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PubMedDate not supplied

Th2-mediated atopic disease protection in Th1-mediated rheumatoid arthritis.

OBJECTIVE: The balance between CD4+ T-helper (h) cell subsets (Th1 and Th2) plays an important role in the pathogenesis of rheumatoid arthritis (RA) and atopy. While RA is believed to be a Th1 mediated disease, Th2 cells predominate in atopic disorders. The purpose of this study was to investigate differences in the occurrence of allergy, hay fever, house dust mite sensitivity and asthma, as well as total serum IgE levels in RA patients and controls. METHODS: The case history of atopic disorders was assessed in 134 RA patients and compared to those found in 305 healthy blood donors. RA patients also answered clinical questions concerning disease activity and severity. Total serum IgE levels were measured in both groups, taking into consideration disease modifying therapy. RESULTS: A significantly lower occurrence of medical history of hay fever (2.3%) and house dust mite sensitivity (3.1%) was found among RA patients compared to controls (24.2% and 12.2%, respectively; p < 0.0001 and p < 0.003 respectively). Moreover, RA patients had significantly lower total serum IgE levels than control subjects (p < 0.0001). RA was less severe in patients with atopy compared to non-atopic RA patients. CONCLUSION: These results support the concept that RA and atopy antagonize each other and that a change in the cytokine patterns of Th1 and Th2 cells could provide an indication for curative effects on RA.

Age Distribution↗
PubMed1992

Slow channel calcium blockers attenuate reoxygenation-mediated vascular contraction, but augment anoxia-mediated vascular contraction.

Anoxia and reoxygenation modulate vasomotor tone. To determine the effect of the slow channel calcium blockers verapamil and diltiazem in vascular smooth muscle contraction during states of altered oxygenation, rat aortic rings with intact endothelium were contracted with norepinephrine (NE) or the thromboxane A2 mimic U46,619 and then exposed abruptly to anoxia (switch from 95% O2 to 95% N2) for 30 min and then reoxygenated (switch from 95% N2 to 95% O2). Anoxia caused a transient 40 +/- 9% (mean +/- SE, n = 15) increase in contraction, whereas reoxygenation resulted in an initial decrease followed by a large (83 +/- 21%) increase in contraction. Treatment of vascular rings with verapamil or diltiazem (1 microgram/ml or 2 microM) decreased contractile response to the agonists (p less than 0.01). Both these agents consistently augmented the magnitude and duration of anoxia-induced contraction (p less than 0.01). In other experiments, pretreatment of vascular rings with NG-monomethyl-L-arginine (L-NMMA), an inhibitor of endothelium-derived relaxing factor (EDRF) synthesis, or with oxyhemoglobin, an inhibitor of EDRF activity, or de-endothelialization resulted in marked (p less than 0.01) decrease in anoxic contraction, indicating that anoxia-induced contraction is caused by modulation of EDRF. Treatment of aortic rings with verapamil also reduced acetylcholine-mediated relaxation (from 86 +/- 6% to 45 +/- 5%, p less than 0.02) and cyclic GMP accumulation (from 192 +/- 53 to 111 +/- 35 fmol/mg, p less than 0.02), indicating reduction in EDRF synthesis or activity by verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

Antibody dependent cellular cytotoxicity and complement mediated cytotoxicity on leukemic cells mediated by anti K562 monoclonal antibodies.

Three anti K562 monoclonal antibodies (MAb) 4.3, 4.6 and 4.8 reacting predominantly with cells of myeloid lineage, were tested for antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). MAb 4.6 (IgG3k) effectively mediated ADCC against K562 cells and fresh leukemic targets with effectors from healthy donors. However, for ADCC on chronic myeloid leukemia (CML) targets, effectors from CML patients in remission needed modulation with IL-2. All MAb showed significant CDC against peripheral blood (PB) and bone marrow (BM) cells obtained from CML patients in chronic phase, and untreated acute myeloid leukemia (AML) patients. MAb displayed no CDC against PB and BM cells from CML patients in remission and BM cells of Hodgkin's Disease (HD) patients with normal BM cellularity. In clonogenic assay, colony forming units (CFU) in the BM aspirate obtained from CML patients in chronic phase were significantly reduced by treatment with MAb and complement.

