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Results for “cell type targeted”

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At least 19 recordsLinked to original sources

PubMed1975

Selective and non-selective lymphocytotoxicity in human melanoma: observation on the effect of long-term culture and fetal bovine serum on target-cell sensitivity to lymphocytes.

In vitro cell mediated cytotoxicity (CMC) assays have been conducted in a human melanoma system with a 3H-proline retention technique. Melanoma target cells from long-term cultures ("cell lines") are found to exhibit increased susceptibility for lymphocyte cytotoxicity in comparison to the same target cells from short-term culture. The higher sensitivity of the "cell line" derived target cells is seen with lymphocytes, irrespective of diagnosis of the donor. In parallel experiments with the target cells grown in medium supplemented with fetal calf serum (FCS) and AB+ human serum (from a normal male doner), the melanoma target cells grown with FCS do not show any enhanced cytotoxicity, suggesting no causal relationship of such enhanced sensitivity of "cell line"-derived target cells to "heterologous melanoma antigens" that might have been acquired by the target cells following the use of FCS in tissue culture. In controlled assays of in vitro CMC, lymphocytes from melanoma patients (14/44) exhibited selective cytotoxicity (destruction of only one target-cell type) against the melanoma target cells, whereas only 3/97 control lymphocytes (other malignancies and normal donors) showed such melanoma-selective cytotoxicity. This difference is statistically significant at p less than 0.001. Non-selective cytotoxicity (destruction of two or more unrelated target cell types) was seen with lymphocytes from 9/44 melanoma patients, 13/51 patients with other malignancies and 8/46 normal donors. No correlation of selective cytotoxicity could be established with donors' age, sex, stage of disease, therapy or history of blood transfusion. Such a correlation may emerge as our series becomes larger. Despite the lack of any correlation between selective cytotoxicity and disease status, our study reaffirms the existence of selective cytotoxicity by melanoma patients' lymphocytes against melanoma target cells.

Animals↗

PubMed1975

Relationship of cloning inhibition factor, "lymphotoxin" factor, and proliferation inhibition factor release in vitro by mitogen-activated human lymphoctes.

Human lymphocytes were stimulated in vitro with mitogens, phytohemagglutinin and concanavalin A to secrete proliferation inhibitory factor (PIF), cloning inhibitory factor (CIF), and lymphotoxin (LT). These three activities were demonstrable in the same supernatant, moreover, the particular effect observed was shown to depend on the concentration of the medium and the type of target cell employed. In general, the medium effects on target cells were: a) cytotoxic at high concentrations, b) growth inhibitory at intermediate concentrations, and c) only temporarily growth inhibitory at low concentrations. The absolute concentration producing a certain effect varied, depending on the target cell type employed. In addition, the sensitivity of the target cells to LT parallels the sensitivity of the cell to each of the other activities, PIF and CIF, and no species specificity was observed.

Adenoids↗

PubMed1977

Testosterone and cellular response.

With the possible exception of male germ cells, the androgen responsiveness of all the target cell types in the mammalian body appears to be mediated by a single species of nuclear-cytosol androgen-receptor protein which is apparently specified by the X-linked Tfm locus. Although this receptor has the highest binding affinity to DHT, it can in the absence of DHT function with TES, albeit less efficiently. For the testosterone-dependent differentiation of embryonic organs, the androgen responsiveness of underlying mesenchymal cells appears to be more important than that of epithelial elements. Some of the androgen effects on apparent target cell types are through the indirect route involving the hypothalamopituitary axis.

Androgen-Insensitivity Syndrome↗

PubMed2025

Transcript-guided targeted cell enrichment for scalable single-nucleus RNA sequencing.

Large-scale single-cell atlases have revealed many aging- and disease-associated cell types, yet these populations are often underrepresented in heterogeneous tissues, limiting detailed molecular analyses. To address this, we developed EnrichSci-a scalable, microfluidics-free platform that combines hybridization chain reaction RNA fluorescence in situ hybridization (FISH) with combinatorial indexing to profile single-nucleus transcriptomes of target cell types with full gene-body coverage. Applied to oligodendrocytes in the aging mouse brain, EnrichSci uncovered aging-associated molecular dynamics across distinct oligodendrocyte subtypes, revealing both shared and subtype-specific gene expression changes. Additionally, we identified aging-associated exon-level signatures missed by conventional gene-level analyses, highlighting post-transcriptional regulation as a critical dimension of cell-state dynamics in aging. By coupling transcript-guided enrichment with a scalable sequencing workflow, EnrichSci provides a versatile approach to decode dynamic regulatory landscapes in diverse cell types from complex tissues.

