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PubMed1982

Development and plasticity of visual and vestibular generated eye movements.

Slow phase horizontal eye movements, elicited by the vestibulo-ocular reflex (VOR) and/or visual pursuit (VP) systems, were examined in normal children (NC, 9-16 years) and normal adults (NA). At slow frequencies of sinusoidal stimulation of the body (with the head immobilized) and/or of a visual target, the NC (9-12 years) exhibited (a) immature VP and VOR Suppression and mature VOR Enhancement in the presence of a visual image; (b) immature VOR Suppression and mature VOR Enhancement in the presence of a non-visual image of the spatial location of a visual target, an extra-retinal signal; (c) inability to augment or depress the VOR gain with a non-visual image; (d) mature VOR Suppression ratios; and (e) adjustment of VOR gain to a high value. The maturational process was featured by (a) parallel development of VP and VOR Suppression; (b) modification of the VOR gain; and (c) an increasing ability to augment or depress the VOR with a non-visual image. The observations in NC (9-12) are ascribed to a maturational lag of an extra-retinal process interacting with mature retinal and vestibular processes and, hence, suggest that both the retinal and vestibular contributions to ocular stability predate the development of an extra-retinal signal. When mature, the central nervous system utilizes both extra-retinal and retinal signals to mediate adaptive regulation of VOR gain and to preserve stable visual pursuit motion and VOR Suppression. Our findings also suggest that during tasks requiring visual-vestibular interaction, VP and VOR mechanisms appear to be indirectly rather than directly coupled.

Adolescent↗
PubMed1989

Stereotactic frame for neuroradiology and charged particle Bragg peak radiosurgery of intracranial disorders.

The application of heavy charged particle Bragg peak radiosurgery for the treatment of intracranial vascular and other disorders requires a system of precise patient immobilization and stereotactic localization of defined intracranial targets. The process of using stereotactic neuroradiological procedures (including cerebral angiography, CT scanning and magnetic resonance imaging) for target definition and localization, and complex treatment planning constrain such a system to be adaptable and reusable. This paper describes a removable stereotactic frame-mask system that is used to immobilize and reposition the patient during stereotactic neuroradiological procedures and charged particle radiosurgery. It consists of four parts--(a) a plastic mask for immobilizing the patient's head; (b) a lucite-graphite mounting frame; (c) a set of fiducial markers; and (d) interfaces between the frame for immobilization and fixation to various diagnostic and therapeutic patient couches. The relationship between each component and the radiosurgical procedure is discussed. This system has proven to be safe, reliable, and noninvasive and it does not require fixation to the bones of the face or skull. When integrated into the radiosurgical treatment planning and localization procedures developed at Lawrence Berkeley Laboratory, it is capable of reliably repositioning the patient to 1 mm in each of three planes and contouring the intracranial target reliably to this accuracy. The application of this stereotactic system in heavy charged particle radiosurgery of intracranial arteriovenous malformations is described in other reports.

Cerebral Angiography↗
PubMed2000

Phosphorylation of microtubule-associated protein 2 (MAP2) and its relevance for the regulation of the neuronal cytoskeleton function.

Neurons, the basic information processing units of the nervous system, are characterized by a complex polar morphology which is essential for their function. To attain their precise morphology, neurons extend cytoplasmatic processes (axons and dendrites) and establish synaptic connections in a highly regulated way. Additionally, neurons are also subjected to small plastic changes at the adult stage which serve to regulate synaptic transmission. Every step of neuronal development is genetically controlled by endogenous determinants, as well as by environmental signals including intercellular contacts, extracellular matrix and diffusible signals. Cytoskeletal components are among the main protein targets modified in response to most of those extracellular signals which ultimately determine neuronal morphology. One of the major mechanisms controlling the neuronal cytoskeleton is the modification of the phosphorylation state of cytoskeletal proteins via changes in the relative activities of protein kinases and phosphatases within neurons. In particular, the microtubule-associated protein 2 (MAP2) family of proteins is an abundant group of cytoskeletal components which are predominantly expressed in neurons and serve as substrates for most of protein kinases and phosphatases present in neurons. MAP2 phosphorylation seems to control its association with the cytoskeleton and it is developmentally regulated. Moreover, MAP2 may perform many functions including the nucleation and stabilization of microtubules (and maybe microfilaments), the regulation of organelle transport within axons and dendrites, as well as the anchorage of regulatory proteins such as protein kinases which may be important for signal transduction. These putative functions of MAP2 have also been proposed to play important roles in the outgrowth of neuronal processes, synaptic plasticity and neuronal cell death. Thus, MAP2 constitutes an interesting case to understand the regulation of neuronal function by the alteration of the phosphorylation state of cytoskeletal proteins in response to different extracellular signals. Here we will review the current knowledge about the regulation of MAP2 function through phosphorylation/dephosphorylation and its relevance in the broader context of neuronal functions.