Adolescent↗
PubMed1990

Cell-mediated killing: effector mechanisms and mediators.

Cytolytic T lymphocytes and natural killer cells appear to mediate cell killing by several different mechanisms. In one mechanism, a pore-forming protein, called perforin or cytolysin, is exocytosed by the effector cell and is inserted into the plasma membrane of the target cells, thereby collapsing its permeability barrier. Alternatively, the cytolytic cells activate a pathway of programmed cell death that causes specific fragmentation of target cell DNA. The physiological circumstances that determine which mechanism will be employed by the effector cells have not yet been fully determined. Recent experiments suggest that perforin is employed in situations in which there are high local concentrations of interleukin-2, such as cancer and acute viral infections, while a role for the programmed cell death pathway remains to be elucidated.

Animals↗
PubMedDate not supplied

Impaired insulin-mediated erythrocyte magnesium accumulation is correlated to impaired insulin-mediated glucose diposal in aged non-diabetic obese patients.

Basal erythrocyte magnesium levels were significantly lower in obese than lean subjects. In vitro incubation in the presence of 100 mU/l insulin significantly increased magnesium erythrocyte levels in both groups of subjects. However, even in the presence of 100 mU/l, the erythrocyte magnesium content of obese patients was lower than that of control subjects. The in vitro dose-response curve of the effect of insulin on magnesium erythrocyte accumulation was shifted to the right when the red cells of obese were used, with a highly significant reduction of the maximal effect. Such reduction of the maximal effect of insulin suggests that the impairment of insulin-induced erythrocyte magnesium accumulation observed in obese patients results essentially from a post-receptor defect. In obese patients, net increase in erythrocyte magnesium levels (calculated as the difference between basal and 100 mU/l insulin-induced erythrocyte magnesium levels) was negatively correlated with basal plasma insulin levels (r = 0.79 p less than 0.01), and with body mass index (r = 0.81 p less than 0.01) while it was positively correlated with the glucose disappearance rate after glucose load (r = 0.67 p less than 0.05) and glucose metabolic clearance rate (r = 0.71 p less than 0.01). These results demonstrate that insulin-induced erythrocyte magnesium accumulation is impaired in patients with obesity and that such defect is correlated to impaired -- mediated glucosal disposal in the patients.

Aged↗
PubMed1989

C3a-induced contraction of guinea pig ileum consists of two components: fast histamine-mediated and slow prostanoid-mediated.

Guinea pig ileum is the classical experimental model for assessing the biological activity of complement-derived anaphylatoxins. Nevertheless, it is still at issue whether C3a-induced ileal contraction is entirely dependent on histamine release. We report that the contraction of the intestinal smooth muscle in response to C3a is characterized by two components, fast and slow, whose incidence and amplitude is strictly dependent on C3a concentration; the larger the concentration of C3a, the greater the incidence and magnitude of the fast component and the less frequent the slow component. The fast and slow components were characterized by a sigmoid and bell-shaped concentration-response curve, respectively. The fast component was associated with the release of endogenous histamine, increased in magnitude with the quantity of histamine released and was prevented by the histamine H1 receptor antagonist pyrilamine. On the contrary, there was no correlation between the quantity of histamine released by C3a and the magnitude of the slow component. Instead, the slow component was associated with the release of PGE2 and was prevented by the cyclooxygenase inhibitor indomethacin. Neither component was affected by the leukotriene receptor antagonist FPL 55712. Our data indicate that C3a-induced ileal contraction is partially histamine dependent in that histamine mediates only the fast component, whereas cyclooxygenase metabolites are responsible for the slow component.

Animals↗
PubMed1986

Putative roles for lysophospholipids as mediators and lipoxygenase-mediated metabolites of arachidonic acid as potentiators of stimulus-secretion coupling: dual mechanisms of p-hydroxymercuribenzoic acid-induced insulin release.

