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At least 649 records · Page 36Linked to original sources
PubMed1982

T cell-mediated immunity in malaria. I. The Ly phenotype of T cells mediating resistance to Plasmodium yoelii.

CBA mice that recover from Plasmodium yoelii 17X infection are resistant to reinfection. T cells from these mice transfer immunity to nonimmune recipients. To analyze the nature and mode of action of these T cells, we transferred selected subsets into T cell-deprived recipients. Treatment of the T cells with anti-Ly-1 but not anti-Ly-2 serum and C abrogated their ability to transfer immunity. A mixture of anti-Ly-1 and anti-Ly-2 serum-treated cells (i.e., a population devoid of Ly-123 cells) transferred a level of immunity comparable to that of unselected T cells. Hence, the T cells mediating resistance to P. yoelii 17X were primarily of the Ly-1+23- phenotype. T cell-deprived mice reconstituted with these immune Ly-1 cells developed a) high levels of IgM and IgG antibodies, b) DTH responses to parasitized RBC, and c) enhanced blood monocyte responses. The addition of immune B cells to the Ly-1 population dramatically increased its ability to transfer immunity and induce antibody production. B cells from immune CBA/N mice had no such effect. Thus, the transfer of optimal protective immunity against malaria stems from an interaction between Ly-1 cells and a select B cell subset that CBA/N mice lack. This "selective synergy" is a protective mechanism against pathogens that has not been previously appreciated.

Animals↗
PubMed1981

Comparison of the natural cell mediated and antibody dependent cell mediated cytotoxicity measured as a function of target cell number in patients with mammary tumors and healthy female blood donors.

Peripheral blood lymphocytes of 84 patients with mammary tumors (73 malignant, 11 benign diseases) and 79 healthy female blood donors were tested in three cytotoxicity assays. Natural cell mediated cytotoxicity (NCMC) was measured against K562 cell line, antibody dependent cellular cytotoxicity (ADCC) was tested against K562 cell line sensitized with hyperimmune rabbit anti K562 sera and human 0, Rh positive (C, D, E pos.) erythrocytes sensitized with Ripley antibodies. Effector cell activity was measured as a function of the target cell number in the new cytotoxic capacity test. Maximums were determined experimentally and also by extrapolation from the measured values using the Michaelis-Menten equation. It was found, that activity of patients was lower than that of the controls in all the three tests already at an early stage of the malignant disease. Therefore introduction of the new cytotoxic capacity test to screen NCMC and ADCC is suggested.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1978

Leukocyte-adherence inhibition: a specific assay of cell-mediated immunity dependent on lymphokine-mediated collaboration between T lymphocytes.

The leukocyte-adherence inhibition (LAI) assay was studied to determine its immunologic relevance and identify the cell populations on which it depends. Two systems were employed: peripheral blood leukocytes from humans immunized with KLH, and lymph node cells from rats immunized with DNP-BCG. In both cases, LAI responses appeared about 3 to 4 days after immunization, reached a peak about 3 to 4 weeks later, and diminished thereafter. Reimmunization resulted in a booster-like response. LAI analysis in both systems showed dose-response dependency. Responses could be elicited only with the immunizing antigen. Virtual depletion of phagocytic cells had no effect on the response. E-rosette-forming cells gave an excellent response to KLH and also produced an active supernatant (lymphokine). Cells not forming spontaneous E-rosettes were inactive and could not produce active supernatants. Only those nonimmune cells that formed E-rosettes could respond to active supernatants. Thus, the LAI response is a specific indicator of cell-mediated immunity. T lymphocytes probably are required both at the antigen-reactive stage and at the stage of responding to the T cell-dependent lymphokine.

Animals↗
PubMed1994

Lipofectin-mediated versus adenovirus-mediated gene transfer in vitro and in vivo: comparison of canine and porcine model systems.

