in an appreciable augmentation in the generation of TNP-reactive cytotoxic effector cell activity as measured by subsequent in vitro sensitization with TNP-conjugated cells. The possible mechanisms by which enhanced TNP-reactive cytotoxic effector cell activity was elicited under conditions identical to those that induced unresponsiveness for TNP-contact sensitivity are discussed.

Animals↗

PubMedDate not supplied

Dopamine-beta-hydroxylase effectors in neuroblastoma.

Investigation of dopamine-beta-hydroxylase (DBH) serum activity as a potential diagnostic/prognostic tool for neuroblastoma did not confirm previous reports. However, age-dependent differences in normal children's DBH "activation" by water dilution +/- copper addition was revealed. These findings of age-related DBH effector differences suggest that the strong age relationship of DBH activity may be due to alterations in effectors. Additionally, these effectors may be variably affected by assay methodology, influencing DBH results obtained in neuroblastoma and other disease states.

Age Factors↗

PubMed1979

Characteristics of complexes for arming and inhibiting effector cells for antibody-dependent cell-mediated cytotoxicity.

The size of IgG aggregate effective in the inhibition or arming of human effector cells for antibody-dependent cell-mediated cytotoxicity (ADCC) was investigated using heat- and alkalipolymerized rabbit IgG or purified antibody fractionated by gel filtration. In contrast to the inhibition of ADCC against chicken erythrocytes, which was marked when effector cell were pre-incubated with high molecular weight aggregates (19S or greater), small polymers were most effective in arming for cytotoxicity against antigen-coated chicken red cells. Our data also demonstrate that while the cytotoxic potential of armed cells is short-lived and rapidly lost during culture at 37 degrees C but not 4 degrees C, the reduced capacity of these cells to kill antibody-coated targets is not altered by similar incubation at 37 degrees C. The differences in the size of aggregate active in arming and inhibition, and the stability of the two phenomena are compatible with the hypothesis that large aggregates may cause more cross-linking and redistribution of effector cell Fc receptors than small polymers of IgG.

Antibody-Dependent Cell Cytotoxicity↗

PubMed1984

Functional activity in vivo of effector T cell populations. II. Anti-tumor activity exhibited by syngeneic anti-MoMULV-specific cytolytic T cell clones.

The functional activity in vivo of murine tumor-specific cytolytic T lymphocyte populations and clones was studied. Tumor cell destruction induced after the i.v. injection of cytolytic effector cells was quantitated by monitoring the elimination of 131IUdR-labeled tumor cells in the peritoneal cavity by using whole-body counting techniques. Mixed leukocyte-tumor cell cultures were established by using spleen cells from C57BL/6 regressor mice that had rejected an intramuscular tumor induced by the injection of MSV-MoMuLV virus. This effector cell population was observed to eliminate syngeneic MoMuLV-induced tumor cells in a dose-dependent manner. Treatment of the effector cell population with monoclonal anti-Lyt-2 antibodies plus complement totally abrogated their ability to induce tumor cell destruction in the peritoneal cavity. MSV-MoMuLV-specific Lyt-2+ cytolytic T cell clones derived by micro-manipulation of T lymphocyte-tumor cell conjugates were also tested for functional activity in vivo. Several clones induced a rapid, specific elimination of 131I-labeled MBL-2 tumor cells from the peritoneal cavity after i.v. injection, whereas others were inactive. Both active and inactive clones were highly cytolytic and secreted MAF/IFN-gamma lymphokines. In contrast to previous results obtained in a tumor allograft model, the MSV-MoMuLV-specific cytolytic T cell clones that were active in vivo did not proliferate in vitro in response to stimulation with irradiated tumor cells plus filler spleen cells in the absence of an added source of interleukin 2.

Animals↗

PubMed1984

Cell contact-mediated macrophage activation for antileishmanial defense. I. Lymphocyte effector mechanism that is contact dependent and noncytotoxic.