This paper explores the mechanism whereby insulin (I) secretion is stimulated by p-hydroxymercuribenzoic acid (PHMB), an agent which inhibits the esterification of arachidonic acid (AA) into phospholipids in intact rat islets. An effect of PHMB on I release could be seen even at substimulatory glucose concentrations (0-1.7 mM) and was resistant to blockade of energy flux using antimycin A, or of glucose metabolism using mannoheptulose. It was, however, inhibited by Ni++, Co++, La , replacement of chloride in the buffer by the impermeant anion isethionate or reduced ambient temperature (16 degrees C), but not by extracellular Ca++ depletion or 8-(N,N-diethylamino) octyl 3,4,5-trimethoxy-benzoate hydrochloride (a putative stabilizer of intracellular Ca++ stores); thus PHMB's effect may require the translocation of membrane-associated Ca++ stores, leading to exocytotic hormone release. Although PHMB increases the accumulation of lipoxygenase-derived metabolites of AA, I secretion at 1.7 mM glucose unexpectedly was resistant to cyclooxygenase or lipoxygenase inhibition and could not be reproduced by exogenous AA (0.18 through 262 microM). However, it could be mimicked closely by exogenous lysophosphatidylcholine, which also shared with PHMB an identical profile of reversibility and pharmacologic inhibitability. Lysophospholipid (lyso-PL)-induced I release could not be attributed to detergent effects because, for example, it occurred in the absence of significant 51Cr release. The lyso-PL effect demonstrated structural specificity (lysophosphatidyl-ethanolamine and lysophosphatidylserine being essentially inactive) and was specific for lyso-PLs as neither phosphatidylcholine itself nor glycerophosphorylcholine (the deacylation product of lysophosphatidylcholine) had any effect. In contrast to the effects of lyso-PLs, the energy-dependent effects of glucose (16.7 mM) or the amino acid alpha-ketoisocaproic acid (15 mM) on I release were abrogated by inhibitors of phospholipases or lipoxygenase. This effect of phospholipase inhibition could be circumvented by exogenous lyso-PLs. We conclude that lyso-PLs (generated by energy-dependent phospholipid deacylation or by inhibition of reacylation) may be true mediators of I release, whereas the role of concomitantly generated oxygenation products of AA is restricted to the modulation of stimulated release.

Animals↗
PubMed1986

Lidocaine inhibits macrophage mediated cytotoxicity and enhances neutrophil mediated cytotoxicity.

Peripheral blood monocyte derived macrophages and polymorphonuclear leukocytes (PMNs) obtained from normal donors kill tumor cells in vitro. However, if lidocaine is added to the macrophage tumor cell suspensions in microgram concentrations (0.1 micrograms-0.1 mg), there is marked inhibition of tumor cell killing. The inhibitory effect for the macrophages resulted from an effect of lidocaine on the effector cells. When the effector cells were preincubated with lidocaine, inhibition in macrophage mediated cytotoxicity was observed. Cytotoxicity was also inhibited when 0.01 mg of lidocaine was added to the macrophage monolayers either at the time of addition of the tumor cells or 15-60 min after addition of the tumor cells whereas no inhibition of cytotoxicity occurred when lidocaine was added more than 60 min after the initiation of the cytotoxic reaction. For the neutrophils it was observed that the lidocaine actually had an enhancing effect rather than inhibitory effect on their ability to kill tumor cells.

Antineoplastic Agents↗
PubMed1985

Reduced platelet-mediated and enhanced leukocyte-mediated fibrinolysis in experimentally induced diabetes in rats.

Studies of fibrinolytic activity in diabetes mellitus have produced conflicting results. This may be a result of methodologic insensitivity or of variable contributions of the different blood components to whole blood fibrinolysis. To explore these two possibilities, we used a sensitive solid-phase radiometric assay to examine the fibrinolytic activity of whole blood, platelet-rich plasma, leukocytes, and platelet- and leukocyte-poor plasma prepared from control rats and rats with streptozocin-induced diabetes at various times after induction of diabetes. Fibrinolytic activity of whole blood from diabetic rats after 7 days was significantly reduced, and remained reduced after longer durations of diabetes up to 28 days. Platelet-rich plasma from diabetic rats had decreased fibrinolytic activity, which followed the same time course of changes as in whole blood. The platelet contribution to whole blood fibrinolysis was further reduced in vivo after 14 days of diabetes by a reduced whole blood platelet count. In contrast, fibrinolytic activity of leukocytes from diabetic rats became enhanced after 7 days of diabetes. After 49 days of diabetes, the whole blood leukocyte count was reduced, and in vivo would offset the enhanced activity. Plasma fibrinolytic activity was small compared with that of whole blood and was unaltered in diabetic rats. We conclude that altered platelet function contributes to decreased fibrinolytic activity of whole blood in diabetic rats, and that this may be partially offset by enhanced leukocyte-mediated fibrinolysis.

