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Biomedical subjects

M Pope

Publications and source records attributed to M Pope.

At least 37 records · Page 2Linked to original sources
PubMed1996

Replication of HIV-1 in dendritic cell-derived syncytia at the mucosal surface of the adenoid.

Human immunodeficiency virus-type 1 (HIV-1) replicates actively in infected individuals, yet cells with intracellular depots of viral protein are observed only infrequently. Many cells expressing the HIV-1 Gag protein were detected at the surface of the nasopharyngeal tonsil or adenoid. This infected mucosal surface contained T cells and dendritic cells, two cell types that together support HIV-1 replication in culture. The infected cells were multinucleated syncytia and expressed the S100 and p55 dendritic cell markers. Eleven of the 13 specimens analyzed were from donors who did not have symptoms of acquired immunodeficiency syndrome (AIDS). The interaction of dendritic cells and T cells in mucosa may support HIV-1 replication, even in subclinical stages of infection.

Adenoids↗
PubMed1996

Dendritic cells and the replication of HIV-1.

Dendritic cells (DCs) are a distinct lineage of white cells that arise from CD34+ progenitors in the bone marrow. DCs exhibit many specializations that lead to efficient antigen capture and presentation to T cells, both CD4+ helpers and CD8+ killers. In several human tissues, DCs express the CD4 receptor for HIV-1. Some early reports described the explosive infection of blood-derived DCs by HIV-1 and a severe compromise of their presenting function. In contrast, other studies described active HIV-1 replication when DCs were interacting with CD4+ T cells. This productive infection could begin with a low viral burden in DCs but required that the DCs retain their normal binding and stimulatory function for T cells. In this review we first summarize those features of the DC system that seem pertinent to HIV-1 infection. Then we consider the current literature on the interaction of HIV-1 with DCs, from several different tissues, in HIV-1-infected patients or following challenge with HIV-1 in vitro. The literature leads to the hypothesis that HIV-1 infection is a battleground in which DCs could be leading both of the armies, the aggressor that promotes HIV-1 replication from relatively small numbers of infected cells and the defender that mediates T cell-dependent resistance.

Animals↗
PubMed1996

The presence and effects of mammalian signal molecules in immunocytes of the insect Leucophaea maderae.

Opioid peptides activate immunocytes and opiate alkaloids inhibit this activation in the mussel, Mytilus edulis. Here we present evidence that cells of another invertebrate, Leucophaea maderae, can be influenced in a similar way by the Met-enkephalin analogue D-Ala2-Met5-enkephalin (DAMA) and morphine. Effects of different signal molecules on Leucophaea hemocytes were evaluated by computer-assisted image analysis of their conformational state. A small percentage of the untreated cells were found to display spontaneous conformational changes after 25 min of incubation without pharmacological agents which was noted as a decrease in both circularity factor and shape factor values. Activation caused the cells to become elliptical, a feature that appears to be characteristic of Leucophaea immunocytes. Administration of DAMA induced a similar activation of most of the cells. After 30 min these DAMA-activated cells started to display distinct locomotory activity not seen in the controls. alpha-Melanocyte-stimulating hormone (MSH, 10(-7)) added to the incubation medium after DAMA-activation caused the cells to return to their original "rounded" conformation. In addition, the presence of immunoreactive interleukin (IL-1), adrenocorticotropin (ACTH) and tumor necrosis factor (TNF) in the hemolymph was demonstrated. These data suggest an interaction between both vertebrate-type immunological signal molecules and neuropeptides in the regulation of immunological cells in Leucophaea.

Adrenocorticotropic Hormone↗
PubMed1996

A mathematical model of the impact response of the seated subject.

A model of the lumbar spine, pelvis and buttocks is developed, based on linear horizontal and vertical systems along with a rotational subsystem. The model can mimic qualitatively different experimental observations of transmission of vibrations from the seat to L3 in the sitting posture. It is concluded that while the model lacks detailed sophistication, it adds to our qualitative understanding of the biomechanics of seated vibrations by pointing to those subsystems responsible for the observed transfer functions.