Animals↗
PubMed1994

Laminar distribution and neuronal targets of GABAergic axon terminals in cat primary auditory cortex (AI).

The form, density, and neuronal targets of presumptive axon terminals (puncta) that were immunoreactive for gamma-aminobutyric acid (GABA) or its synthesizing enzyme, glutamic acid decarboxylase (GAD), were studied in cat primary auditory cortex (AI) in the light microscope. High-resolution, plastic-embedded material and frozen sections were used. The chief results were: 1) There was a three-tiered numerical distribution of puncta, with the highest density in layer Ia, an intermediate number in layers Ib-IVb, and the lowest concentration in layers V and VI, respectively. 2) Each layer had a particular arrangement: layer I puncta were fine and granular (less than 1 micron in diameter), endings in layers II-IV were coarser and more globular (larger than 1 micron), and layer V and VI puncta were mixed in size and predominantly small. 3) The form and density of puncta in every layer were distinctive. 4) Immunonegative neurons received, in general, many more axosomatic puncta than immunopositive cells, with the exception of the large multipolar (presumptive basket) cells, which invariably had many puncta in layers II-VI. 5) The number of puncta on the perikarya of GABAergic neurons was sometimes related to the number of puncta in the layer, and in other instances it was independent of the layer. Thus, while layer V had a proportion of GABAergic neurons similar to layer IV, it had only a fraction of the number of puncta; perhaps the intrinsic projections of supragranular GABAergic cells are directed toward layer IV, as those of infragranular GABAergic neurons may be. Since puncta are believed to be the light microscopic correlate of synaptic terminals, they can suggest how inhibitory circuits are organized. Even within an area, the laminar puncta patterns may reflect different inhibitory arrangements. Thus, in layer I the fine, granular endings could contact preferentially the distal dendrites of pyramidal cells in deeper layers. The remoteness of such terminals from the spike initiation zone contrasts with the many puncta on all pyramidal cell perikarya and the large globular endings on basket cell somata. Basket cells might receive feed-forward disinhibition, pyramidal cells feed-forward inhibition, and GABAergic non-basket cells would be the target of only sparse inhibitory axosomatic input. Such arrangements imply that the actions of GABA on AI neurons are neither singular nor simple and that the architectonic locus, laminar position, and morphological identity of a particular neuron must be integrated for a more refined view of its role in cortical circuitry.

Animals↗
PubMed2006

Deviation of skin marker from bone target during movement of the scapula.

BACKGROUND: Recording movement of the scapula by non-invasive techniques is fraught with technical difficulty. One convenient method involves placing a single marker on the skin overlying the acromion. The purpose of this study was to compare translatory discrepancies between marker and underlying bone for seven markers affixed to the skin overlying different parts of the scapula. METHODS: The markers were small plastic spheres filled with machine oil, clearly visible on magnetic resonance imaging (MRI), placed over seven loci of the scapula, including the acromion, spine, medial border, lateral border, and inferior angle. Nine healthy men participated, assuming three positions in the MRI apparatus: (1) arm at the side of the trunk (starting position); (2) arm in full elevation over the head; and (3) hand placed behind the back at the thoracolumbar area. Visible markers and three loci of the scapula itself were digitized on each MRI scan, enabling calculation of changes in location of each marker relative to the scapula between the starting position and either of the other two positions. RESULTS: Among the seven loci examined, the marker placed atop the acromion deviated least from its target, 39 +/- 1 mm (mean +/- standard deviation) for full elevation and 15 +/- 1 mm for moving the hand behind the back. Markers along the medial border and at the inferior angle exhibited relatively large deviations, on the order of 8 mm for full elevation and 3 mm for moving the hand behind the back. CONCLUSIONS: For the two movements studied, involving full range of motion in the shoulder complex, translation of the scapula is most accurately recorded if the marker is placed over the acromion, but the systematic error is too large for such tracking to be deemed precise.

Acromioclavicular Joint↗
PubMed2006

Personal cytometers: slow flow or no flow?

