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PubMed2006

A transient microenvironment loaded mainly with macrophages in the early developing human pancreas.

We have previously shown that the human developing pancreas, as a tissue under construction and remodeling, is composed of epithelial ducts and differentiated endocrine cells surrounded by mesenchyme. The physiologic importance of resident tissue leukocytes, expected to enter through the mesenchyme in remodeling functions, prompted us to investigate human developing pancreases for the presence of leukocyte lineages and for expression of cytokines and receptors involved in their recruitment and differentiation. Immunohistochemistry studies were performed on 69 human, paraffin-embedded pancreases at 6-12 weeks of development (WD). Cytokines and receptor transcripts were monitored by reverse transcription (RT)-PCR, by immunohistochemistry when antibodies were available or by in situ hybridization (ISH). We show that numerous cells expressing CD45RA, HLADR and CD68 antigens are cellular components of the mesenchyme of all the pancreases at 6-12 WD. So-called constitutive chemokines (SLC (CCL19), stromal-derived factor 1 (SDF1) (CXCL12)) and a macrophage-specific growth/survival factor, colony-stimulating factor 1 (CSF1), were detected in epithelial duct cells. Both epithelial and mesenchymal cells expressed chemokine receptors, suggesting a role in leukocyte recruitment and possibly in early pancreatic development. In conclusion, we demonstrated the presence of CD45RA resident leukocyte-derived lineages, mostly macrophages, in the early human pancreatic mesenchyme. These cells may have migrated in the tissue through the vascular system, attracted by constitutively expressed chemokines, and locally surviving through CSF1 signaling. The role of macrophages in epithelium/mesenchyme interaction-mediated pancreatic development remains to be demonstrated.

Biomarkers↗
PubMed1990

Differentiation of crypt epithelium in human palatine tonsils: the microenvironment of crypt epithelium as a lymphoepithelial organ.

The differentiation of the keratinocytes of the human palatine tonsils were studied by means of light and electron microscopy and immunohistochemistry using a polyclonal (K) and two monoclonal antikeratin antibodies (PKK1, PKK2). In the surface epithelium, the basal cells, cuboidal or columnar in shape, undergo progressive terminal differentiation and are transformed into the flattened cells of the upper layers. K reacts with both the basal and spinous layers, while PKK1 and PKK2 mark exclusively the basal layer. In the neck portion of the crypt, cavities containing one or aggregated lymphocytes with amorphous substances are observed in the spinous layer. The cavities are surrounded by elongated cytoplasmic processes of transformed epithelial cells bearing surface microvilli. These transformed epithelial cells display intense PKK1- and PKK2-positive reactions, whereas other conventional polygonal cells in the vicinity remain PKK1- and PKK2-negative as do those in the surface epithelium. In the deep portion of the crypt, where numerous lymphocytes invade the epithelium, the epithelial cells are transformed into star-shaped reticulum cells showing PKK1- and PKK2-positive reactions. The extended and branched cytoplasmic processes interconnect with one another constituting a complex network of reticulum cells, the well known reticulation of the crypt epithelium. Ten-nm filaments are usually oriented parallel to the longitudinal axis of transformed epithelial cells. Our observations suggest that the cell-shape transformation, i.e., from conventional polygonal epithelial cells into epithelial reticulum cells, occurs when the epithelial cells are in close contact with the infiltrating lymphocytes, and that this transformation is accompanied by a change in keratin phenotype.

Adolescent↗
PubMed2006

Role of the microenvironment in multiple myeloma bone disease.

Multiple myeloma bone disease occurs in over 70-80% of patients with myeloma and represents a significant source of morbidity and mortality. Early in multiple myeloma bone disease there is a balance between osteoclast activation and osteoblast suppression. However, this balance appears to be lost in advanced disease, resulting in the development of lytic lesions and bone destruction. Osteoclast activation occurs through a variety of factors, including receptor activator of nuclear factor-kappaB ligand, macrophage inflammatory protein-1alpha, interleukin-3 and interleukin-6, resulting in osteoclast stimulation and bone resorption. There is also significant osteoblast suppression through the inhibitory actions of interleukin-3, dickkopf 1, secreted frizzled-related protein-2 and interleukin-7. Understanding the mechanisms behind myeloma bone disease will help to identify potential future therapeutic interventions to help ameliorate or prevent osteoblast suppression and decrease osteoclast activation, with the goal of improving the overall quality of life for patients with multiple myeloma.