BACKGROUND: Restenosis after coronary angioplasty might be prevented by locally delivered gene therapy in conjunction with percutaneous transluminal coronary angioplasty (PTCA), since this approach should provide a sustained source of therapeutic protein within the dilated lesion. However, the potential application of gene therapy is limited by the technical barrier of efficiently transferring genes to vascular cells. METHODS: We used cultured coronary smooth muscle cells of human, porcine, and canine origin to evaluate three methods of gene transfer: recombinant adenovirus, liposomal complexes (Lipofectin), and Lipofectin supplemented with hemagglutinin. We then compared Lipofectin- and adenovirus-mediated direct gene transfer in canine and porcine coronary arteries. RESULTS: The lipofection of cultured smooth muscle cells was enhanced by adding hemagglutinin, yielding luciferase levels that were 631-fold (human), ninefold (porcine), and sevenfold (canine) higher than with Lipofectin alone. However, the recombinant adenovirus directed even higher levels of gene expression, yielding luciferase levels that were 113,000-fold (human), 450-fold (porcine), and 230-fold (canine) higher than with Lipofectin alone. After percutaneous transluminal local delivery to intact canine coronary arteries, the adenovirus produced 55 times more luciferase than did Lipofectin. In living porcine coronary arteries, adenovirus produced 95 times more luciferase than did Lipofectin. CONCLUSION: Recombinant adenovirus produces far more recombinant protein than does Lipofectin after percutaneous transluminal direct gene transfer to canine and porcine coronary arteries. Adenoviral vectors may therefore prove useful in evaluating the potential of gene therapy in large animal models of coronary restenosis.

Adenoviridae↗
PubMed1978

Cell-mediated cytotoxicity and serum-mediated blocking: evidence that their associated determinants on human tumor cells are different.

The preceding paper showed that patients with gliomas may have lymphocyte-mediated cytotoxic activity (LMC) directed against at least two determinants on the glioma cell surface. The present study showed that serum from patients with gliomas could block this LMC. The blocking activity, however, was specific for different determinants on the glioma cell than those to which the LMC was directed. Blocking activity was specific for tumor cells homotypic to those of the serum donor. It was effective, however, in blocking the cytotoxic activity against these cells of lymphocytes from patients with tumors either homotypic or heterotypic to that of the serum donor. Likewise, although patients with glioblastomas or melanomas had LMC against fetal glial cells, sera from such patients were unable to block the LMC against these fetal glial targets. The specificity of the blocking activity was confirmed by absorption of the sera with various normal and neoplastic cells. These studies have thus shown an immunologic functional dichotomy among different determinants on the glioma cell surface.

Absorption↗
PubMed1994

Endogenous gamma-aminobutyric acid (GABA) mediates ethanol inhibition of vagally mediated reflex bradycardia elicited from aortic baroreceptors.

We have previously demonstrated that ethanol depresses baroreflex bradycardia by potentiating the similar action of endogenous gamma-aminobutyric acid (GABA) in the medullary dorsal vagal complex. In the present study we examined the relative contribution of the sympathetic vs. the parasympathetic nervous system and aortic vs. carotid sinus baroreceptors in this effect. Depressor baroreflex responses were elicited in urethane-anesthetized male Sprague-Dawley rats by i.v. injection of graded bolus doses of phenylephrine or by electrical stimulation of the aortic nerve at different frequencies. Methyl-atropine (2 mg/kg i.v.) greatly attenuated, and bilateral cervical vagotomy completely eliminated, phenylephrine-induced reflex bradycardia, whereas propranolol (1 mg/kg i.v.) caused a moderate decrease in the reflex bradycardic response. Ethanol (1 g/kg i.v) did not influence the residual reflex bradycardia after methyl-atropine, but significantly decreased the residual reflex bradycardia after propranolol. Aortic nerve stimulation caused frequency-dependent hypotension, which was unaffected by methyl-atropine, and bradycardia, which was eliminated by methyl-atropine. Depletion of endogenous GABA by pretreatment of rats with 3-mercaptopropionate slightly increased the bradycardic response to aortic nerve stimulation and eliminated its susceptibility to inhibition by ethanol. Acute aortic nerve denervation moderately reduced the reflex bradycardic response to phenylephrine, which was no longer sensitive to inhibition by ethanol. These findings suggest that 1) ethanol inhibits baroreflex bradycardia but not hypotension, 2) the effect of ethanol is selective regarding both the afferent (aortic vs. carotid baroreceptors) and efferent limbs of the reflex (vagal vs. sympathetic) and 3) the effect of ethanol is mediated through endogenous GABA, probably at the level of the dorsal brainstem.

Animals↗
PubMed1976

Studies of the mechanism of lymphocyte-mediated cytolysis. VII. Two stages in the T cell-mediated lytic cycle with distinct cation requirements.

The lysis of allogeneic cells by cytolytically active T lymphocytes has been shown to involve two stages, Each with distinct cation requirements. Cytolysis required the presence of Ca++ ions, but addition of Mg++ to Ca++ containing medium synergistically enhanced target cell destruction. This synergistic effect resulted form kinetically separable events mediated by these cations. Thus, optimal adhesions between killer and target cells necessitated the presence of Mg++; interactions also occurred, but less efficiently, in the presence of Ca++. Lymphocyte-target cell interactions resulting from the present of Mg++ did not lead to the lysis of the target cell, until Ca++ were added. A "late" stage of the establishment of a target cell lesion is thus uniquely served by Ca++.