Animals↗
PubMed1976

Antigen-specific and nonspecific mediators of T cell/B cell cooperation. III. Characterization of the nonspecific mediator(s) from different sources.

T cell-containing lymphoid populations produce a nonantigen-specific mediator(s) (NSM) which can replace T cell helper function in vitro in the response of B cells to sheep red blood cells (SRBC), but not to the hapten-protein conjugate, trinitrophenyl-keyhole limpet hemocyanin, (TNP-KLH). NSM produced under three conditions: 1) stimulation of KLH-primed cells with KLH; 2) allogeneic stimulation of normal spleen cells; and 3) stimulation of normal spleen cells with Con A (but not PHA) are indistinguishable on the basis of their biologic activity and m.w., estimated as 30 to 40,000 daltons by G-200 chromatography. Production of NSM is dependent on the presence of T cells. The action of NSM on B cells responding to SRBC in the presence of 2-mercaptoethanol is unaffected by severe macrophage depletion. Extensive absorption of NSM with SRBC failed to remove its activity, confirming its nonantigen-specific nature.

Animals↗
PubMed1976

Cell-mediated immunity to friend virus-induced leukemia. IV. In vitro generation of primary and secondary cell-mediated cytotoxic responses.

Primary and secondary cell-mediated cytotoxic responses to FBL-3 cells, a syngeneic Friend virus-induced leukemia in C57BL/6 mice, could be generated by in vitro techniques as tested by the 125IUdR release assay. The specificity of the cytotoxic reactions appeared to be directed against the Friend type-specific antigen and the FMR (Friend, Moloney, Rauscher) antigen which were also the major antigens for transplantation immunity to FBL-3. In comparison to the primary cytotoxic response, the secondary cytotoxic response was accelerated (detected at an earlier time after sensitization), enhanced (gave much higher levels of cytotoxicity), was also longer lasting, and could be induced by a wide dose range of tumor cells. The secondary response could only be induced with lymphocytes obtained from regressors that were resistant to FBL-3 challenge; lymphocytes from mice with progressive tumor growth had no detectable secondary response. It was found that both induction phase and the effector phase of cytotoxic responses were T cell dependent. The characteristics of these reactions were thus very similar to those obtained with in vivo immunization or challenge, providing a good correlation with in vivo tumor immunity.

Animals↗
PubMed1982

In vitro studies on the cell-mediated immune response to human brain tumors. I. Requirement for third-party stimulator lymphocytes in the induction of cell-mediated cytotoxic responses to allogeneic cultured gliomas.

For study of those properties of human gliomas that might contribute to their ability to escape cell-mediated immune attack, cultured human glioma cells were examined for their ability to elicit allogeneic cytolytic lymphocyte responses in vitro. Of 9 glioma lines, 5 were unable to elicit allogeneic cytolytic lymphocyte responses in mixed lymphocyte--tumor cultures although the concentration of stimulating glioma cells was varied over a fortyfold range. However, lymphocytes specifically cytolytic for 4 of the nonstimulatory lines could be generated if irradiated, third-party stimulator lymphocytes were added to cultures containing responder lymphocytes and glioma cells. The specific cytolytic lymphocytes produced in these cultures were inactivated by treatment with the monoclonal anti-T-cell antibody OKT3 plus complement and were thus identified as T-cells. However, nonspecific, non-T-lytic effectors were also generated. The results of these experiments demonstrated that certain cultured gliomas possessed a defect in immunogenicity that can be overcome by "help" from an allogeneic mixed lymphocyte reaction. The possible nature of this help and the potential implications of these results for the immunotherapy of human gliomas are discussed.