Bone Diseases↗
PubMed2005

Nutritive phagocyte incubation chambers provide a structural and nutritive microenvironment for germ cells of Strongylocentrotus droebachiensis, the green sea urchin.

Here we characterize the germinal epithelia of both sexes of Strongylocentrotus droebachiensis, the green sea urchin, throughout its annual gametogenic cycle, using light and electron microscopy and cytochemistry. In both sexes, germinal epithelia include two interacting cellular populations: nutritive phagocytes (NPs) and germ cells. After spring spawning, NPs accumulate nutrients; amitotic oogonia and often mitotic spermatogonia occur in clusters beneath NPs; and subsequent gametogenic stages are residual or absent. During the summer, NP nutrients are mobilized for use in vitellogenesis by residual primary oocytes or to support limited spermatogenesis. In addition, some residual primary oocytes may degenerate and be phagocytized by NPs. Significant nutrient mobilization from NPs and substantial gonial cell mitoses (indicative of new gametogenesis) occur in the fall. In both sexes, all of these changes are facilitated by NPs that form basal incubation chambers near the gonadal wall and within which germ cells are surrounded by nutrients released from the NPs. In females, germ cells at several stages of gametogenesis may be housed in separate chambers in the same NP. Primary oocytes also carry out jelly coat formation, meiosis, and cortical granule translocation within NP incubation chambers. In males, many NPs cooperate to provide large continuous chambers that contain spermatogenic cells at diverse stages. In both sexes these chambers persist throughout the year and isolate gametogenesis from the gonadal lumen. NPs become slender and shorten as their nutrients are depleted. Ova or spermatozoa are stored in the gonadal lumen. Post-spawning, NPs phagocytize differentiated germ cells while simultaneously enclosing intact gonial and residual gametogenic cells in basal chambers near the gonadal wall. In light of our observations, we suggest investigating proteins that may be important in the structural, phagocytic, and nutritive functions of NPs and for which corresponding genes have already been identified in the genome of S. purpuratus, the closely related purple sea urchin.

Animals↗
PubMed1998

Transplantation of allogeneic islets of Langerhans in the rat liver: effects of macrophage depletion on graft survival and microenvironment activation.

Early impairment of islet function and graft loss limit the success of allogeneic islet transplantation. Nonspecific inflammatory events occurring at the transplant site immediately after grafting, involving the production of cytokines and free radicals and sinusoidal endothelial cell (SEC) activation, may contribute to islet cell damage. To evaluate whether Kupffer cell inactivation would result in prolonged allograft survival in a model system of intrahepatic islet transplantation in rats, we systemically administered either gadolinium chloride (GdCl3) or dichloromethylene diphosphonate (Cl2MDP) to assess the effects of macrophage inactivation on rejection and on the release of proinflammatory molecules, as well as to assess the functional profile of SEC. The results obtained were compared with those observed in untreated, sham-injected animals and in rats receiving intraportal infusions of microbeads. Transient macrophage inhibition, particularly in hepatic Kupffer cells, is associated with significant prolongation of graft survival after intraportal islet allotransplantation (ITx) in rats: 7.2 days in the control group versus 11.9 days in the GdCl3 group (P < 0.01) and 15.6 days in the Cl2MDP group (P < 0.0006), respectively. Although systemic release of inflammatory mediators was observed only when islet transplantations were performed and it could be inhibited by macrophage-targeting treatments, perturbation of the functional profile of endothelial cells was also observed when microembolization was induced by the use of microbeads and could not be prevented by macrophage inhibition. These experiments provide evidence to support the concept that macrophages play a key role in early inflammatory events known to adversely affect islet engraftment and suggest that manipulation of nonspecific immune activation by inhibition of macrophage function may facilitate hepatic engraftment of islet allografts. The mechanisms mediating this effect are likely to include prevention of release of tumor necrosis factor-alpha, interleukin-1beta, and NO and interference with the rate of immune response to the islets.

Animals↗
PubMedDate not supplied

The pathophysiology of the ocular microenvironment. I. Preliminary report on the possible involvement of copper in ocular inflammation.

