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Biomedical subjects

M Pope

Publications and source records attributed to M Pope.

At least 19 recordsLinked to original sources
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

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

Induction of Lyt-2+ cytotoxic T lymphocytes following primary and secondary Salmonella infection.

Investigations of the cytotoxic activity of T cells induced following one or two intraperitoneal doses of live Salmonella revealed that cytotoxicity was restricted to the Lyt-2+ T-cell subset and was enhanced following secondary infection with Salmonella. Initial studies using the lectin-dependent cellular cytotoxicity (LDCC) assay detected Lyt-2+ cytotoxic T cells in peritoneal cell suspensions of S. enteritidis 11RX (11RX)-infected mice, with the peak of activity occurring 5 days after infection. This did not correlate with the proliferative activity of these cells, which peaked 10-12 days after infection. Secondary challenge with 11RX or S. typhimurium C5 (C5) induced a rapid increase in the cytotoxic activity of Lyt-2+ peritoneal T cells and was detected even 21 days later. The antigen specificity of some of these cells was confirmed in cytotoxicity assays using P815 tumour cells infected with 11RX organisms as targets. No cytotoxic activity was detected in the spleen cell suspensions of infected (and normal) mice unless the cells were first activated by in vitro culture with concanavalin A (Con A). Both types of activated spleen cells showed LDCC but Salmonella-specific cytotoxic Lyt-2+ T cells were detected only in spleen cell (SC) cultures prepared from mice challenged with a second dose of Salmonella.

Animals↗
PubMed1994

Detection of Salmonella-specific L3T4+ and Lyt-2+ T cells which can proliferate in vitro and mediate delayed-type hypersensitivity reactivity.

This study was based on an initial observation that, although culture of T cells from Salmonella-infected mice with concanavalin A induced both L3T4+ T cells and Lyt-2+ T cells to proliferate, there was a relative increase in the responsiveness of the Lyt-2+ T cells in suspensions harvested from mice with secondary infection. Accordingly, primed T cells, obtained from the peritoneal cavities and spleens of mice that had received one or two intraperitoneal doses of Salmonella were examined for the presence of antigen-specific, class I major histocompatibility complex (MHC)-restricted Lyt-2+ T cells. After primary infection with avirulent Salmonella enteritidis 11RX (11RX) only L3T4+ T cells could be induced to proliferate in response to formalin-killed 11RX organisms, and a second dose of live 11RX did not change the phenotype of the responding T-cell population. In contrast, secondary challenge with S. typhimurium C5 (C5) generated cell populations where both L3T4+ and Lyt-2+ T cells proliferated when cultured with formalin-killed 11RX. Transfer of delayed-type hypersensitivity (DTH) using mixtures of primed T cells and either killed or live Salmonella organisms demonstrated that DTH was mediated by L3T4+ T cells, and secondary infection with either the 11RX or C5 strain did not change this result. However, antigen-specific Lyt-2+ T cells which mediated DTH reactivity were detected using a Salmonella-infected cell line which expressed MHC-coded class I but not class II products. These Lyt-2+ T cells were present in the spleen and peritoneal cavity after secondary infection and in the peritoneal cavity late after a primary infection with 11RX.

Animals↗
PubMed1993

Malignant benign neonatal sacrococcygeal teratoma.

Thirty-six patients with benign neonatal sacrococcygeal teratoma (SCT) were treated in our medical center from 1972 to 1990. Mean gestational age was 38.6 +/- 3.3 weeks with a mean birth weight of 3,484.0 +/- 938.5 g. Twenty-nine patients (89%) were females. The majority of the tumors (75%) contained cystic components and 96% were Altman classification I and II. The initial surgical removal of the SCT (including the coccyx) was carried out during the first 7 days of life. Six patients (22%) developed recurrence of the tumor. Three were benign and reappeared locally after 12 +/- 3 months and were reexcised. The mean serum alpha-fetoprotein level in this group was 13 +/- 1 g/L. The malignant recurrence (all originally reported as being mature benign SCT) appeared at 20.3 +/- 1.5 months and had markedly elevated serum alpha-fetoprotein levels (7,320 +/- 4,630 micrograms/L). All the patients in this group had multimodal therapy including complete excision of the recurrent tumor. We conclude that SCT, although histologically benign, has an alarming potential to recur either as a benign or malignant tumor during the first 2 years of life. Close follow-up for at least 3 years (frequent examination, serum alpha-fetoprotein, and diagnostic imaging) is recommended for all patients who had undergone excision of SCT in the newborn period.

Combined Modality Therapy↗
PubMed1992

Effect of tension and placement of a prosthetic anterior cruciate ligament on the anteroposterior laxity of the knee.