Animals↗

PubMed1978

Antibody-dependent cell-mediated cytotoxicity to herpes simplex virus type 2 infected target cells in the course of cervical carcinoma.

The antibody-dependent cell-mediated cytotoxicity (ADCC) assay was used as a sensitive instrument to study if specific antibodies acting synergistically with lymphocytes to induce target cell destruction, could be detected in sera from patients with cervical carcinoma. Significant cytotoxicity to herpes simplex type 2 (HSV-2) infected target cells was observed in sera of 17 out of 23 (74%) surviving patients with cervical cancer who were followed with at least two serum samples. A rise in cytolytic activity was also observed in 11 out of 23 cases. Seven out of 14 tumor-bearing cervical cancer patients with progressing cervical lesions showed significant cytotoxicity, but four of the seven had lost activity in later sera. When 43 patients surviving the observation period of 24--60 months with no signs of residual tumors were compared with 23 severely ill cervical cancer patients, patients with less advanced cancer had significantly higher cytolytic activity.

Animals↗

PubMed2026

Cell type-selective targeting by heterobifunctional protein binders via in-cell enrichment.

Non-catalytic heterobifunctional protein binders promise to expand the range of therapeutic options by establishing complexes between key target proteins and accessory presenter proteins equipped with additional properties. Here, we systematically investigate the rational design of such molecules, explore the biochemical basis of complex formation and determine how they achieve cellular efficacy using the endogenously expressed immunophilin FKBP12 as presenter protein and the transcriptional regulator BRD4 as target protein. We present classes of bifunctional molecules that enable selective, FKBP12-dependent killing of specific cell types at subnanomolar concentrations and allow to differentiate between closely related bromodomains of the BET family. We propose that the strongly potentiated efficacy of these bifunctional compounds is based on cellular enrichment through binding to the highly abundant presenter protein FKBP12, a mechanism we term "CellTrap". Our findings substantiate the concept that highly expressed, non-essential proteins can be repurposed as selective recruiters to expand therapeutic windows of existing small-molecule inhibitors, opening new avenues for designing targeted drugs with improved cell-type specificity.

Tacrolimus Binding Protein 1A↗

PubMed1979

In vitro expression of cytotoxicity by macrophages is independent of the actual serum concentration.

In utilizing the same effector and target cells, similar arrangement and population density of cells but varying the actual serum concentration in the range between 1 and 50% fetal calf serum, it was attempted to accurately assess the dependence of in vitro cytolysis expressed by adherent, predominantly phagocytic mononuclear cells ('macrophages') on the actual serum concentration. The results show that the extent to which cytotoxicity by activated macrophages against a given target cell type was expressed, was within a comparable range independent of the actual serum concentration. This holds true for each of the 9 target cell lines examined although with some of the cell lines there was a certain tendency towards high cytotoxicity in the range between 5 and 20% serum.

Animals↗

PubMed1977

In vitro cytotoxicity of serum and peripheral blood leukocytes for equine herpesvirus type 1-infected target cells.

The immune response in horses following experimental infection with equine herpesvirus type 1 (EHV-1) was assessed by measuring cytotoxicity for EHV-1-infected target cells. A technique was developed, using [125I]5-iodo-2'-deoxyuridine ([125I]IUDR)-labeled equine fetal kidney cells infected with EHV-1 as the target cells. It was shown that peripheral blood leukocytes from a recovered horse were capable of lysing target cells, as measured by the loss of radio-active label. Following the experimental infection of specific-pathogen-free ponies with EHV-1, cytotoxicity was obtained with fresh autologous serum, peripheral blood leukocytes in autologous serum, and washed peripheral blood leukocytes. Cytotoxicity of the serum and peripheral blood leukocytes was detected as early as one day after infection. It is suggested that cytotoxic antibodies or cells could play an important part in restricting virus spread after infection of the horse with EHV-1.