Animals↗
PubMed1996

Lack of requirement for SHP-1 in both Fas-mediated and perforin-mediated cell death induced by CTL.

The Fas (CD95)-transmitted cell death signal has been reported to involve a protein tyrosine phosphatase, SHP-1. We analyzed the role of SHP-1 in the Fas-dependent as well as the perforin-dependent pathways of CTL-mediated killing using target cells prepared from SHP-1-deficient motheaten mice. Con A blast targets prepared from both a motheaten mouse and a phenotype-normal littermate were equally sensitive to the cytolysis and DNA fragmentation induced by both perforin-deficient Fas-dependent CTL and Fas ligand-deficient perforin-positive CTL. Fas-induced DNA degradation detected by the terminal deoxynucleotide transferase reaction was also observed in the killing of motheaten thymocytes by a Fas-based CTL as well as by anti-Fas mAb. These data cast doubt on the involvement of SHP-1 in Fas-induced lymphoid cell death.

Animals↗
PubMed1998

In vitro transesterification of cocaethylene (ethylcocaine) in the presence of ethanol. esterase-mediated ethyl ester exchange esterase-mediated ethyl ester exchange.

This study reports that cocaethylene undergoes an esterase-mediated ethyl ester exchange with ethanol, resulting in an increase in the apparent in vitro t1/2, compared with control conditions. Homogenized liver from male Sprague Dawley rats in pH 7.4 phosphate buffer was centrifuged at 9000g, and the resulting supernatant (S9) fraction was collected. Tubes containing the rat S9 fraction and 50 microM cocaethylene plus aqueous buffer (control), 50 mM ethanol, or 51. 3 mM 2H6-ethanol were incubated at 37 degrees C for 4 hr. Samples were collected from the incubation tubes at various times, extracted with a solid-phase extraction system, and assayed for cocaethylene and 2H5-cocaethylene by GC/MS. Concentration-time profiles were constructed and kinetic parameters were determined. The experiment was repeated in the presence of specific and nonspecific esterase inhibitors. Enzyme kinetic parameters were also determined. Cocaethylene underwent ethyl ester exchange, being converted to 2H5-cocaethylene in the presence of 2H6-ethanol. The average apparent in vitro t1/2 value for cocaethylene (13.0 +/- 1.4 min) incubated with the S9 fraction and buffer only was increased approximately 5-fold (67.8 +/- 0.3 min) in the presence of ethanol. Formation of 2H5-cocaethylene was totally blocked with the addition of bis-(p-nitrophenyl)phosphate but was unaffected by physostigmine. The intrinsic metabolite formation clearance of 2H5-cocaethylene from cocaethylene and 2H6-ethanol (1.92 +/- 0.03 microl/min.mg protein) was several times greater than the corresponding value for cocaethylene formation from cocaine and ethanol (0.94 +/- 0.01 microl/min.mg protein) or 2H6-ethanol (0.87 +/- 0.04 microl/min.mg protein).

Animals↗
PubMed1998

Dominant signals leading to inhibitor kappaB protein degradation mediate CD40 ligand rescue of WEHI 231 immature B cells from receptor-mediated apoptosis.

Recently, we demonstrated maintenance of nuclear factor (NF)-kappaB/Rel factors plays a major role in B cell survival. Treatment of WEHI 231 immature B cells with an Ab against the surface IgM protein (anti-IgM) induces apoptosis that can be rescued by engagement of CD40 receptor. The dramatic decrease in high basal levels of NF-kappaB/Rel activity induced by anti-IgM treatment led to cell death. CD40 ligand (CD40L) treatment prevented the drop in NF-kappaB/Rel factor binding by inducing a sustained decrease in inhibitor (I) kappaB-alpha and transient decrease in IkappaB-beta protein levels. In this study, we have investigated the regulation of these NF-kappaB/Rel-inhibitory proteins. In exponentially growing WEHI 231 cells, the IkappaB-alpha and IkappaB-beta proteins decayed with an approximate t1/2 of 38 and 76 min, respectively, which was blocked effectively upon addition of the proteasome-specific inhibitor (benzylcarbonyl)-Leu-Leu-phenylalaninal (Z-LLF-CHO). Anti-IgM treatment stabilized IkappaB-alpha and IkappaB-beta proteins. CD40L treatment resulted in a dramatic decrease in t1/2 (< 5 min) for both IkappaB molecules, which was inhibited by addition of Z-LLF-CHO. CD40L treatment also caused a delayed increase in IkappaB-beta mRNA levels, most likely contributing to the observed recovery of IkappaB-beta levels. Microinjection of IkappaB-alpha-glutathione S-transferase fusion protein into nuclei of WEHI 231 cells ablated protection by CD40L from receptor-mediated killing. Furthermore, CD40L rescued apoptosis induced upon microinjection of a vector expressing wild-type IkappaB-alpha, but not a 32A/36A mutant form of IkappaB-alpha, unable to be phosphorylated and hence degraded. Thus, control of turnover of IkappaB proteins by CD40L plays a major role in maintenance of NF-kappaB/Rel and resultant rescue of WEHI 231 cells from apoptosis.

