Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cellular Microenvironment”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,459 records · Page 81Linked to original sources
PubMed1997

Toxicity of mustard gas skin lesions.

Although the exact pathogenesis of mustard gas-induced dermal toxicity remains elusive, morphopathological data gathered in controlled animal and in vitro investigations is providing important clues as to approximate mechanisms. Our laboratory has been studying dermal effects of the chemical warfare agent, sulfur mustard, in a variety of animal models, cultured isolated human cells, and in vitro organotypic skin models. Published anatomical, pathological, and ultrastructural results of these studies have documented consistent cellular and basement membrane zone effects irrespective of the model. Cellular effects include the early targeting of basal cells of the stratum basale to the exclusion of other epidermal cells, with nuclear and cytoplasmic indications of cell injury and cell death. Effects on the basement membrane zone include the formation of characteristic microvesicles in the lamina lucida of those models which possessed structural components of a true basement membrane. We are now investigating effects on proteins of the basement membrane microenvironment and correlate in the present paper the morphopathology of sulfur mustard dermal lesions with immunohistochemical study of bullous pemphigoid antigen, laminin, type IV collagen, and type VII collagen.

Animals↗
PubMed2005

Human mesenchymal stem cells require monocyte-mediated activation to suppress alloreactive T cells.

Human bone marrow-derived mesenchymal cells (MSCs) are precursors of nonhematopoietic mesenchymal cells of the bone marrow microenvironment. MSCs were shown to inhibit alloreactive T lymphocytes, but the mechanism and mediators of this effect are not fully understood. Here we describe a novel interaction between blood monocytes and bone marrow-derived, culture-expanded MSCs, which results in inhibition of T-lymphocyte activation. We found that CD14+ monocytes from blood activate MSCs to secrete inhibitory molecules that lead to inhibition of alloreactive T cells. This cellular communication is not contact-dependent, but rather is mediated by soluble factors that include interleukin (IL)-1beta. MSC-mediated inhibition of alloreactive T lymphocytes is associated with downregulation of activation markers CD25, CD38, and CD69 detected both in CD4+ and CD8+ T lymphocytes. The cytokines secreted by MSCs that mediate T-cell inhibition include transforming growth factor-beta1, but not IL-10. The interaction between blood monocytes and the MSCs represents a unique immune regulatory paradigm that can potentially be exploited in clinic.

Antigens, CD↗
PubMed2005

Development of occlusive neointimal lesions in distal pulmonary arteries of endothelin B receptor-deficient rats: a new model of severe pulmonary arterial hypertension.

BACKGROUND: Human pulmonary arterial hypertension (PAH) is characterized by proliferation of vascular smooth muscle and, in its more severe form, by the development of occlusive neointimal lesions. However, few animal models of pulmonary neointimal proliferation exist, thereby limiting a complete understanding of the pathobiology of PAH. Recent studies of the endothelin (ET) system demonstrate that deficiency of the ET(B) receptor predisposes adult rats to acute and chronic hypoxic PAH, yet these animals fail to develop neointimal lesions. Herein, we determined and thereafter showed that exposure of ET(B) receptor-deficient rats to the endothelial toxin monocrotaline (MCT) leads to the development of neointimal lesions that share hallmarks of human PAH. METHODS AND RESULTS: The pulmonary hemodynamic and morphometric effects of 60 mg/kg MCT in control (MCT(+/+)) and ET(B) receptor-deficient (MCT(sl/sl)) rats at 6 weeks of age were assessed. MCT(sl/sl) rats developed more severe PAH, characterized by elevated pulmonary artery pressure, diminished cardiac output, and right ventricular hypertrophy. In MCT(sl/sl) rats, morphometric evaluation revealed the presence of neointimal lesions within small distal pulmonary arteries, increased medial wall thickness, and decreased arterial-to-alveolar ratio. In keeping with this, barium angiography revealed diminished distal pulmonary vasculature of MCT(sl/sl) rat lungs. Cells within neointimal lesions expressed smooth muscle and endothelial cell markers. Moreover, cells within neointimal lesions exhibited increased levels of proliferation and were located in a tissue microenvironment enriched with vascular endothelial growth factor, tenascin-C, and activated matrix metalloproteinase-9, factors already implicated in human PAH. Finally, assessment of steady state mRNA showed that whereas expression of ET(B) receptors was decreased in MCT(sl/sl) rat lungs, ET(A) receptor expression increased. CONCLUSIONS: Deficiency of the ET(B) receptor markedly accelerates the progression of PAH in rats treated with MCT and enhances the appearance of cellular and molecular markers associated with the pathobiology of PAH. Collectively, these results suggest an overall antiproliferative effect of the ET(B) receptor in pulmonary vascular homeostasis.