We wished to determine the optimal tension required to restore normal joint laxity to anterior cruciate ligament (ACL)-deficient knees using a braided polyethylene ACL prosthesis (PACL). In 10 cadaveric specimens, we measured the anteroposterior (AP) laxity of the intact knee at 10 degrees, 30 degrees, 60 degrees, and 90 degrees of flexion. The ACL was then removed and replaced with the PACL using tunnel-tunnel (T-T) and "over-the-top" (OTT) placement techniques. In both positions, the PACL was initially tensioned to 0, 9, 18, and 27 N with the knee flexed to 30 degrees. AP joint laxity was then measured at each flexion angle. With an increase in initial tension, there was a corresponding decrease in AP laxity. At 30 degrees and 90 degrees of flexion, AP laxity was not significantly different from normal using T-T placement and an initial tension of 0 N. At 90 degrees of flexion, AP laxity was not significantly different from normal using OTT placement at 0 or 9 N of initial tension. For both positions, all other tension levels and flexion angles constrained AP laxity. No laxity differences were detected between the OTT and T-T positions at any flexion angle. The variability in AP laxity of the T-T position was significantly greater than OTT. With a 150-N anterior shear force applied to the proximal tibia, the maximum tensions developed in the PACL were not significantly different between the two positions except at 90 degrees. The results suggest that implantation of the PACL is best performed using OTT positioning with an initial tension of 0 N applied at 30 degrees of knee flexion.

Adult↗
PubMed1992

Effect of one-legged exercise on the strength, power and endurance of the contralateral leg. A randomized, controlled study using isometric and concentric isokinetic training.

The purpose of this investigation was to study the effect of one-legged exercise on the strength, power and endurance of the contralateral leg. The performance of the knee extensor and flexor muscle of 20 healthy young adults (10 men and 10 women) was first tested by Cybex II+ and 340 dynamometers. Then 10 subjects were chosen at random to train using one leg three times a week for 7 weeks whilst the other 10 served as controls. During the 8th week, the tests were repeated. Both quadriceps and hamstring muscles of the trained subjects showed a cross-transfer effect from the trained limb to the untrained side. This concerned the strength and power, as well as endurance characteristics of these muscles. The average change in peak torque of the quadriceps muscle was +19% (P less than 0.001) in the trained limb, +11% (P less than 0.01) in the untrained limb and 0% in the control limbs. In hamstring muscles the changes were +14% (P less than 0.01), +5% and -1%, respectively. Concerning muscle endurance (work performed during the last 5 contractions in the 25-repetition test) the corresponding changes were +15% (P less than 0.01), +7% (P less than 0.01), and -1% in quadriceps muscle, and +17% (P less than 0.05), +7%, and -3% in hamstring muscles. The average strength benefit in the untrained limb was +36% (hamstring muscles) and +58% (quadriceps muscle) of that achieved in the trained limb. Untrained hamstring muscle showed better benefits in the endurance parameters than in strength or power parameters, while in the quadriceps muscle this effect was reversed. A positive relationship was observed between the changes (greater improvement in the trained limb resulted in greater improvement in the untrained limb) (hamstring muscles: r = 0.83, P less than 0.001, quadriceps muscle: r = 0.53, P less than 0.001). In endurance parameters, this relationship was almost linear while in the strength and power parameters the results were more in favour of a curvilinear relationship with limited benefit.

Adult↗
PubMed1992

Measurement of height loss during whole body vibrations.

An experimental, in vivo study was performed to measure height changes in subjects exposed to whole body vibrations while seated. Twelve women, with an average age of 22 years, were exposed to sinusoidal vibrations for 5 mins. The vibration frequency was 5 Hz, and the acceleration was 0.1 g Rms. The height loss stemming from vibration exposure was compared with that experienced while sitting without being subjected to vibrations. The height losses that always occurred from the two exposures were corrected for the effect of posture change. The height loss from vibration was significantly greater than when no vibration was present. Height loss due to posture change was responsible for approximately 50% of the total height loss. From this study it was concluded that whole body vibrations cause increased height loss.

Adult↗
PubMed1992

Antigen-presenting characteristics of peritoneal cells of Salmonella enteritidis 11RX-infected mice.

Investigation of the possibility that infection with intracellular bacterial parasites such as Salmonellae may modulate the function of antigen-presenting cells (APC) revealed no major change in APC function of peritoneal cells (PC) harvested from the peritoneal cavity of mice 1-3 days after intraperitoneal immunization with S. enteritidis 11RX. Analysis of the phenotype of the Salmonella-primed T cells which responded when cultured with PC from either normal or infected mice and Salmonella-antigen showed that only L3T4+ T cells proliferated. This was also true when PC from normal and infected mice were compared for their ability to induce allogeneic responses; both L3T4+ and Lyt-2.2+ T cells were induced to proliferate, with the majority belonging to the class I restricted, Lyt-2.2+ phenotype. Significant levels of alloantigen-specific Lyt-2.2+ cytotoxic T-cell activity were also induced in both types of cultures. However, a minor population of adherent cells which inhibited Salmonella antigen-specific T-cell proliferation in vitro was detected in peritoneal cell suspensions harvested 3 days after intraperitoneal immunization with S. enteritidis 11RX. Further characterization of these peritoneal cells revealed that they also inhibited the induction of in vitro T-cell responses to alloantigens. It is likely that the cells mediating these inhibitory effects belonged to a macrophage-like subset.

Animals↗