Animals↗
PubMed2026

Phytoplasma-plant interactions: effector-mediated host reprogramming, hormonal crosstalk, metabolic alterations and plant-mediated vector manipulation.

Phytoplasmas are wall-less, phloem-restricted bacterial pathogens that infect over 1,000 plant species, causing substantial losses in agriculture, horticulture, and forestry worldwide. Despite their reduced genomes and limited metabolic autonomy, these obligate parasites colonize diverse hosts through secreted effector proteins that extensively reprogram plant development, metabolism, immune signalling, and vector interactions. Advances in genomics, transcriptomics, proteomics, metabolomics, and functional studies have substantially clarified the molecular basis of phytoplasma pathogenicity and symptom development. This review synthesizes current understanding of phytoplasma-plant interactions, covering phytoplasma biology, genome evolution, and the infection cycle across plant and insect vector hosts. We examine the molecular functions of key effectors, SAP11, SAP54/PHYL1, SAP05, TENGU, SWP1, and recently identified virulence factors, focusing on how they target host transcription factors, phytohormone networks, protein degradation pathways, and immune responses to promote colonization and disease progression. We further discuss how phytoplasma infection disrupts phytohormone signalling, primary and secondary metabolism, and developmental programs to produce characteristic disease symptoms, with particular attention to pathogen-induced changes in host volatiles and nutritional quality that alter vector behaviour and enhance transmission. Finally, we summarize insights from multi-omics studies and emerging management strategies, including CRISPR-based genome editing, RNAi, rapid molecular diagnostics, resistant cultivars, microbiome-based approaches, and sustainable vector control, and highlight key knowledge gaps and priorities for developing effective, environmentally sustainable phytoplasma disease management.

Phytoplasma↗
PubMed2006

Aldose reductase mediates the lipopolysaccharide-induced release of inflammatory mediators in RAW264.7 murine macrophages.

Abnormal production of inflammatory cytokines and chemokines is a key feature of bacterial endotoxin, lipopolysaccharide (LPS)-induced inflammation, and cytotoxicity; however, the mechanisms regulating production of inflammatory markers remain unclear. Herein, we show that inhibition of the aldehyde-metabolizing enzyme aldose reductase (AR; AKR1B3) modulates NF-kappaB-dependent activation of inflammatory cytokines and chemokines in mouse serum, liver, heart, and spleen. Pharmacological inhibition or small interfering RNA ablation of AR prevented the biosynthesis of tumor necrosis factor-alpha, interleukin 1beta, interleukin-6, macrophage-chemoattractant protein-1, and cyclooxygenase-2 and prostaglandin E(2) in LPS-activated RAW264.7 murine macrophages. The AR inhibition or ablation significantly attenuated LPS-induced activation of protein kinase C (PKC) and phospholipase C (PLC), nuclear translocation of NF-kappaB, and phosphorylation and proteolytic degradation of IkappaBalpha in macrophages. Furthermore, treatment of macrophages with 4-hydroxy-trans-2-nonenal (HNE), and cell-permeable esters of glutathionyl-4-hydroxynonanal (GS-HNE) and glutathionyl-1,4-dihydroxynonane (GS-DHN) activated NF-kappaB and PLC/PKC. Pharmacological inhibition or antisense ablation of AR that catalyzes the reduction of GS-HNE to GS-DHN prevented PLC, PKC, IKKalpha/beta, and NF-kappaB activation caused by HNE and GS-HNE, but not by GS-DHN, suggesting that reduced GS-lipid aldehydes catalyzed by AR propagate LPS-induced production of inflammatory markers. Collectively, these data provide evidence that inhibition of AR may be a significant therapeutic approach in preventing bacterial endotoxin-induced sepsis and tissue damage.