Animals↗
PubMed2004

GABAergic mechanisms constraining the activity of the hypothalamo-pituitary-adrenocortical axis.

There are two major inhibitory mechanisms that constrain the activity of the hypothalamo-pituitary-adrenocortical axis: the hormonal negative feedback and the neural inhibition including that posed by the GABAergic neurons. This chapter summarizes our recent morphologic and functional findings on the role of gamma-aminobutyric acid (GABA) in the transcriptional regulation of hypophyseotropic neuropeptide genes in the parvocellular neurosecretory cells of the hypothalamic paraventricular nucleus (PVH). We used organotypic hypothalamic slice cultures and in vivo microinjection protocols in combination with in situ histologic and ultrastructural procedures to address the role of local interneurons in the regulation of hypothalamic effector neurons. Under basal conditions, an intrinsic GABAergic mechanism in the PVH microenvironment was revealed that by itself, without limbic contribution, impinged a tonic inhibitory influence on the parvocellular corticotropin-releasing hormone (CRH) neurons in vitro. In vivo, remote inputs were superimposed on the local circuit, allowing differential transcriptional regulation of CRH and arginine vasopressin (AVP) genes in the hypophyseotropic neurons. During stress, GABAergic cells that are known to project to the PVH become activated and are involved in restraining the cellular, transcriptional, and hormonal responses to stress.

Animals↗
PubMed2026

Cancer Immunotherapy: Therapeutic Limitations and Next-Generation Precision Strategies.

Cancer immunotherapy has reshaped oncology, largely through immune checkpoint inhibitors that release the brakes on tumor-reactive T cells. Yet the benefit remains uneven, and that unevenness traces back to a few basic biological limits. Checkpoint blockade amplifies immunity that is already present; it does not create tumor specificity de novo. Poor Ag quality, defective Ag presentation, a suppressive microenvironment, and epigenetically fixed T-cell exhaustion together set a ceiling on what checkpoint release can achieve. Next-generation strategies try to move past these limits by reorganizing immunotherapy around the functional layers of the immune response. Cancer vaccines define tumor-specific neoantigens and expand the responses against them. Ab-based approaches tune inhibitory signaling, draw immune cells toward the tumor, and trigger immunogenic cell death. Cellular therapies-chimeric Ag receptor T cell, TCR-engineered T cells, and tumor-infiltrating lymphocytes (TILs)-boost effector potency, with TIL therapy notable for preserving tumor-reactive repertoires shaped in vivo. Rather than rivals, these modalities are best seen as complementary layers-Ag definition, immune priming, effector optimization, and microenvironmental conditioning-to be combined in a programmable way. As genomic profiling, immunopeptidomics, and high-dimensional immune monitoring mature, the field is shifting from checkpoint-centered release toward precision immunoengineering, in which tumor-specific immunity is deliberately designed, aligned, and sustained.

Cancer vaccines↗
PubMed1985

Modulation of stromal cell function in DBA/2J and B6C3F1 mice exposed to benzene or phenol.