Acceleration↗
PubMed1995

Low levels of HIV-1 infection in cutaneous dendritic cells promote extensive viral replication upon binding to memory CD4+ T cells.

Earlier work has identified a cell population that replicates HIV-1 in the absence of standard T cell stimuli. The system consists of dendritic cells and memory T lymphocytes that emigrate from organ cultures of human skin and together support a productive infection with HIV-1. These emigrants resemble cells that can be found in mucous membranes and that normally traffic in afferent lymph. Here, we report that a low level of infection in the dendritic cell can initiate extensive HIV-1 replication in cocultures with T cells. First we extended our earlier work to larger skin specimens from cadavers. As long as the organ cultures were set up within 36 h of death, the emigrant leukocytes were comparable to cells from fresh surgical specimens in number, phenotype, and function. These mixtures of dendritic cells and T cells provided the milieu for a productive infection with several virus isolates. When purified dendritic cells were separately pulsed with virus and then mixed with T cells that had not been pulsed with HIV-1, active infection ensued. The infectivity of HIV-pulsed dendritic cells persisted for at least 1.5 d in culture, but was blocked if AZT was added during that time to block reverse transcription in the dendritic cells. The number of copies of proviral DNA in the dendritic cells corresponded to < 100 copies per 5 X 10(4) cells, but upon mixing with T cells, > 10(4) copies were found 5-7 d later. By contacting syngeneic T cells, extralymphoid depots of dendritic cells--even with a low viral burden as has been reported in vivo--may contribute to chronic HIV-1 replication in infected individuals.

Antiviral Agents↗
PubMed1995

Coexpression of NF-kappa B/Rel and Sp1 transcription factors in human immunodeficiency virus 1-induced, dendritic cell-T-cell syncytia.

Productive infection of T cells with human immunodeficiency virus 1 (HIV-1) typically requires that the T cells be stimulated with antigens or mitogens. This requirement has been attributed to the activation of the transcription factor NF-kappa B, which synergizes with the constitutive transcription factor Sp1 to drive the HIV-1 promoter. Recently, we have found that vigorous replication of HIV-1 takes place in nonactivated memory T cells after syncytium formation with dendritic cells (DCs). These syncytia lack activated cells as determined by an absence of staining for Ki-67 cell cycle antigen. The expression and activity of NF-kappa B and Sp1 were, therefore, analyzed in isolated T cells and DCs from humans and mice. We have used immunolabeling, Western blot analysis, and electrophoretic mobility shift and supershift assays. T cells lack active NF-kappa B but express Sp1 as expected. DCs express high levels of all known NF-kappa B and Rel proteins, with activity residing primarily within RelB, p50, and p65. However, DCs lack Sp1, which may explain the failure of HIV-1 to replicate in purified DCs. Coexpression of NF-kappa B and Sp1 occurs in the heterologous DC-T-cell syncytia that are induced by HIV-1. Therefore, HIV-1-induced cell fusion brings together factors that upregulate virus transcription. Since DCs and memory T cells frequently traffic together in situ, these unusual heterologous syncytia could develop in infected individuals and lead to chronic HIV-1 replication without ostensible immune stimulation.

Animals↗
PubMed1995

Enhanced HIV-1 replication in V beta 12 T cells due to human cytomegalovirus in monocytes: evidence for a putative herpesvirus superantigen.

HIV-1 replicates more efficiently in cultured IL-2-dependent CD4 T cells expressing V beta 12 T cell receptors (TCRs) rather than other TCRs (Laurence et al., 1992). A viral reservoir is frequently established in V beta 12 T cells in HIV-1-infected patients. Here we show that cytomegalovirus (CMV) is responsible for V beta 12-selective HIV-1 replication that is indistinguishable from the effect of known superantigens (SAGs). This effect is dependent on direct contact of T cells with CMV-infected monocytes. CMV infection, but not ie1 or ie2 transfection, reproduces this effect in a monocytoid cell line (U937). In HIV-infected patients, the presence of CMV antibodies correlates with an HIV-1 viral load preferentially skewed to the V beta 12 subset. Together, these data suggest that a CMV gene product is responsible for a SAG-driven V beta 12-selective HIV-1 reservoir in vivo.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Maturation and migration of cutaneous dendritic cells.