Leishmania are obligate intracellular protozoa in mammalian hosts. They infect and replicate within macrophages. Antileishmanial host defense is largely cell mediated. We conducted studies in vitro to investigate the ability of lymphocytes to activate macrophages for antileishmanial effects. Draining lymph node lymphocytes from C57BL/6 mice with cutaneous Leishmania tropica major infection were co-cultured in suspension with syngeneic, starch-elicited peritoneal macrophages infected in vitro with homologous parasites. In the presence of these effector lymphocytes, parasite replication was inhibited, and in some cases intracellular parasites were destroyed. In contrast, control lymphocytes from complete Freund's adjuvant-treated or Listeria-infected mice exerted no antileishmanial effects. Antileishmanial effects were greatest when Leishmania-sensitized lymphocytes were in direct contact with parasitized macrophages. Effector lymphocytes did not cause detectable damage to infected macrophages. Lymphocytes that induced the most profound antileishmanial effects in vitro were those obtained from mice entering a phase of spontaneous clinical resolution of their infections. We conclude that macrophages can be activated for microbicidal effects by direct contact with appropriately sensitized lymphocytes. This antigen-specific, contact-mediated lymphocyte effector mechanism may be important in host defense against certain intracellular microorganisms such as Leishmania.

Animals↗

PubMed1984

Mutational analysis of primosome assembly sites. I. Distinct classes of mutants in the pBR322 Escherichia coli factor Y DNA effector sequences.

The assembly of the primosome, a multienzyme complex responsible for priming of lagging-strand DNA synthesis in Escherichia coli, occurs on defined regions of DNA. These primosome assembly sites are on the order of 70 nucleotides in length, yet they share little DNA sequence homology. In order to understand the interaction of the primosomal proteins with these sites, the isolation of single-base substitution mutants of the wild-type sequences has been undertaken. The response of 32 of these mutated primosome assembly sites to increasing concentrations of monovalent and divalent cations when they were used as DNA effectors for E. coli replication factor Y-catalyzed ATP hydrolysis and their efficiency as primosome-dependent DNA replication templates have revealed the existence of four distinct classes of mutations in primosome assembly sites. Class I mutations have essentially no effect on the activities elicited by the DNA site; thus, it is likely that they define nonessential or spacer nucleotide residues. Class II mutated DNAs require higher Mg2+ concentrations than the wild-type DNA to be fully activated as factor Y ATPase effectors and cannot be stimulated in the ATPase reaction by monovalent salt at suboptimal levels of Mg2+. The implication of this mutant phenotype on the role of secondary and tertiary DNA structure in determining an active site is examined in the accompanying article (Soeller, W., Abarzúa, P., and Marians, K. J. (1984) J. Biol. Chem. 259, 14293-14300). Class III mutations coinactivate both the ATPase effector and DNA replication template activity of the site, indicating that they probably represent essential contact points between factor Y and the DNA. Class IV mutated DNAs behave in a manner similar to class II mutated DNAs in the ATPase reaction, but have a replication template activity intermediate between that of the class III and class II mutant DNAs. It is possible that these mutant DNAs are deficient in their ability to catalyze, during primosome assembly, a step subsequent to that of factor Y binding.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphatases↗

PubMed1982

Functional activity in vivo of effector T cell populations. I. Antitumor activity exhibited by allogeneic mixed leukocyte culture cells.

The in vivo activity of murine cytolytic T lymphocyte-containing effector cell populations generated in vitro was studied in a tumor allograft model system by monitoring the elimination of 131I-IUdR-labeled tumor cells with whole-body counting techniques. Mice were irradiated sublethally and 16 hr later 131I-labeled tumor cells were injected either subcutaneously or i.p. Simultaneously, graded doses of various effector cell populations were injected i.v. and the mice were counted daily to assess the potential elimination of the radiolabeled tumor cells. Thus, allogeneic 2 degrees mixed leukocyte culture cells were observed to eliminate allogeneic but not syngeneic tumor cells in a dose-dependent manner, with as few as 0.2 x 10(6) effector cells causing significant destruction of 2 x 10(6) allogeneic tumor cells. The protective effect of the mixed leukocyte culture cells was considerably reduced when Lyt-2+-bearing lymphocytes were eliminated by treatment with monoclonal antibody plus complement. In additional experiments, Lyt-2+ lymphocytes positively selected by enrichment on antibody-coated petri dishes gave efficient protection, in the absence of Lyt-2- cells. Surprisingly, when several different cloned, specific, long-term allogeneic cytolytic T cells lines were injected either i.p. of i.v., tumor cell destruction was observed only after i.p. injection.

Animals↗

PubMed1982

Effect of helper T cells on prevention of tolerance induction in effector T cells responsible for syngeneic tumor immunity.