The concentration of copper [( Cu]) in the extracellular fluid compartments of rabbit eyes was found to increase approximately 30-fold during experimental uveitis, generally paralleling increases in [protein]. However, during the recovery phase the decrease in [Cu] lags behind the decrease in [protein] in some rabbits, suggesting the presence of abnormally high levels of non-protein-associated Cu. Intravitreal injection of CuSO4 (6 micrograms of Cu/eye) causes an inflammatory response and evidence of tissue damage. A better understanding of trace element metabolism is clearly required to further elucidate the mechanism of ocular inflammation and associated tissue damage.

Animals↗
PubMed1995

Interaction between ionizing radiation, estrogens and antiestrogens in the modification of tumor microenvironment in estrogen dependent multicellular spheroids.

MCF7 human breast cancer cells growing as multicellular spheroids were examined as a model of three-dimensional cellular organization. Estrogen-free medium inhibited spheroid formation. In medium containing estrogens, the antiestrogen hydroxytamoxifen decreased the spheroid growth rate. Analyses with the recursion formula after Gompertz fitting showed that the rate of exponential decrease in growth rate (alpha) was alpha 0.099 +/- 0.013 d-1, and the decrease in alpha' was 0.061 +/- 0.015 d-1 for 0.1 microM hydroxytamoxifen and control spheroids respectively. MCF7 cells which had been growth arrested in an estrogen-free medium showed a significant decrease in radiosensitivity (surviving fraction at 2 Gy, SF2 = 63%) when compared with 0.1 nM 17 beta-estradiol-treated cells (SF2 = 38%). No differences in radiosensitivity were seen in MCF7 spheroids in estrogen-supplemented medium (radiation dose necessary to control 50% of spheroids (SCD50) was 5.51 Gy; derived alpha, beta and SF2 were 0.301 +/- 0.110 Gy-1, 0.018 +/- 0.005 Gy-2, and 51% respectively) when compared with monolayer cultures in the same medium (alpha = 0.316 +/- 0.059 Gy-1, beta = 0.023 +/- 0.006 Gy-2 and SF2 = 50%). In the spheroid model, manipulating the cellular environment, i.e., with estrogen treatment, modulates sensitivity to ionizing radiation.

Breast Neoplasms↗
PubMed1996

Selective homing of human leukemic B-cell precursors to specific lymphohematopoietic microenvironments in SCID mice: a role for the beta 1 integrin family surface adhesion molecules VLA-4 and VLA-5.

We used a SCID mouse xenograft model to study the in vivo growth patterns of primary leukemic cells from six patients with newly diagnosed B-cell precursor (BCP) acute lymphoblastic leukemia (ALL), including two patients with t(1;19) ALL, two patients with t(4;11) ALL, and two patients with t(9;22) ALL. Leukemic cells from these six patients caused overt leukemia in SCID mice with extensive multiple organ involvement. Leukemic BCP from SCID mice xenografted with leukemic cells from two t(9;22) ALL patients expressed very high levels of both VLA-4 and VLA-5 regardless of the tissue of origin. By comparison, in SCID mice xenografted with leukemic cells from the two patients with t(1;19) ALL and two patients with t(4;11) ALL, leukemic BCP from the bone marrow samples expressed high levels of VLA-4 as well as VLA-5, whereas the vast majority of leukemic BCP in the liver or spleen samples expressed neither of these adhesion molecules at significant levels. These results suggest that the expression of VLA-4 and VLA-5 on t(1;19) or t(4;11) leukemia cells likely determines their binding capacity to bone marrow stroma and may affect their migration to extramedullary tissues. Our findings are in accord with and extend previous studies which demonstrated that extracellular matrix and integrins influence development, compartmentalization, and migration of BCP during B-cell ontogeny. The described SCID mouse model system provides a unique opportunity to study the adhesion receptors which regulate the selective homing of human leukemic BCP to specific SCID mouse organs.

Animals↗
PubMed1988

Ligand/receptor interactions--the influence of the microenvironment on macroscopic properties. Electrostatic interactions with the membrane phase.