Dendritic cells have been isolated from the epidermis, dermis, and lymphatics of skin. Cells from each cutaneous compartment can exhibit the distinct morphology, surface phenotype, and strong T-cell-stimulating activity of dendritic cells that are isolated from other organs. Of importance are the mechanisms by which the maturation and movement of dendritic cells are regulated within intact tissues. Epidermal dendritic cells turn over slowly in the steady state. Stimuli, including contact allergens and transplantation, perhaps by inducing a release of cytokines such as granulocyte macrophage-colony-stimulating factor, mobilize these dendritic cells into the dermis and lymph. This migration is accompanied by the maturation of dendritic cell functions; e.g., antigen-presenting major histocompatibility complex molecules and B7 costimulators increase markedly. On the other hand, there is a sizable, steady-state flux of dendritic cells in afferent lymph draining the skin, which suggests a constant traffic through the dermis that is independent of sessile epidermal dendritic cells. When explants of skin are placed in organ culture, dendritic cells emigrate into the medium for 1-3 d. The dendritic cells are mature and can bind tightly to small memory T cells that also migrate in these cultures. The emigrated mixtures of dendritic cells and T cells should be useful in the study of many clinical states. This is illustrated by recent experiments showing that migratory skin cells are readily infected with human immunodeficiency virus (HIV)-1. A strong productive infection takes place in the absence of exogenous cytokines, foreign sera, or mitogens or antigens. The dendritic cell-T-cell conjugates are the essential site for infection. This cellular milieu may model events during the sexual transmission of HIV-1, where relevant mucosal surfaces are covered by skin-like epithelia. The capture of CD4+ memory T cells by dendritic cells may explain the chronic drain of immune memory in HIV infection.

Animals↗
PubMed1995

Both dendritic cells and memory T lymphocytes emigrate from organ cultures of human skin and form distinctive dendritic-T-cell conjugates.

Prior studies of mouse skin in organ culture have shown that dendritic cells selectively emigrate from the explants over 1-3 d. This emigration may model the movements of dendritic cells that can occur in situ, as in transplantation and contact sensitivity. In this study, we cultured explants of normal human skin that had been removed with a dermatome. Dendritic cells with characteristic morphology and mixed leukocyte response-stimulatory activity emigrated. The dendritic cells had the expected phenotype, e.g., rich in major histocompatibility complex class II and accessory molecules such as B7-1, intercellular adhesion molecule-1, and leukocyte function-associated antigen-3. Small lymphocytes also were present in the emigrated populations and proved to be T cells exclusively, almost entirely of the TcR alpha beta and memory type (CD45RAweak, CD45RO LFA-3/CD58+), with a CD4:CD8 subset ratio of about 2:1. Some of the T cells were bound tightly to the dendritic cells. These conjugates did not dissociate after exposure to trypsin or to calcium- and magnesium-free medium, or during cytofluorography. This made it possible to sort distinct populations of single dendritic cells, single T cells, and conjugates of the two cell types. Conjugates would continue to form from mixtures of separated dendritic cells and T cells in culture. Therefore, cutaneous dendritic cells and memory T lymphocytes emigrate from human skin explants, and some of these cells form distinctive conjugates that we hypothesize contribute to immunologic recall reactions.

Cell Communication↗
PubMed1995

Pattern of disease after murine hepatitis virus strain 3 infection correlates with macrophage activation and not viral replication.