Inbred B6C3F1 (B6) mice are more resistant to benzene myelotoxicity than are inbred DBA/2J (D2) mice. This difference may be due to increased sensitivity of the hemopoietic microenvironment in D2 mice to benzene or benzene metabolites relative to B6 mice. The objectives of this investigation were to determine whether stromal cells which support hemopoiesis in the marrow were more sensitive to benzene in D2 mice than in B6 mice and to determine whether these strains would continue to express differences in susceptibility to phenol, an oxidative metabolite of benzene. Mice were given benzene (100 mg/kg) or phenol (100 mg/kg) intraperitoneally, twice a day for four consecutive days. On Day 5 marrow cell suspensions were removed from mice given benzene or phenol and from controls, plated in culture and assayed for (1) the relative number of adherent stromal cell (ASC) colonies present, (2) the number of granulocyte/monocyte precursors from benzene or phenol treated mice that could be supported by ASC from normal mice in coculture, and (3) the number of granulocyte/monocyte precursors from normal mice which could be supported by ASC from benzene or phenol treated mice. After benzene administration, only reductions in body weight and marrow cellularity followed the expected pattern and were reduced to a greater extent among D2 mice than B6 mice. Benzene had no significant effect on ASC colonies or on the number of granulocyte/monocyte precursors present. In contrast, the ability of ASC to support hemopoiesis of granulocyte/monocytes from normal donors was reduced to a greater degree among B6 mice than among D2 mice which paradoxically showed an increase in the ability to support hemopoiesis in coculture. Phenol significantly reduced the ability of ASC to support hemopoiesis of granulocyte/monocyte precursors but no preferential effect between strains was evident. These results suggest that benzene, but not phenol, is metabolized differently between the two strains and that bone marrow stromal cells, components of the hemopoietic microenvironment, are sensitive targets for benzene or its oxidative metabolites.

Animals↗
PubMed1991

The role of cellular immunology in asthma.

It is now clear how activated T lymphocytes, through the elaboration of proinflammatory lymphokines, may orchestrate the inflammatory response seen in the asthmatic bronchial mucosa. This activation presumably follows recognition of specific antigen by the T lymphocytes. What is the nature of the putative activating antigen(s) in asthma? They might originate from an external source. Viral respiratory infections may be responsible for some exacerbations of asthma and may even initiate persistent airways obstruction, but it is unlikely that they can be implicated in every case. Aeroallergens are other obvious candidates, although it has already been argued that the atopic phenotype is not a prerequisite for the development of asthma, nor does atopy inevitably result in the development of airways hyperresponsiveness. An attractive alternative hypothesis is that the T lymphocytes may be inappropriately recognizing antigens in the bronchial mucosa; in other words asthma may be an "autoimmune" disease. An analysis of possible selective clonal expansion of T lymphocytes at the mucosal surface may provide evidence for a localized response against a limited range of antigens. It will be of particular importance to determine the amount and proportions of lymphokines secreted by T lymphocytes within the mucosal microenvironment, since properties of cells in the peripheral blood or even bronchoalveolar lavage (BAL) fluid are likely to reflect only dimly those of cells at this site. Furthermore, there is now good evidence that diapedesis of lymphocytes from the circulation to mucosal surfaces is a selective process mediated through specific "addressing" molecules on high endothelial venules at these sites. One example of such a molecule is that recognized by the monoclonal antibody Hermes-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗
PubMed1996

HIV and pulmonary immune responses.

The lung is a central organ in human immunodeficiency virus (HIV)-induced pathophysiology, becoming infected during the asymptomatic period of the disease. The presence of HIV elicits a discrete virus-specific cytotoxic T lymphocyte (CTL)-mediated immune response in the pulmonary microenvironment. Here, Carlo Agostini and colleagues provide a framework for understanding the mechanisms underlying the spread of the retrovirus and the consequent progression of disease in patients with AIDS-associated lung involvement.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Plasmin binding to the plasminogen receptor enhances catalytic efficiency and activates the receptor for subsequent ligand binding.