BACKGROUND: Although some manufacturers have optimistically described instruments with prices in the 40,000 US dollars range as "personal cytometers", analogy with the personal computer suggests that the target price for a true "personal" cytometer should be under 5,000 US dollars. Since such an apparatus could find a wide range of applications in cytomics in both developing and developed countries, it seemed desirable to consider its technical and economic feasibility. METHODS: Using resolution targets and a variety of fluorescent bead standards immobilized on filters and/or slides, we evaluated high-intensity LEDs as fluorescence excitation sources, relatively inexpensive CCD cameras as detectors, and 35 mm camera lenses and plastic low-power microscope optics for light collection in a simple, inexpensive low-resolution imaging cytometer. RESULTS: The components tested could be combined toproduce an instrument capable of detecting fewer than 10,000 molecules of cell-associated fluorescent label, and thus applicable to a broad range of cytometric tasks. CONCLUSIONS: Given the requirements for light sources, detectors, optics, mechanics, electronics and data analysis hardware and software, and the components presently available, it should be easier to reach the desired 5,000 US dollars price point with an image cytometer than with a flow cytometer.

Flow Cytometry↗
PubMed1986

Low frequency of NK-cell progenitors and development of suppressor cells in IL-2-dependent cultures of spleen cells from low NK-reactive SJL/J mice.

Studies were performed to determine the basis for low NK activity in the spleens of SJL/J mice. In contrast to substantial boosting by IL-2 or IFN of NK activity of spleen cells from high NK-reactive strains of mice, no detectable effect of these cytokines on SJL spleen cells was seen. When SJL spleen cells were cultured for 7 days in the presence of IL-2, the frequency of proliferating cells was comparable to that of other strains of mice. However, the SJL spleen cells showed a frequency of NK-cell progenitors which was at least 50 times lower than that of the CBA/J spleen cells. In addition to having no detectable effector-cell activity, the cultures of SJL spleen cells contained suppressor cells which were able to inhibit the NK activity of spleen cells from other strains of mice. These suppressor cells did not adhere to plastic or nylon wool and were found in low-density fractions after Percoll density gradient centrifugation. The cultured SJL spleen cells had a high percentage of cells capable of binding to NK-susceptible target cells, which was similar to that seen in lytic cultures from other strains of mice. Thus, the suppressor activity may be attributable to competitive inhibition of the interaction of effector cells with target cells. Although several of the characteristics of suppressor cells were similar to those of cultured effector cells, they may not represent inactive or pre-NK cells since their progenitors were Thy1+ and AsialoGM1- whereas the progenitors of cultured effector cells in high NK strains were Thy1- and GM1+. The ability to eliminate the progenitors of the suppressor cells by pretreatment of spleen cells with anti-Thy1 plus C' also suggested that the low or undetectable NK activity of the cultured SJL cells is not attributable to suppression but may be due to an inherent deficit of NK cells.

Animals↗
PubMed1988

Induction of tumor growth inhibitory factor (TGIF) in human mononuclear cells by OK-432, a streptococcal preparation.

A tumor growth inhibitory factor (TGIF) was induced in the culture supernatant from mixed culture of human peripheral blood mononuclear cells (PBMC) and a streptococcal preparation, OK-432, in vitro. The activity generated in the supernatant increased in a time-dependent fashion and first appeared 6 h after the initiation of culture, reaching its maximum around 48 h. The TGIF was cytostatic against seven of ten human tumor targets, but not against three murine tumor targets. Tumor cell growth was inhibited by a transient contact, i.e., 1 h, with TGIF. The TGIF was produced by lymphocytes but not by monocytes, because the activity was usually enhanced by elimination of plastic-adherent cells from the original PBMC fraction. The TGIF was relatively stable against heating at 56 degrees C for 30 min, but the activity was totally destroyed after heating at 70 degrees C for 5 min. The molecular weight of TGIF was estimated to be about 43 x 10(3) daltons by gel filtration. No interferon (IFN) activity was detected in the TGIF-positive fractions obtained by gel filtration, and the TGIF-positive fractions did not inhibit the growth of tumor necrosis factor (TNF)-sensitive mouse L929 cells. The TGIF activity was not significantly affected in neutralizing tests using specific antibodies against human IFN and TNF. The OK-432 was administered i.p. for management of cancer patients with malignant ascites. Ascites-derived mononuclear cells (ASMC) were obtained before and 3 to 5 days after OK-432 injection. The ASMC obtained after the injection produced TGIF in vitro in the absence of OK-432; the preinjection ASMC showed no such production. A positive correlation was found between TGIF-producing activity by ASMC and the effect of OK-432 injection on ascites volume. These results indicate that TGIF is induced in mononuclear cells by OK-432 not only in vitro but also in vivo and plays an important role in inhibition of tumor growth in cancer patients.