The heterogeneous environment in which ligand/receptor interactions occur often leads to complex binding behaviour. We consider here the ligand/membrane interaction, emphasizing the possibilities of electrostatic modulation of the overall binding characteristics. The binding of Substance P to neutral or negatively charged planar lipid bilayers was monitored using the capacitance minimization technique. The electrostatic attraction to the charged bilayer potentiates the interaction by more than two orders of magnitude and leads to a nonlinearity in the Scatchard plot of bound vs. bulk concentrations. The Boltzmann accumulation factor, along with the direct measurement of the surface potential, provides an easy explanation of the effect. The general importance of electrostatic accumulation (or repulsion) at surfaces is discussed and the concept applied to examples from the literature.

Chemical Phenomena↗
PubMed1998

Regulation of adhesion and migration in the germinal center microenvironment.

T cell dependent humoral immune responses are initiated by the activation of naive B cells in the T cell areas of the secondary lymphoid tissues. This primary B cell activation leads to migration of germinal center (GC) cell precursors into B cell follicles where they engage follicular dendritic cells (FDC) and T cells, and differentiate into memory B cells or plasma cells. Both B cell homing to the GC and interaction with FDC critically depend on integrin-mediated adhesion. We have recently indentified the c-met-encoded receptor tyrosine kinase and its ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF), as a novel paracrine signalling pathway regulating B cell adhesion (van der Voort et al., 1997, J. Exp. Med. 185, 2121-2131). The c-Met protein is expressed on B cells localized in the dark zone of the GC (centroblasts) and is induced by CD40 plus BCR ligation. Stimulation of c-Met with HGF/SF, which is produced at high levels by tonsillar stromal cells and FDC, leads to receptor phosphorylation and to enhanced integrin-mediated adhesion of B cells to both VCAM-1 and fibronectin. Interestingly, these responses to HGF/SF are promoted by heparan-sulfate proteoglycan forms of CD44 (CD44-HS). Like c-Met, CD44-HS is induced on B cells by CD40 ligation. It efficiently binds HGF/SF and strongly promotes signalling through c-Met. We conclude that integrin regulation during antigen specific B cell differentiation involves cross-talk between the HGF/SF-c-Met pathway and CD44-HS.

Animals↗
PubMed2003

Influence of adjunct use and cheese microenvironment on nonstarter bacteria in reduced-fat cheddar-type cheese.

This study investigated population dynamics of starter, adjunct, and nonstarter lactic acid bacteria (NSLAB) in reduced-fat Cheddar and Colby cheese made with or without a Lactobacillus casei adjunct. Duplicate vats of cheese were manufactured and ripened at 7 degrees C. Bacterial populations were monitored periodically by plate counts and by DNA fingerprinting of cheese isolates with the random amplified polymorphic DNA technique. Isolates that displayed a unique DNA fingerprint were identified to the species level by partial nucleotide sequence analysis of the 16S rRNA gene. Nonstarter biota in both cheese types changed over time, but populations in the Colby cheese showed a greater degree of species heterogeneity. The addition of the L. casei adjunct to cheese milk at 10(4) cfu/ml did not completely suppress "wild" NSLAB populations, but it did appear to reduce nonstarter species and strain diversity in Colby and young Cheddar cheese. Nonetheless, nonstarter populations in all 6-mo-old cheeses were dominated by wild L. casei. Interestingly, the dominant strains of L. casei in each 6-mo-old cheese appeared to be affected more by adjunct treatment and not cheese variety.

Carbohydrate Metabolism↗
PubMed2006

Calf respiratory disease and pen microenvironments in naturally ventilated calf barns in winter.

Relationships between air quality, a variety of environmental risk factors, and calf respiratory health were studied in 13 naturally ventilated calf barns during winter. A minimum of 12 preweaned calves were randomly selected and scored for the presence of respiratory disease in each barn. An air sampling device was used to determine airborne bacteria colony-forming units per cubic meter (cfu/m3) of air in calf pens and central alleys within the barns. Airborne bacteria samples were collected on sheep blood agar (BAP) and eosin methylene blue (EMB) agar plates. Temperature and relative humidity were recorded in each calf pen, the barn alley, and outside the barn. Samples of bedding were collected in each pen and DM was measured. Pen bedding type and a calf nesting score (degree to which the calves could nestle into the bedding) was assigned to each barn. Calf numbers, barn and pen dimensions, ridge, eave, and curtain openings, and exterior wind speed and direction were determined and used to estimate building ventilation rates. Factors that were significantly associated with a reduced prevalence of respiratory disease were reduced pen bacterial counts (log10 cfu/m3) on BAP, presence of a solid barrier between each calf pen, and increased ability to nest. Individual calf pen bacterial counts were significantly different from barn alley bacterial counts on both BAP and EMB. Significant factors associated with reduced calf pen bacterial counts on BAP were increasing pen area, increasing number of open planes of the calf pen, decreasing pen temperature, and wood-particle bedding. Significant factors associated with reduced alley bacterial counts on BAP were increased ventilation changes per hour, increased barn volume per kilogram of calf, reduced pen bacterial counts, and barn type.