Specific cell surface receptors for plasminogen (Pg) are expressed by a wide variety of cell types. The colocalization of receptors for Pg and its activators restricts plasmin (Pm) activity to specific sites and serves to promote fibrinolysis and local Pg activation. These studies show that both Pg and Pm bind to cellular receptors on monocytoid U937 cells. Limited Pm pretreatment of the cells enhances total Pg binding and alters the kinetics of Pm binding. Furthermore, surface-bound Pg is converted to Pm in the absence of exogenous activators. Cell-bound Pm exhibits a 12-fold increase in catalytic efficiency (kcat/Km) relative to Pm free in solution. These studies demonstrate that Pg/Pm receptor occupancy can be regulated by Pm in the microenvironment and may play a significant regulatory role in fibrinolysis and extravascular proteolysis.

Cell Line↗
PubMed1989

Intra-thymic nurse cell lymphocytes can induce a graft-versus-host reaction with high efficiency.

Thymic nurse cells (TNC) are multicellular complexes composed of morphologically intact thymocytes internalized within epithelial cells. Due to their unusual features, they have been suspected to provide an appropriate microenvironment for T-cell repertoire acquisition. In recent functional studies in the chicken system, we have shown that intra-thymic nurse cell-lymphocytes (TNC-L) are highly efficient inducers of a graft-versus-host reaction (GvHR) in an allogeneic chorionallantoic membrane (CAM) assay, manifested by the formation of visible colonies, so-called pocks. Immunohistochemical and electron microscopical assessment of pocks revealed no differences between the cellular components and ultrastructural features of GvHR induced by TNC-L or peripheral blood lymphocytes (PBL). In addition, the stimulation of this local GvHR by interleukin 2 (IL-2) was demonstrated.

Animals↗
PubMed2006

Surface engineering approaches to micropattern surfaces for cell-based assays.

The ability to produce patterns of single or multiple cells through precise surface engineering of cell culture substrates has promoted the development of cellular bioassays that provide entirely new insights into the factors that control cell adhesion to material surfaces, cell proliferation, differentiation and molecular signaling pathways. The ability to control shape and spreading of attached cells and cell-cell contacts through the form and dimension of the cell-adhesive patches with high precision is important. Commitment of stem cells to different specific lineages depends strongly on cell shape, implying that controlled microenvironments through engineered surfaces may not only be a valuable approach towards fundamental cell-biological studies, but also of great importance for the design of cell culture substrates for tissue engineering. Furthermore, cell patterning is an important tool for organizing cells on transducers for cell-based sensing and cell-based drug discovery concepts. From a material engineering standpoint, patterning approaches have greatly profited by combining microfabrication technologies, such as photolithography, with biochemical functionalization to present to the cells biological cues in spatially controlled regions where the background is rendered non-adhesive ("non-fouling") by suitable chemical modification. The focus of this review is on the surface engineering aspects of biologically motivated micropatterning of two-dimensional (flat) surfaces with the aim to provide an introductory overview and critical assessment of the many techniques described in the literature. In particular, the importance of non-fouling surface chemistries, the combination of hard and soft lithography with molecular assembly techniques as well as a number of less well known, but useful patterning approaches, including direct cell writing, are discussed.

Adsorption↗
PubMed2006

Molecular biology of oral cavity squamous cell carcinoma.

Significant advances have been made in understanding the mechanisms that contribute to carcinogenesis in OCSCC. This progress has led to the development of therapeutic strategies that target dysregulated processes in the tumor microenvironment (Fig. 11) [72]. The introduction of angiogenesis inhibitors, growth factor receptor tyrosine kinase inhibitors, and cell cycle regulators into clinical trials for the management of OCSCC has resulted from the great strides made in the understanding of tumor biology. It is important for those caring for patients who have OCSCC to have a firm background in tumor biology, because many future therapies will be based on this complex panorama of cellular physiology.

Carcinoma, Squamous Cell↗
PubMed1999

Cytoskeleton and integrin-mediated adhesion signaling in human CD34+ hemopoietic progenitor cells.