Animals↗

PubMed1975

Cytotoxicity mediated by soluble macrophage product(s).

The soluble macrophage product(s) released by nonimmune mouse peritoneal macrophages exposed to endotoxin or from listeria-immune macrophages after incubation with specific antigen mediated cytotoxic activity against malignant cell types and, to a lesser extent, against normal cells. Only undiluted supernatants from nonimmune or listeria-immune macrophages cultured with medium 199 alone exerted some degree of cytotoxicity on the different target cell types tested. The macrophage product(s) retained cytotoxic activity storage at minus 20 degrees C, was stable when heated at 56 degrees C for 30 minutes, but was completely inactivated when exposed at 100 degrees C for 5 minutes. In the presence of 15 mug exogenous lysozyme/ml, the cytotoxic activity of the macrophage product(s) was significantly enhanced.

Animals↗

PubMed2025

Lentiviral CRISPRa/i in the adult prairie vole brain: modulating neuronal gene expression without DNA cleavage.

Prairie voles (Microtus ochrogaster) are a powerful model for studying the neurobiology of social bonding, yet tools for region- and cell type-specific gene regulation remain underdeveloped in this species. Here, we present a lentivirus-mediated CRISPR activation and interference (CRISPRa/i) platform for somatic gene modulation in the prairie vole brain. This system enables non-mutagenic, titratable regulation of gene expression in the adult brain without germline modification. Our dual-vector system includes one construct expressing dCas9-VPR (VP64-p65-Rta) referred to as CRISPRa or dCas9-KRAB-MeCP2 (Kruppel-associated box-methyl CpG binding protein 2), referred to as CRISPRi under a neuron-specific promoter, and a second construct delivering a U6-driven sgRNA (single guide RNA) alongside an elongation factor 1 alpha (EF1α)-driven mCherry reporter. We detail the design, production, and stereotaxic delivery of these tools and demonstrate their application by targeting four genes implicated in social behavior (Oxtr, Avpr1a, Drd1, and Drd2) across two mesolimbic brain regions: the nucleus accumbens and ventral pallidum. Gene expression analyses confirmed robust, bidirectional transcriptional modulation for selected targets, establishing a proof of concept for CRISPRa/i in this non-traditional model. The dual-vector design is readily adaptable to other gene targets, cell types, and brain regions, and can be multiplexed to provide a flexible and scalable framework for investigating gene function in behaviorally relevant circuits. These advances represent the first successful implementation of somatic CRISPRa/i in prairie voles and expand the genetic toolkit available for this species.

Avpr1a↗

PubMed1978

Recognition of virally transformed cells by lymphocytes from patients with prostatic cancer.

Data presented describe the first assay using human peripheral blood lymphocytes (PBL) against two unique virally transformed cell lines in vitro. Human cells transformed by a cytomegalovirus (CMV-Mj) isolated from normal human prostate tissue were used as target cells in microcytoxicity assays with lymphocytes from 100 patients. Three target cell types were used: control human embryonic lung cells (HEL), transformed HEL cells (CMV-Mj-HEL-2), and transformed HEL cells retrieved from tumors induced in athymic nude mice (CMV-Mj-HEL-2, T-1) by injection of CMV-Mj-HEL-2 cells. PBL preparations from 84% of all patients tested significantly killed CMV-Mj-HEL-2, T-1 cells. However, only PBL from patients with prostatic carcinoma were cytotoxic for CMV-Mj-HEL-2 cells significantly more often than for control HEL. The implications of this approach are discussed.

Adult↗

PubMed1979

Metabolism of cyclic AMP in isolated renal tubules: effects of prostaglandins and parathyroid hormone.