Astrocytoma↗
PubMed1983

Studies on the induction and expression of T cell-mediated immunity. XIV. Antigen-nonspecific oxidation-dependent cellular cytotoxicity (ODCC) mediated by sodium periodate oxidation of cytotoxic T lymphocytes.

Alloimmune murine thymus-derived cytotoxic lymphocytes (CTL) generated in vivo or in vitro are shown to lyse antigen-nonspecific target cells (tumor cells, Con A, and LPS blasts) following treatment of CTL with an oxidizing agent, sodium periodate (NaIO4). It has been shown that NaIO4 oxidizes terminal sialic acid residues of cell surface macromolecules. The presence of reactive aldehyde groups, generated by NaIO4 modification, is required for the expression of antigen-nonspecific cytotoxicity because treatment of modified cells with a reducing agent such as potassium borohydride (KBH4) resulted in the abrogation of cytotoxicity. However, KBH4 treatment of unmodified or NaIO4-modified CTL has no effect on antigen-specific cytotoxicity. The modification of CTL by NaIO4 is sufficient to lead to the formation of lymphocyte-target cell conjugates and lysis of bound targets. Monoclonal antibodies directed against the Lyt-2 antigens of CTL, but not Lyt-1 antigens, in the absence of complement inhibited the nonspecific cytotoxicity resulting from NaIO4 modification of effector lymphocytes. These findings suggest that the mere interaction with or perturbation of appropriate cell surface molecule(s) of effector lymphocytes such as Lyt antigens by receptor-ligand interaction in SCMC or by NaIO4 modification in ODCC may lead to the expression of cytotoxicity. The present studies demonstrate a functional role of surface carbohydrates on CTL in cell-to-cell recognition and interactions. Furthermore, the results suggest that target cell modification is not a requisite for recognition and lysis in an antigen-nonspecific cytotoxic system such as ODCC. However, partial blocking of ODCC by alloantibodies directed against the H-2 of unmodified target cells suggests that NaIO4-modified CTL recognize unrelated target H-2 antigens. The implication of these findings on the molecular mechanism of cell-mediated cytotoxicity is discussed.

Animals↗
PubMed1984

IgE-mediated triggering signals for mediator release from human mast cells and basophils.

Human basophils were developed in suspension culture of mononuclear cells of cord blood in the presence of conditioned medium of phytohemagglutinin-stimulated human T cells, from which interleukin 2 had been eliminated. Approximately 50-90% of cells recovered after 2-4 wk of culture were basophil granulocytes, which bear receptors with high affinity for human IgE. Sensitization of the cells with human IgE followed by challenge with anti-IgE resulted in the release of histamine and arachidonic acid (AA). In both the cultured basophils and human lung mast cells, bridging of cell-bound IgE with anti-IgE induced a transient increase in phospholipid methylation and intracellular cyclic AMP (cAMP), and these processes were followed by Ca2+ uptake and release of both histamine and AA. As demonstrated in rat mast cells, evidence was obtained that the activation of a proteolytic enzyme and phospholipid methylation induced by the bridging of IgE receptors are involved in the subsequent increase in AMP, and are an essential step for transduction of triggering signals for mediator release.

Basophils↗
PubMed1980

The comparative selectivity of adjuvants for humoral and cell-mediated immunity. II. Effect on delayed-type hypersensitivity in the mouse and guinea pig, and cell-mediated immunity to tumour antigens in the mouse of Freund's incomplete and complete adjuvants, alhydrogel, Corynebacterium parvum, Bordetella pertussis, muramyl dipeptide and saponin.