Animals↗
PubMed1998

Analysis of an excitable dendritic spine with an activity-dependent stem conductance.

Dendritic spines are the major target for excitatory synaptic inputs in the vertebrate brain. They are tiny evaginations of the dendritic surface consisting of a bulbous head and a tenuous stem. Spines are considered to be an important locus for plastic changes underlying memory and learning processes. The findings that synaptic morphology may be activity-dependent and that spine head membrane may be endowed with voltage-dependent (excitable) channels is the motivation for this study. We first explore the dynamics, when an excitable, yet morphologically fixed spine receives a constant current input. Two parameter Andronov-Hopf bifurcation diagrams are constructed showing stability boundaries between oscillations and steady-states. We show how these boundaries can change as a function of both the spine stem conductance and the conductance load of the attached dendrite. Building on this reference case an idealized model for an activity-dependent spine is formulated and analyzed. Specifically we examine the possibility that the spine stem resistance, the tunable "synaptic weight" parameter identified by Rall and Rinzel, is activity-dependent. In the model the spine stem conductance depends (slowly) on the local electrical interactions between the spine head and the dendritic cable; parameter regimes are found for bursting, steady states, continuous spiking, and more complex oscillatory behavior. We find that conductance load of the dendrite strongly influences the burst pattern as well as other dynamics. When the spine head membrane potential exhibits relaxation oscillations a simple model is formulated that captures the dynamical features of the full model.

Dendrites↗
PubMed1983

Morphological aspects of the teleostean visual system: a review.

This review is concerned with results of research carried out in the last two decades regarding visual pathways and centers in teleosts. It covers neither morphology of the retina nor development and plasticity. The optic nerve is considered in terms of axonal composition and retinotopic organization. The connections to the retina and from the retina are subsequently reviewed, and a general scheme is proposed for the retinofugal targets in thalamus and pretectum. The tectum opticum is then reviewed as regards its afferent connections from retina, telencephalon, diencephalon, mesencephalon and brainstem, with details on distribution of terminals, cell types contacted and synaptic structure. The efferent tectal connections are reviewed next, including their plausible cells of origin. Finally, a general diagram of the teleostean visual system is presented, and several circuits within this diagram are emphasized and discussed.

Afferent Pathways↗
PubMed2004

The role of monoamines in the actions of established and "novel" antidepressant agents: a critical review.

Monoaminergic pathways are highly responsive to aversive stimuli and play a crucial role in the control of affect, cognition, endocrine secretion, chronobiotic rhythms, appetite, and motor function, all of which are profoundly disrupted in depressive states. Accordingly, a perturbation of monoaminergic transmission is implicated in the aetiology of depressive disorders, and all clinically available antidepressants increase corticolimbic availability of monoamines. However, their limited efficacy, delayed onset of action, and undesirable side effects underlie ongoing efforts to identify improved therapeutic agents. Sequencing the human genome has raised the hope not only of better symptomatic control of depression, but even of the prevention or cure of depressive states. In the pursuit of these goals, there is currently a tendency to focus on selective ligands of "novel" nonmonoaminergic targets. However, certain classes of novel agent (such as neurokinin(1) receptor antagonists) indirectly modulate the activity of monoaminergic networks. Others may act "downstream" of them, converging onto common cellular substrates controlling gene expression, synaptic plasticity, and neurogenesis. Further, by analogy to the broad-based actions of currently employed drugs, multitarget agents may be better adapted than selective agents to the management of depression-a complex disorder with hereditary, developmental, and environmental origins. It is, thus, important to continue the creative exploration of clinically validated and innovative monoaminergic strategies within a multitarget framework. In this light, drugs combining monoaminergic and nonmonoaminergic mechanisms of action may be of particular interest. The present article provides a critical overview of monoaminergic strategies for the treatment of depressive states, both established and under development, and discusses interactions of novel "nonmonoaminergic" antidepressants with monoaminergic mechanisms.

Antidepressive Agents↗
PubMed2006

Mechanisms underlying the recovery of lower urinary tract function following spinal cord injury.