Concentrations of cyclic AMP (cAMP) were increased in isolated renal cortical tubules from hamsters by both parathyroid hormone (PTH) and prostaglandin E1 (PGE1) with maximal effects of PGE1 being 6-8 fold greater than those of PTH during a 10 min period. However, cAMP concentrations in cells treated with 1-methyl-3-isobutylxanthine (MIX) were increased with maximal concentrations of either hormone to the same degree. Similar effects of both hormones were observed on adenylate cyclase activity in renal homogenates. Simultaneous addition of hormones produced changes in both cAMP concentrations in intact tubules as well as adenylate cyclase activity of homogenates which were not completely additive. Degradation of cAMP, estimated in intact tubules as the difference in cAMP levels in the presence and absence of MIX, was increased by both hormones, however, changes were 2-3 fold greater in tubules exposed to PTH than to PGE1. Neither hormone directly altered cAMP phosphodiesterase (PDE) activity in either 30,000 x g supernatant or pellets from renal cortical homogenates. The results suggest that both hormones increase the production of cAMP in renal cortical tubules and may share a common target cell type in this response. Degradation of cAMP, however, is differentially effected by the two hormones, probably reflecting differences exerted on intracellular mechanisms regulating the enzymatic hydrolysis of cAMP.

1-Methyl-3-isobutylxanthine↗

PubMed2026

Genome-wide association analyses highlight the neuronal contribution to multiple sclerosis susceptibility.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease. Previous genetic studies have identified susceptibility loci that primarily impact immune cells and microglia. Here we performed a multi-ancestry genome-wide association study of 20,831 MS cases and 729,220 controls and identified 236 susceptibility variants outside of the major histocompatibility complex, including four novel genomic loci. We also derived a polygenic score for MS; while optimized for European ancestry, it is informative for African American and Latino individuals. Integrating single-cell data from blood and brain tissue, we identified 76 candidate causal genes. Inhibitory neurons emerged as a key target cell type for MS-associated variants, with seven loci, including STAT3, displaying altered expression only in these cells. The STAT3 variant is also associated with cognition and white matter integrity in individuals with no MS and greater sNfL levels in individuals with MS, suggesting that MS susceptibility may reflect reduced central nervous system resilience to inflammatory challenges.

Humans↗

PubMed1977

Mycoplasma-dependent activation of normal lymphocytes: induction of a lymphocyte-mediated cytotoxicity for allogeneic and syngeneic mouse target cells.

Mycoplasma arthritidis, M. hominis, and M. arginini were tested for their ability to induce a cytotoxic response from normal CBA mouse lymphocytes against 51Cr-labeled allogeneic target cells. In most cases, the mycoplasmas alone were not toxic for the target cells. Furthermore, the mycoplasmas did not result in decreased lymphocyte viability but, in fact, contributed to enhanced lymphocyte survival. In the absence of normal CBA lymphocytes, mycoplasmas alone did not induce a significant amount of cell damage in either the allogeneic or the syngeneic target cells. Strains of M. arthritidis and M. hominis, when added to the lymphocyte-target cell mixtures, induced statistically significant increases in 51Cr release from both target cell types at each assay period after 6 h. The release of 51Cr was taken as a measure of cell death. M. arginini induced only low levels of cytotoxicity or none at all. Both arthritogenic and non-arthritogenic strains of M. arthritidis induced the cytotoxic response. The degree of cytotoxicity produced was directly related to the size of the initial inoculum. The presence or absence of serum in the culture medium did not contribute significantly to the cytotoxicity response.

Animals↗

PubMed1978

Inhibitory effects of extracellular products from oral bacteria on human fibroblasts and stimulated lymphocytes.

Extracellular products of 12 strains of Streptococcus mutans and 5 additional species of oral bacteria were analyzed for their ability to inhibit proliferation of fibroblastoid cells (HeLa and AV3) and blast transformation of human peripheral blood lymphocytes obtained from normal individuals. Products from S. mutans strains AHT and BHT, Streptococcus intermedius, and Actinomyces viscosus inhibited [3H]thymidine uptake by fibroblastoid cells and phytohemagglutinin-stimulated lymphocytes. Products from S. mutans E49, Streptococcus salivarius, and Actinomyces naeslundii inhibited blast transformation of human lymphocytes but did not significantly inhibit the growth of fibroblastoid cells. Preparations from S. intermedius gave the greatest inhibitory activity against both target cell types; initial characterization of this preparation suggested a single factor active in both assays, in that the heat lability and Sephadex G-200 elution profile were similar for the inhibitory activity seen with the two cell types. The molecular weight of the inhibitor, estimated by gel filtration on Sephadex G-200 and Ultragel AcA34, was approximately 160,000. The results strongly suggest that oral bacteria produce heat-labile substances that interfere with fibroblast proliferation and alter the lymphocytic immunological response.