Murine hepatitis virus strain (MHV-3) produces a strain-dependent pattern of disease which has been used as a model for fulminant viral hepatitis. This study was undertaken to examine whether there was a correlation between macrophage activation and susceptibility or resistance to MHV-3 infection. Peritoneal macrophages were isolated from resistant A/J and susceptible BALB/cJ mice and, following stimulation with MHV-3 or lipopolysaccharide (LPS), analyzed for transcription of mRNA and production of interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), mouse fibrinogen-like protein (musfiblp), tissue factor (TF), leukotriene B4, and prostaglandin E2 (PGE2). Macrophages from BALB/cJ mice produced greater amounts of IL-1, TNF-alpha, TGF-beta, leukotriene B4, and musfiblp following MHV-3 infection than macrophages from resistant A/J mice, whereas in response to LPS, equivalent amounts of IL-1, TNF-alpha, TGF-beta, and TF were produced by macrophages from both strains of mice. Levels of mRNA of IL-1, TNF-alpha, and musfiblp were greater and more persistent in BALB/cJ than in A/J macrophages, whereas the levels and kinetics of IL-1, TNF-alpha, and TF mRNA following LPS stimulation were identical in macrophages from both strains of mice. Levels of production of PGE2 by MHV-3-stimulated macrophages from resistant and susceptible mice were equivalent; however, the time course for induction of PGE2, differed, but the total quantity of PGE2 produced was insufficient to inhibit induction of musfiblp, a procoagulant known to correlate with development of fulminant hepatic necrosis in susceptible mice. These results demonstrate marked differences in production of inflammatory mediators to MHV-3 infection in macrophages from resistant A/J and susceptible BALB/cJ mice, which may explain the marked hepatic necrosis and fibrin deposition and account for the lethality of MHV-3 in susceptible mice.

Animals↗
PubMed1995

Control of uterine stromal mitosis in relation to uterine sensitivity and decidualization in mice.

The relationship between mitosis, ovarian hormones, decidual stimuli and decidualization was investigated using progestagen-treated ovariectomized mice. Oestradiol, or the intraluminal instillation of oil or saline, all stimulated stromal mitosis. When oil or saline was instilled following oestradiol, the response depended on the dose of oestradiol, the interval between the oestradiol and the instillation, and the time when the mice were killed. After 20 ng oestradiol, the instillation of oil 7 h later induced large mitotic and decidual responses that were evident within 17 h of instillation and increased with time. Smaller mitotic and decidual responses were obtained when the interval between oestradiol and oil was 24 h; there was no response when the interval was 42 h. When a higher dose (100 ng) of oestradiol was given, oil injected 7 h later initially stimulated mitosis (at 17 h), but this effect was reduced at 24 h and no decidualization occurred. After instilling oil 24 or 42 h after 100 ng oestradiol, the mitotic response was limited, and there was no decidual response. Regardless of the dose of oestradiol, saline induced only a transient mitotic response and no decidualization occurred. It is concluded that there are three stimuli that can cause stromal mitosis in the progestagen-treated mouse uterus: oestrogen, an intraluminal stimulus (blastocyst, oil or saline) and factors associated with decidualization. Oestradiol not only induces mitosis, but also produces a period of heightened sensitivity to the mitotic effects of intraluminal stimuli. In addition, low doses of oestradiol induce a period of sensitivity to decidual stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

The response of the flexion-relaxation phenomenon in the low back to loading.

Fick hypothesized in 1911 that the erector spinae muscles are not active when the trunk is in the fully flexed position. This effect was later called the flexion-relaxation phenomenon (FRP) and is believed to be the result of the ligaments and other passive elements of the spine taking over the load of the muscles. This study examined the effect of loading on the EMG activity of five males and five females during postures of standing at 45 degrees, 90 degrees, and full flexion. The results showed major differences in the relationship between the electromyographic signal (EMG) of the erector spinae and loading for the four postures. The erector spinae muscles did not activate in positions of full flexion (or even 90 degrees for some subjects) for loading as high as 50% of their maximum voluntary contraction, suggesting that alternative muscles are being activated and that the passive tissues may be put under higher loads than originally thought in these positions. The results suggested that the FRP could be used as a biofeedback tool to illustrate to workers that their muscles are not turning on in the fully flexed positions, and therefore, these positions should be avoided.

Adolescent↗
PubMed1994

Conjugates of dendritic cells and memory T lymphocytes from skin facilitate productive infection with HIV-1.