Corynebacterium parvum was the only adjuvant of those tested which consistently potentiated delayed-type hypersensitivity (DTH) to sheep red blood cells (SRBC) in the mouse, although this required the antigen-adjuvant mixture to be injected subcutaneously in the footpad rather than the flank. For induction of DTH to ovalbumin (OVA) in the guinea pig, C. parvum and MDP could be substituted for the mycobacteria in FCA. C. parvum was effective in aqueous solution provided that the OVA was absorbed onto alhydrogel. Saponin also potentiated DTH when injected with OVA in aqueous solution. C. parvum was the sole adjuvant of those tested to promote protective cell-mediated immunity (CMI) to M4 fibrosarcoma cells. It is concluded that C. parvum is a promising candidate adjuvant for promoting CMI induction without recourse to a water-in-oil emulsion.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1981

Monocyte-mediated antibody-dependent cell-mediated cytotoxicity: the role of the metabolic burst.

Human monocytes respond to opsonized microorganisms with a "metabolic burst" composed of an increase in oxygen consumption, an increase in hexose monophosphate shunt (HMPS) activity, and the generation of reactive oxygen species (ROS). We investigated the role of the metabolic burst in antibody-dependent cell-mediated cytotoxicity (ADCC) by human monocytes toward anti-D coated erythrocyte target cells because recent studies suggested a role for oxygen-dependent bactericidal mechanisms in ADCC. In normal monocytes, we found that ADCC was nearly halved under hypoxic conditions. Several agents known to impair activation of the burst, such as vincristine, cation chelators, and a sulfhydryl reagent, all decreased cytotoxicity if added before initiation of contact between target and effector cells. Cytotoxicity was inhibited by 2-deoxyglucose but not fluoride, suggesting a nonglycolytic role for glucose in ADCC, perhaps in the HMPS pathway. Although these data suggested a role for the metabolic burst in ADCC, scavengers of ROS did not impair cytotoxicity, and monocytes from chronic granulomatous disease (CGD) patients who had a defective metabolic burst had normal levels of ADCC. We conclude that ADCC toward anti-D coated erythrocyte target cells was the result of at least two independent but closely related cytotoxic pathways. Although one of these pathways appeared to involve the metabolic burst, the potentially cytotoxic reactive oxygen species did not appear to play a role in this system.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1981

Surface IgG-mediated mixed lymphocyte culture and cell-mediated lympholysis responses by immunocompetent thymus cells.

Radiolabeled preparations of murine surface immunoglobulin have been shown to bind selectively to immunocompetent responder thymus cells. Such bound immunoglobulin (especially IgG) facilitate the mixed lymphocyte culture and cell-mediated lympholysis responses between immunocompetent thymus-cell subsets. Papain digest of IgG also promote alloantigen recognition between immunocompetent thymocytes; most of the activity residues in the Fc piece. The binding of IgG per se does not activate responder thymocytes. Alloantigen-specific MLC and CML responses in vitro appear to require the participation of alloantigen receptors on the responder cell, the expression of alloantigens by the stimulator thymus cells and the binding of B-cell immunoglobulin by the immunocompetent responder thymocytes. When any of these processes are interrupted an alloantigen-specific response is not generated in vitro.

Animals↗
PubMed1980

Cell-mediated immunity in interstitial nephritis. III. T lymphocyte-mediated fibroblast proliferation and collagen synthesis: an immune mechanism for renal fibrogenesis.

Fibroblast proliferation and collagen synthesis play an important role in the progression of intersititial nephritis. To evaluate the involvement of immune mechanisms in this process, we induced intersititial nephritis in guinea pigs utilizing injections of tubular antigens. Over a 3-week period, injected animals developed a nephritis characterized by mononuclear infiltrates and expanding areas of fibrotic scar formation. Involved kidneys contained increased collagen as compared to controls. To identify mediators of the observed fibrogenesis, T lymphocytes from nephritic and control animals were stimulated with soluble tubular antigens. Dialyzed supernatants from control lymphocyte cultures contained an inhibitor of both fibroblast proliferation and collagen synthesis. In contrast, supernatants from nephritic animals demonstrated absence of inhibition and a progressively increasing titer of a factor that enhanced both kidney fibroblast proliferation and collagen synthesis. As the disease progressed, however, nephritic lymphocytes also began secreting an inhibitor of proliferation that could be detected in low levels. These studies suggest, therefore, that immune mechanisms and altered lymphocyte function may play an important role in the development, progression, and regulation of renal fibrogenesis in intersititial nephritis.

Animals↗