The lower urinary tract has two main functions, the storage and periodic expulsion of urine, which are regulated by a complex neural control system in the brain and lumbosacral spinal cord. This neural system coordinates the activity of two functional units in the lower urinary tract: (1) a reservoir (the urinary bladder) and (2) an outlet (consisting of bladder neck, urethra and striated muscles of the pelvic floor). During urine storage the outlet is closed and the bladder is quiescent, thereby maintaining a low intravesical pressure over a wide range of bladder volumes. During micturition the outlet relaxes and the bladder contracts to promote the release of urine. This reciprocal relationship between bladder and outlet is generated by visceral reflex circuits, some of which are under voluntary control. Experimental studies in animals indicate that the micturition reflex is mediated by a spinobulbospinal pathway passing through a coordination center (the pontine micturition center) located in the rostral brainstem. This reflex pathway is in turn modulated by higher centers in the cerebral cortex that are presumably involved in the voluntary control of micturition. Spinal cord injury at cervical or thoracic levels disrupts voluntary control of voiding as well as the normal reflex pathways that coordinate bladder and sphincter functions. Following spinal cord injury, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. Studies in animals indicate that the recovery of bladder function after spinal cord injury is dependent in part on plasticity of bladder afferent pathways and the unmasking of reflexes triggered by capsaicin-sensitive C-fiber bladder afferent neurons. The plasticity is associated with changes in the properties of ion channels and electrical excitability of afferent neurons, and appears to be mediated in part by neurotrophic factors released in the spinal cord and the peripheral target organs.

Adrenergic Fibers↗
PubMed1997

De novo protein synthesis in isolated axons of identified neurons.

Neurons are highly polarized cells that contain a wealth of cytoplasmic and membrane proteins required for neurotransmission, synapse formation and various forms of neuronal plasticity. Typically, these proteins are differentially distributed over somatic, dendritic and axonal compartments. Until recently, it was believed that all proteins destined for various neuronal sites were synthesized exclusively in the somata and were subsequently targeted to appropriate extrasomal compartments. The discovery of various messenger RNA molecules in both dendrites and axons is suggestive of de novo protein synthesis in extrasomatic regions. The latter process has been demonstrated in few neuronal svrstems, but direct proof for the axonal transcription of a specific protein from a given messenger RNA is still lacking. This lack of fundamental knowledge in the field of cellular and molecular neurobiology is due primarily to both anatomical and experimental difficulties encountered in most animal preparations studied thus far. In this study we developed a neuronal experimental system comprising of individually identified neurons and their isolated axons from the mollusc Lymnaea stagnalis. We injected a foreign messenger RNA encoding a peptide precursor into the isolated axons of cultured neurons; and utilizing cellular, molecular and immunocytochemical techniques, we provide direct evidence for specific protein synthesis in isolated axons. The Lymnaea model provides us with an opportunity to examine the role and specificity of de novo protein synthesis in the extrasomal regions.

Animals↗
PubMed1999

Diverse behavioural defects caused by mutations in Caenorhabditis elegans unc-43 CaM kinase II.

Calcium/calmodulin-dependent serine/threonine kinase type II (CaMKII) is one of the most abundant proteins in the mammalian brain, where it is thought to regulate synaptic plasticity and other processes. Activation of the multisubunit kinase by calcium is effectively cooperative and can persist long after transient calcium rises. Despite extensive biochemical characterization of CaMKII and identification of numerous in vitro kinase targets, little is known about its function in vivo. Here we report that unc-43 encodes the only Caenorhabditis elegans CaMKII. A gain-of-function unc-43 mutation reduces locomotory activity, alters excitation of three muscle types and lengthens the period of the motor output of a behavioural clock. Null unc-43 mutations cause phenotypes generally opposite to those of the gain-of-function mutation. Mutations in the unc-103 potassium channel gene suppress a gain-of-function phenotype of unc-43 in one tissue without affecting other tissues; thus, UNC-103 may be a tissue-specific target of CaMKII in vivo.

Amino Acid Sequence↗
PubMed2006

Long-term memory deficits in Pavlovian fear conditioning in Ca2+/calmodulin kinase kinase alpha-deficient mice.