Aldehyde Reductase↗
PubMed1996

Brain synaptosomes display a diadenosine tetraphosphate (Ap4A)-mediated Ca2+ influx distinct from ATP-mediated influx.

Studies undertaken to compare the effects of Ap4A and ATP on altering intrasynaptosomal Ca2+ levels from deermouse brain reveal that both ligands induce a rapid influx of extracellular Ca2+. The Ca2+ profile elicited by 167 microM Ap4A is "spike-like" (half-time for decline to baseline, 19.1 +/- 1.2 sec), in contrast to the gradual decline observed with ATP (104.0 +/- 7.4 sec). DIDS (4-4'-diisothiocyano-2,2'-disulfonic acid stilbene) and suramin preincubation alter only the ATP-induced Ca2+ profile. Cross-desensitization studies indicate that prior application of ATP does not significantly affect the Ca2+ influx elicited by Ap4A, and that prior application of Ap4A does not affect the Ca2+ influx elicited by ATP. These results demonstrate that extracellular Ap4A and ATP elicit distinct intrasynaptosomal Ca2+ influx profiles, and suggest that these two nucleotides may be interacting with distinct purinoceptor subclasses or purinoceptor-effector complexes. Subjecting the synaptosomes simultaneously to depolarization and Ap4A, or to depolarization and ATP, induces an additive effect on Ca2+ influx. Preincubation with verapamil negates the effects of depolarization without modifying the ligand-elicited Ca2+ fluxes. These results indicate the presence of Ap4A and ATP ligand-gated channels that may function as modulators of neuronal activity.

Adenosine Triphosphate↗
PubMed1999

Lectin-Mediated Drug Targeting: Discrimination of Carbohydrate-Mediated Cellular Uptake between Tumor and Liver Cells with Neoglycoconjugates Carrying Fucose Epitopes Regioselectively Modified in the 3-Position.

The circumvention of efficient "carbohydrate traps" in the liver is required for targeting glycoconjugates on tumor cells. As shown in the model system of bovine serum albumin (BSA) conjugates, the nature of R(1)-R(3) of the fucose epitope plays an important role in the discrimination of cellular uptake between tumor and liver cells as well as in the cytotoxic activity.

Journal Article↗
PubMed1999

Dual role of TNF-alpha in NK/LAK cell-mediated lysis of chronically HIV-infected U1 cells. Concomitant enhancement of HIV expression and sensitization of cell-mediated lysis.

The U937-derived chronically HIV-infected U1 cell line and uninfected U937 cell clones were efficiently lysed by both unstimulated (NK) and IL-2-stimulated (lymphokine-activated killer; LAK) peripheral blood mononuclear cells (PBMC) of healthy HIV-seronegative donors. Pretreatment of target cells with IFN-gamma down-modulated killing of both U1 cells and two U937 cell clones, and up-regulated MHC class I expression. In contrast, TNF-alpha enhanced the sensitivity of infected U1 cells, but not of U937 cell clones to NK / LAK cell lysis. Co-cultivation of IL-2-stimulated PBMC with U1 cells triggered expression and replication of HIV by cell-cell contact, and this effect was inhibited by anti-TNF-alpha antibodies (Ab); virus production was partially inhibited by zidovudine. Of interest, anti-TNF-alpha Ab protected U1 cells from LAK cell activity. Thus, TNF-alpha can induce HIV expression from chronically infected U1 cells, but also plays an important role in sensitizing these cells to lysis.

Coculture Techniques↗
PubMed2004

Homoharringtonine mediates myeloid cell apoptosis via upregulation of pro-apoptotic bax and inducing caspase-3-mediated cleavage of poly(ADP-ribose) polymerase (PARP).

Homoharringtonine (HHT) is a plant alkaloid with antileukemia activity that is currently being used for treatment of acute, chronic leukemias and MDS. In this study, we show that HHT can induce apoptosis in a variety of human myeloid leukemia cell lines (U937, HL-60, HEL, THP, and K562). U937 and HL60 cells undergo rapid apoptosis on treatment with HHT, as indicated by increased annexin V binding capacity, caspase-3 activation, and cleavage of poly(ADP-ribose) polymerase (PARP). In addition, the expression of bax is upregulated during HHT-induced cell death, whereas the expression of bcl-2 is only slightly decreased. Importantly, treatment of primary leukemic cells, obtained from acute myeloid leukemia patients, resulted in rapid apoptosis. Thus, our data provide the mechanism of HHT and justify the use of HHT in the treatment of human myeloid leukemia.

Annexin A5↗