Experimentally, a productive infection with HIV-1 requires that virus be administered to T cells that are activated by mitogens. We describe a productive milieu for HIV-1 within the confines of normal skin that does not require standard stimuli. The milieu consists of dendritic cells and T cells that emigrate from skin and produce distinctive stable, nonproliferating conjugates. These conjugates, upon exposure to each of seven different HIV-1 isolates, begin to release high levels of virus progeny within 4 days. Numerous infected syncytia, comprised of both dendritic and T cells, rapidly develop. We propose that conjugates of dendritic cells and T cells, as found in the external linings of organs involved in sexual transmission of HIV-1, represent an important site for the productive phase of HIV-1 infection. Because the affected T cells carry the memory phenotype, this site additionally provides a mechanism for the chronic depletion of CD4+ memory cells in HIV-1 disease.

CD4-Positive T-Lymphocytes↗
PubMed1994

Susceptibility of dendritic cells to HIV-1 infection in vitro.

We review recent work on the extent of HIV-1 infection of dendritic cells (DCs) and the consequences of exposure to virus. The reported levels of infection of DCs from blood have varied from "explosive" to "undetectable." The only study that used sorted DCs demonstrated little if any infectability, which may not be surprising given the very low levels of CD4 on the populations that were studied. HIV-1-pulsed, highly purified DCs function as potent antigen-presenting cells during the mixed leukocyte reaction and responses to superantigens. At the same time that the HIV-1-pulsed DCs stimulate CD4+ T cells in DC-T clusters, the virus is transferred to the responding lymphocytes and a vigorous productive infection of the T cells takes place. This pool of transferable HIV-1 is short lived in cultured human blood DCs and likely reflects the capacity of these cells to internalize and recycle vesicles in the endocytic pathway, as revealed with experiments using 0.1-micron fluorescent latex beads. Current efforts are directed to analyzing the interaction of HIV-1 with several populations of DCs that express higher levels of CD4. These include DCs studied in fresh, uncultured blood, as well as skin, thymus, and tonsil DCs. In each case, entry and reverse transcription of HIV-1 are seen, but again, coculture with T cells is required for a productive infection to take place. We conclude that DCs could play a critical role in the pathogenesis of HIV-1 infection, but that the interaction with CD4+ T cells is a critical variable in analyzing the extent of productive infection and its consequences.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Infection and apoptotic cell death of CD4+ T cells during an immune response to HIV-1-pulsed dendritic cells.

Interacting dendritic cells and helper CD4+ lymphocytes form a microenvironment that is permissive for HIV-1 replication. The virus need only be pulsed initially onto the dendritic cells, which then transfer HIV-1 to the lymphocytes that are responding to presented antigens or superantigens. We have pursued underlying mechanisms in this system, because it provides a model for the infection of antigen-reactive, primary T cells. Pulsing the T cells with HIV-1 results in much less of a subsequent infection than does pulsing the dendritic cells. The latter pulse occurs effectively in the presence of AZT. Direct examination of the interacting dendritic cells and T cells reveals extensive production of p24 by many of the lymphocytes, including syncytia. The majority of the responding T cells die during the coculture. Apoptosis accounts for much of this death as revealed by in situ nick translation assays for DNA endonucleolysis, and hypodiploid profiles on staining with DNA-binding dyes. Therefore the microenvironment that is generated between antigen-presenting dendritic cells and T cells reveals the cytopathic potential of HIV-1, because there is such extensive and rapid death by apoptosis of antigen-reactive T cells.

Antibodies, Monoclonal↗
PubMed1994

A dynamic material parameter estimation procedure for soft tissue using a poroelastic finite element model.

A three-dimensional finite element model for a poroelastic medium has been coupled with a least squares parameter estimation method for the purpose of assessing material properties based on intradiscal displacement and reactive forces. Parameter optimization may be based on either load or displacement control experiments. In this paper we present the basis of the finite element model and the parameter estimation process. The method is then applied to a test problem and the computational behavior is discussed. Sequential optimization on different parameter groups was found to have superior convergence properties. Some guidelines for choosing the starting parameter values for optimization were deduced by considering the form of the objective function. For load control experiments, in which displacement data is used for the optimization, the starting values for the elastic modulus should be lower in magnitude than an "anticipated" modulus. The permeability starting values should be higher than an anticipated permeability. For displacement control experiments, the reverse is true. The optimization scheme was also tested on data with random variations.

Anisotropy↗