Signaling by the Ca(2+)/calmodulin kinase (CaMK) cascade has been implicated in neuronal gene transcription, synaptic plasticity, and long-term memory consolidation. The CaM kinase kinase alpha (CaMKKalpha) isoform is an upstream component of the CaMK cascade whose function in different behavioral and learning and memory paradigms was analyzed by targeted gene disruption in mice. CaMKKalpha mutants exhibited normal long-term spatial memory formation and cued fear conditioning but showed deficits in context fear during both conditioning and long-term follow-up testing. They also exhibited impaired activation of the downstream kinase CaMKIV/Gr and its substrate, the transcription factor cyclic AMP-responsive element binding protein (CREB) upon fear conditioning. Unlike CaMKIV/Gr-deficient mice, the CaMKKalpha mutants exhibited normal long-term potentiation and normal levels of anxiety-like behavior. These results demonstrate a selective role for CaMKKalpha in contextual fear memory and suggest that different combinations of upstream and downstream components of the CaMK cascade may serve distinct physiological functions.

Animals↗
PubMed1997

Developmental models of brain dysfunctions induced by targeted cellular ablations with methylazoxymethanol.

Abnormal brain development represents one of the major causes of neurological disorders in humans, and determining the factors responsible for generating specific brain malformations represents a formidable task for developmental neurobiology. The knowledge of the precise neurogenetic time table and the use of toxins, like methylazoxymethanol, able to interfere with neuroepithelial cells entering their last mitotic cycle, have allowed for targeted neuronal ablations in specific brain areas of the central nervous system (CNS) when administered at different gestational or postnatal days in various animal species. Of particular relevance are the studies in which ablations of neuronal populations of cortex, hippocampus, and cerebellum have been made. The results obtained show that these early ablations induce a number of neuroanatomic, neurochemical, and electrophysiological changes that give us the possibility to unravel the biochemical strategies utilized by surviving neurons to adapt to the perturbated environment. Most striking are the findings that target deprivation does not affect the survival of afferent neurons in the CNS (except for neurons of the lateral geniculate nucleus), in sharp contrast to the notion of target dependence for peripheral nervous system neurons. Animals showing selective ablations in the Ammon's horn of the hippocampus allow us to understand the complex biochemical pathways leading to changes in activity-dependent synaptic plasticity, and the data underscore the fundamental role of diverse Ca(2+)-dependent protein kinases, and their substrates, in modulating pre- and postsynaptic events during induction and maintenance of long-term potentiation (LTP). Because LTP represents a useful model to study molecular substrates of learning and memory, this animal model might be of relevance in understanding cognitive brain dysfunctions.

Animals↗
PubMed1985

X-ray and magnetic resonance stereotaxy for functional and nonfunctional neurosurgery.

By means of new plastic stereotactic ring and head fixers, stereotactic procedures can be combined with MRI, with stereotactic coordinates obtained from the MRI images. The method was rechecked against CT stereotaxy and shows a good correspondence of the target coordinates. With MRI stereotaxy, structures near bony regions will be more accessible than with CT stereotaxy. Moreover, the MRI procedure seems to have advantages for functional therapy without the necessity of contrast ventriculography.

Brain Neoplasms↗
PubMed1999

Activated lymphocytes promote endothelial cell detachment from matrix: a role for modulation of endothelial cell beta 1 integrin affinity.

In vivo, MHC class I-restricted injury of allogeneic tissue or cells infected by intracellular pathogens occurs in the absence of classical cytolytic effector mechanisms and Ab. Modulation of the target cell adhesion to matrix may be an additional mechanism used to injure vascular or epithelial cells in inflammation. We studied the mechanisms of human umbilical vein endothelial cell (EC) detachment from matrix-coated plastic following contact by concanamycin A-treated lymphocytes as an in vitro model of perforin-independent modulation of EC basement membrane adhesion. Human PBL were depleted of monocytes, stimulated, then added to an EC monolayer plated on either fibronectin or type I collagen matrices. Activated, but not resting, PBL induced progressive EC detachment from the underlying matrix. Injury of the EC monolayer required direct cell contact with the activated lymphocytes because no detachment was seen when the PBL were placed above a Transwell membrane. Moreover plasma membranes prepared from activated but not resting PBL induced EC detachment. Adherent EC stimulated with activated PBL did not show evidence of apoptosis using TUNEL and annexin V staining at time points before EC detachment was observed. Finally, neither the matrix metalloproteinase inhibitors o-phenanthroline and BB-94 nor aprotinin blocked EC detachment. However, activation of EC beta1 integrin using mAb TS2/16 or Mg2+ decreased EC detachment. These data indicate that cell-cell contact between activated PBL and EC reduces adhesion of EC to the underlying matrix, at least in part by inducing changes in the affinity of the endothelial beta 1 integrin.

Adjuvants, Immunologic↗