Age Factors↗
PubMed1982

Effect of subarachnoid hemorrhage on the extracellular microenvironment.

Local experimental subarachnoid hemorrhage (SAH) was produced over the cerebral cortex in 15 cats. The cellular response was monitored using ion-specific electrodes for extracellular potassium (K+) and calcium (Ca++) activity, DC cortical potential, and electrocorticogram. The response was characterized by a profound cellular depolarization and extracellular calcium (Ca++) depletion which accompanied extracellular potassium (K+) accumulation. The prehemorrhage baseline calcium levels measured 1.14 +/- 0.11 mM, and were lowered to 0.4 to 0.7 mM/liter in different experiments. The K+ accumulation reached levels between 16 and 31 mM from a baseline of 3.17 +/- 0.52 mM and were cleared to normal or nearly normal within 5 minutes. The Ca++ levels also returned to normal within 5 minutes, but remained depressed for the duration of the experiment in two animals. These results confirm that blood extravasated into the subarachnoid space had a direct effect on parenchymal elements. The combination of transient K+ elevations and calcium depression may play an important role in the development of vascular spasm by inducing or facilitating a contraction in the muscular layer in the wall of major intracranial vessels.

Animals↗
PubMed1984

Mononuclear lymphoid populations infiltrating the microenvironment of primary CNS tumors. Characterization of cell subsets with monoclonal antibodies.

Mononuclear cell infiltrates are found to varying degrees in 30% to 60% of primary human central nervous system (CNS) gliomas. To explore the immunological importance of this, six operative glial tumors, eight non-glial tumors, and three normal brain specimens were studied. Utilizing an immunoperoxidase method, the authors examined frozen sections for lymphoid infiltrates expressing suppressor/cytotoxic and helper phenotypes, as identified with the Leu-1,2,3 monoclonal antibodies. Four of six gliomas demonstrated lymphoid infiltrates: three tumors exhibited a predominant suppressor/cytotoxic cell phenotype and the fourth showed mixed staining of suppressor/cytotoxic and helper cell phenotypes. Varying degrees of lymphoid infiltration characterized four out of eight non-glial primary CNS tumors. Two cases exhibited a prevalence of suppressor/cytotoxic phenotype cells, while two cases demonstrated a more heterogeneous pattern of phenotype expression. Normal brain sections revealed little or no evidence of mononuclear infiltrates. The immunobiological significance of these findings is discussed in the context of tumor-host interaction within the CNS.

Antibodies, Monoclonal↗
PubMed1993

Bursal secretory dendritic-like cell: a microenvironment issue.

In 1978, Olah and Glick identified in the medulla of the bursa of Fabricius a dendritic cell, the bursal secretory dendritic-like cell (BSDC). The morphology of BSDC, the functional relationship of BSDC to bursal follicle development and the spleen, and the identification in the embryo of the BSDC precursor was reported. The precursor BSDC appeared in the bursa before B cells. A monoclonal antibody to vimentin, an intermediate filament, will identify BSDC and not B cells in posthatch chickens. The vimentin-positive cells, but not B cells, in hatched chicks express complete IgG chain. Taken together, the present data may contribute to the events occurring during the bursal-dependent stages of B cell development. Immunoglobulin gene rearrangement, within the bursa or at extra-bursal sites, and clonal expansion at extra-bursal sites are antigen-independent and dependent, respectively. The bursal-dependent stage includes the expansion of the Ig rearranged cells and gene conversion, which contributes to antibody diversity. The IgG and granular products produced by BSDC may act as ligand and signals for B cell expansion and gene conversion.

Animals↗