Significant progress has been made recently in the understanding of cell adhesion signaling. Many components of focal adhesion complexes have been identified in fibroblasts and endothelial cells, showing considerable overlap and complementarity between growth signaling mediated by growth factor receptors and adhesive signaling mediated by cell adhesion receptors such as integrins. These studies showed that the cytoskeleton is essential for the correct intracellular localization of large signaling complexes that regulate the cellular machinery. Although adhesive interactions are essential to maintain steady-state hemopoiesis, the study of the function and role of adhesive interactions in hemopoietic progenitor and stem cells is less advanced. As in fibroblasts, functional overlap between hemopoietic growth factor receptors and cell adhesion receptors has been demonstrated, with the cytoskeleton likely playing a critical role in integrating information provided by soluble factors and cell adhesion molecules constituting the hemopoietic microenvironment. The intention of this article is to give a critical review of the current knowledge about the cytoskeleton and integrin-mediated signaling in hemopoietic progenitor cells.

Animals↗
PubMed1994

Cytokine modulation of basophil histamine release in wasp-venom allergy.

We report the effect of interleukin-3 (IL-3) and of other cytokines on antigen-induced basophil histamine release in wasp-venom-allergic subjects. Leukocytes from 12 patients with documented anaphylactic sensitivity to wasp venom were preincubated in the presence or absence of IL-3, granulocyte/macrophage-colony stimulating factor (GM-CSF), IL-5, IL-8, or stem cell factor (SCF). Washed cells were then exposed to venom and to other secretagogues, and histamine release in the supernatant was measured fluorometrically. Preincubation of leukocytes with IL-3, GM-CSF, or IL-5 (0.02-2 ng/ml), but not with IL-8 and SCF, caused a dose-dependent enhancement of antigen-induced basophilic histamine release in all subjects tested. Mean maximum increase was about 100% for IL-3, IL-5, and GM-CSF. The priming effect of IL-3 was rapid, persisted up to 12 h, and was not accompanied by a change in cellular histamine. IL-3 had a comparable enhancing effect when basophils were triggered with anti-IgE or N-formylmethionylphenylalanine (FMP). By contrast, IL-3 had no effect on substance-P-induced histamine release. The significant enhancement of basophil releasability to antigen in wasp-venom allergy by very low concentrations of IL-3, GM-CSF, and IL-5 suggests that cytokines in the basophil (mast-cell?) microenvironment could be critical factors in determining the variability of sting reactions in Hymenoptera-venom-allergic subjects.

Adolescent↗
PubMed1996

Basic and clinical overview of the mucosal immune system.

What is clearly evolving today is the concept of mucosal immunity as a discrete system that performs novel immunologic tasks and is uniquely regulated. Although many of the same factors exist in both the systemic and the mucosal immune systems, their structural and functional properties are tailored to different microenvironments. Because it is persistently flooded by a massive antigen load from the environment, the gut-associated lymphoid tissue must continually maintain a delicate balance between active immunity, tolerance, and suppression of immune responses. Homeostasis is essential. Dysfunction of the mucosa's complex immunoregulatory mechanisms may give rise to a diverse panoply of illnesses, including inflammatory bowel disease and celiac sprue. Current research on mucosal interactions at the molecular and cellular level is revolutionizing our understanding of the underlying pathophysiology of these diseases, and may guide their future diagnosis, therapy, and prevention. Indeed, the current wave of investigation has carried the field beyond the realm of mucosal disease, allowing for the harnessing of special mucosal phenomena in the development of new therapeutic modalities and in the treatment of an even wider array of systemic disorders.

Gastric Mucosa↗
PubMed1997

Adenosine acts through a novel extracellular receptor to inhibit granule exocytosis by natural killer cells.