Actinomyces↗

PubMed1976

Antibody-dependent cell-mediated cytotoxicity to target cells infected with type 1 and type 2 herpes simplex virus.

The phenomenon of antibody-dependent cell-mediated cytoxicity (ADCC) has been extended to include target cells acutely infected with herpes simplex type 1 virus (HSV-1) or herpes simplex type 2 virus (HSV-2) in an in vitro system that employs immune human serum and human blood mononuclear cells. The cytotoxic reaction was detectable after 1 hr of incubation and was complete between 4 and 8 hr. The amount of ADCC noted was directly proportional to the logarithm(10) of the effector: target cell ratio (E:T), and ADCC was noted at E:T as low as 1:1. The mononuclear effector cell was present in the blood of both HSV immune and non-immune individuals. The immune serum factor was demonstrated to be an antibody with specificity for HSV membrane antigen(s) and was reactive with target cells infected with either of the two HSV types. The antibody rendered the mononuclear cell cytotoxic by sensitization of the target cell rather than by direct attachment to or "arming" of the mononuclear cell. The physiochemical properties of the antibody as well as its presence in cord blood demonstrated that it is an immunoglobulin on the IgG class.

Absorption↗

PubMed1979

Natural killing of herpes simplex virus type 1-infected target cells: normal human responses and influence of antiviral antibody.

Studies of a mouse model of genetic resistance to herpes simplex virus type 1 (HSV-1) indicate that the marrow-dependent effector cell of allogeneic resistance plays an important role in natural resistance to this virus infection. Since the marrow-dependent effector cell appears to be closely related to the natural killer (NK) cells, an NK assay with HSV-1-infected fibroblasts [NK(HSV-1)] has been developed to study this resistance mechanism in humans. Incubation of effector and target cells for 12 to 14 h gave the greatest percent specific release (%SR) and kept spontaneous (51)Cr release from infected target cells below 35%. Patients with Bruton's agammaglobulinemia demonstrated significant kill indicating antiviral antibody was not necessary. Seropositive individuals gave a 9% greater%SR than seronegative individuals. Depletion of B-cells consistently diminished NK (HSV-1) for seropositive individuals and augmented kill for seronegative individuals. Although antiviral antibody produced in culture may contribute to NK (HSV-1), depletion of B-cells allowed quantitation of NK (HSV-1) to the exclusion of most of the antibody-dependent kill. The NK cells detected by this assay showed many of the properties reported for NK cells with K562 targets. Two patients with severe herpesvirus infections demonstrated NK (HSV-1) responses greater than 2 standard deviations below the normal mean. Since normal individuals with virus infections have higher rather than lower natural kill, the low NK (HSV-1) may reflect their susceptibility to the virus infection.

Antibodies, Viral↗

PubMed2025

Identifying independent causal cell types for human diseases and risk variants.

The SNP-heritability of human diseases is extremely enriched in candidate regulatory elements (cREs) from disease-relevant cell types. Critical next steps are to understand whether these enrichments are driven by multiple causal cell types and whether individual variants impact disease risk via a single or multiple of cell types. Here, we propose CT-FM and CT-FM-SNP, 2 methods accounting for cREs shared across cell types to identify independent sets of causal cell types for a trait and its candidate causal variants, respectively. We applied CT-FM to 63 GWAS summary statistics (average N = 417K) using 924 cRE annotations, primarily from ENCODE4. CT-FM inferred 79 sets of causal cell types, with corresponding SNP-annotations explaining 39.0 ± 1.8% of trait SNP-heritability. It identified 14 traits with independent causal cell types, uncovering previously unexplored cellular mechanisms in height, schizophrenia and autoimmune diseases. We applied CT-FM-SNP to 39 UK Biobank traits and predicted high-confidence causal cell types for 3,091 candidate causal non-coding SNPs-trait pairs. Our results suggest that most SNPs affect a phenotype via a single set of cell types, whereas pleiotropic SNPs might target different cell types depending on the phenotype context. Altogether, CT-FM and CT-FM-SNP shed light on how genetic variants act collectively and individually at the cellular level to affect disease risk.

Journal Article↗