The present study investigates the role of helper T cells in preventing tolerance in effector T cells responsible for syngeneic tumor immunity. Tolerance in T cell-mediated immune responses against X5563 plasmacytoma was induced in syngeneic C3H/He mice by intravenous (iv) administration of 7,000 R X-irradiated X5563 tumor cells. Since the anti-X5563 tumor tolerance was observed irrespective of whether the tumor cells had been modified with trinitrophenyl (TNP) hapten prior to iv inoculation, the ability of TNP-reactive helper T cells to prevent the tolerance induced by iv inoculation of TNP-X5563 tumor cells was examined. TNP-reactive helper T cell activity was generated in C3H/He mice by immunization with TNP-isologous mouse gamma-globulin after inoculation with the TNP-conjugate of a non-immunogenic co-polymer of D-glutamic acid and D-lysine. Intravenous inoculation with TNP-modified X5563 cells induced tolerance in mice not primed with TNP. However, such tolerance was prevented in mice in which TNP-reactive helper T cell activity had been generated. These results indicate that helper T cells play a crucial role in preventing effector T cell tolerance. The mechanisms by which tolerance induction in effector T cells is circumvented are discussed in relation to the generation and delivery of signals required for T cell activation.

Animals↗

PubMed1983

Pre-incubation of human monocytes results in loss of effector activity and diminished stimulation of the autologous mixed lymphocyte reaction.

Human monocytes were cultured at 37 degrees C for 72 h, washed, adjusted for viability and compared to freshly prepared monocytes for stimulation of the autologous mixed lymphocyte reaction (AMLR) and effector function. Pre-incubated monocytes were less potent AMLR stimulators than were freshly prepared cells. Pre-incubated monocytes demonstrated less antibody-dependent tumour killing of CCRF-CEM, less killing of Staphylococci and less spontaneous tumour killing of K-562 than did fresh monocytes. Pre-incubated monocytes produced less prostaglandin E2, demonstrated less surface Ia antigen and were less efficient accessory cells for antigen presentation than were fresh monocytes. AMLR stimulation correlated with monocyte killing (r = 0.95) and PGE2 production (r = 0.98). Thus, monocytes pre-incubated for 3 days are less active effector cells, display less surface Ia antigen and are less potent stimulators of the AMLR than fresh monocytes. Moreover, in this system, monocyte effector activity correlates with ability to stimulate the AMLR.

Antibody-Dependent Cell Cytotoxicity↗

PubMed1984

Influence of 2'-deoxyguanosine upon the development of DTH effector T cells and suppressor T cells in vivo.

Subcutaneous (s.c.) immunization of mice with allogeneic spleen cells can induce delayed-type hypersensitivity (DTH) to both major and minor histocompatibility antigens. Intravenous immunization with allogeneic spleen cells, however, induces a poor state of DTH. Furthermore, i.v. immunization with allogeneic spleen cells, especially if they have been irradiated, induces suppressor T lymphocytes. These suppressor T cells are capable of suppressing the host-vs-graft (HvG) DTH reactivity that normally arises after s.c. immunization. Moreover, they can suppress the development of anti-host DTH effector T cells during graft-vs-host (GvH) reactions. These models for HvG and GvH DTH reactivity were used to study the influence of 2'-deoxyguanosine (dGuo) and guanosine (Guo) on the generation of DTH-reactive T cells and suppressor T cells in vivo. It was found that daily i.p. administration of 0.01 mg dGuo to mice immunized i.v. partially prevented the generation of suppressor T cell activity, whereas daily administration of 0.1 or 1 mg dGuo resulted in a complete abolition. Administration of dGuo has no effect on the anti-host DTH reactivity by spleen cells from nonsuppressed donors except for when a daily dose of 10 mg is administered. This dose proved to be toxic for precursors of DTH effector T cells. Daily i.p. injection of Guo had no effect on the generation of suppressor T cells nor on the generation of DTH effector T cells. The effect of dGuo was found to be due to a direct effect on suppressor T cells and not to the induction of contrasuppressor cells. These data suggest a differential sensitivity of DTH-reactive T cells and suppressor T cells for dGuo. Because suppressor T cells and DTH-reactive T cells require proliferation for expressing maximal functional activity in the systems used, both cell types probably have different enzyme activities involved in the purine metabolism and similar deoxycytidine kinase activities, but have different nucleotidase (5'NT) activities, those in suppressor T cells being the lowest. If so, suppressor T cells will accumulate deoxyguanosine triphosphate, which causes an inhibition of the ribonucleotide reductase activity and thus of the DNA synthesis by these cells.

Animals↗