Adenosine concentrations in solid tumors are elevated as a result of altered metabolism by hypoxic cancer cells within the tumor microenvironment. In this study we show that adenosine inhibits mouse natural killer (NK) cell function by interfering with the process of granule exocytosis. Adenosine, at concentrations ranging from 5-25 microM, had a marked inhibitory effect on granule exocytosis by mouse spleen cells stimulated with phorbol myristate acetate and ionomycin. Selective depletion of spleen cell subsets by antibody and complement treatments established that granule exocytosis was mediated by NK cells. Blocking the cellular uptake of adenosine with NBTI or dilazep failed to prevent the inhibitory effect of adenosine, indicating the involvement of a cell-surface receptor. However, adenosine-induced inhibition of granule exocytosis was not blocked by the nonselective A1 and A2 receptor antagonists theophylline and 8-phenyltheophylline, the A1 receptor antagonist DPCPX, or the A2 receptor antagonist DMPX. In addition, the A3 receptor agonists APNEA and NECA failed to affect granule exocytosis. Taken together, these data provide evidence that adenosine inhibits NK cell granule exocytosis by interacting with a novel extracellular receptor. A similar inhibitory effect of tumor-elaborated adenosine on the function of NK cells and other cytotoxic lymphocytes may contribute to tumor survival in the face of host cell-mediated immune defenses.

Adenosine↗
PubMed1997

Modulation of dye-coupling and proliferation in cultured rat thymic epithelium by factors involved in thymulin secretion.

Cultures of rat thymic epithelium were used to measure the effect of thymulin secretagogues on dye-coupling and proliferation. Dye-coupling was assessed after the injection of lucifer yellow dextran which cannot permeate the connexin pore of gap junctions and the smaller, permeant cascade blue. In addition to gap junctional communication, larger intercellular bridges were demonstrated by the transfer of lucifer yellow dextran between cells. The extent of intercellular communication was found to be influenced by both cell density and the number of passages. In control cultures, intercellular communication was reduced in cell groups of low (< 20 cells/group) or high cell densities (> 100 cells/group) compared with groups of 20-60 cells. The highest coupling indices were found in subcultures 20-30. Taking these factors into account, significant decreases in coupling index were observed after pretreatment of test cultures with factors known to influence the secretion of thymulin (5 U/ml interleukin 1 (alpha and beta), 1 microM progesterone, 1 microM oestrogen, 1 microM testosterone, 1 ng/ml adrenocorticotropic hormone, 100 nM rat growth hormone) but 7.5 ng/ml thymulin had no effect on dye-coupling. The nonspecific gap junction uncoupler, octanol, abolished dye-coupling. Cellular proliferation, as measured by the uptake of tritiated thymidine, showed that the same factors that reduced coupling also increased proliferation. None of these factors affected the number of multinucleate cells present, except interleukin-1beta which caused a significant reduction in the average number of nuclei per cell. Thus rat thymic epithelium in vitro provides a model for the study of the direct action of factors on cells of the thymic microenvironment.

1-Octanol↗
PubMed1992

Immunoglobulin M and D antigen receptors are both capable of mediating B lymphocyte activation, deletion, or anergy after interaction with specific antigen.

A series of immunoglobulin (Ig)-transgenic mice were generated to study the functional capabilities of the IgM and IgD classes of B lymphocyte antigen receptor in regulating both cellular development and responses to specific antigen. B cells from Ig-transgenic mice expressing either hen-egg lysozyme (HEL)-specific IgM or IgD alone were compared with B cells from mice that coexpressed IgM and IgD of the same anti-HEL specificity. In all three types of Ig-transgenic mice, conventional B cells specific for HEL exhibited exclusion of endogenous Ig expression and matured to populate the usual microenvironments in peripheral lymphoid tissues. These peripheral B cells could be stimulated by HEL through either IgM or IgD antigen receptors to generate T cell dependent antibody production in vivo or to enhance T cell independent proliferative responses to lipopolysaccharide in vitro. Conversely, when HEL was encountered in vivo as a self-antigen, B cells expressing HEL-specific IgM or IgD alone were both rendered tolerant. In each case this occurred by clonal anergy in response to soluble autologous HEL, and clonal deletion when HEL was recognized as a membrane-bound self-antigen. Taken together, these findings indicate that IgM and IgD antigen receptors expressed alone on conventional B cells can support normal differentiation, antigen-dependent activation, and induction of self-tolerance, the only overt difference lying in a greater degree of receptor downregulation for IgM relative to IgD after induction of clonal anergy by soluble HEL.

Animals↗