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PubMed1988

Computational study of an excitable dendritic spine.

1. A compartmental model was employed to investigate the electrical behavior of a dendritic spine having excitable membrane at the spine head. Here we used the Hodgkin and Huxley equations to generate excitable membrane properties; in some cases the kinetics were modified to get a longer duration action potential. Passive membrane was assumed for both the spine stem and the dendritic shaft. Synaptic input was modeled as a transient conductance increase (alpha-function) that lies in series with a battery (that corresponds to an excitatory or inhibitory synaptic equilibrium potential). 2. Threshold conditions for an action potential at the spine head membrane were found to be sensitive to the membrane properties at the spine head and to the conductance loading provided by the spine stem and the dendritic tree. Increasing either the number or the open times of the excitable channels had the effect of lowering spike threshold voltage. Increasing the spine stem resistance (RSS) or increasing the input resistance at the spinal base (RSB) also lowered the spike threshold voltage. Because a preexisting dendritic depolarization reduced the spine stem current, this lowered the spike threshold voltage, and this threshold was also shown to be sensitive to the distribution of membrane potential along the dendrite. 3. For each set of spine and dendritic parameters, there was an optimal range of RSS values for which the excitable properties at the spine head membrane resulted in maximal amplification of the dendritic excitatory postsynaptic potential (EPSP), when compared with that produced by a corresponding passive spine. This optimal range depended (with nonlinear sensitivity) on the properties of the voltage-gated channels at the spine head membrane. The maximal amplification found (for each of several sets of parameters) ranged from two to thirteen times. 4. Near this optimal range of RSS values, there was maximal (nonlinear) sensitivity of the dendritic EPSP amplitude to small changes in RSS. A minor decrease resulted in a subthreshold response at the spine head, and this resulted in a large decrease in the EPSP amplitude at the spine base. Increasing the value of RSS above this optimal range decreased the amount of spine stem current flowing to the spine base (by Ohm's law); this decreased the EPSP amplitude at the spine base. The demonstration of this optimum agrees with earlier expectations and results. 5. Excitable dendritic spines can be seen to provide an anatomical arrangement that economizes both excitable and synaptic channels. A small number of these channels (located in spine head membrane) can produce a large dendritic depolarization.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1992

Relationship between receptive and dendritic field size of amacrine cells in the rabbit retina.

1. Intracellular recordings were obtained from 40 amacrine cells in the isolated, superfused retina eyecup of the rabbit. Cells were subsequently labeled with horseradish peroxidase for morphological identification. Many of these cells displayed dendritic morphology consistent with that of amacrine cells described in prior anatomic studies, including starburst, A17, AII, and DAPI-3 cells. 2. The center receptive field of amacrine cells was measured with a 50- or 95-microns-wide, 6.0-mm-long rectangular slit of light that was displaced along its minor axis (parallel to the visual streak) in increments as small as 3 microns. The extent of the receptive field was calculated as the total distance over which the displaced slit could evoke a center response. Area summation of amacrine cells was measured with concentric spots of light with increasing diameters centered over the cell. 3. For a single amacrine cell, the receptive field size was comparable to the extent of its dendritic arbor. For the total population of amacrine cells, there was a strong, linear relationship between receptive field and dendritic field size. The receptive fields were, on average, 27% larger than the corresponding dendritic arbors, but this discrepancy can be accounted for entirely by tissue shrinkage associated with histological processing and a small imprecision of the light stimuli. Area summation measurements were consistent with those of receptive fields and were also related linearly to the dendritic field size of cells. 4. These findings indicate that even when the slit of light was placed at the distal edges of the dendritic arbor, synaptic inputs activated there were propagated effectively to the soma and recorded by microelectrodes placed there. In addition, amacrine cells were capable of summating synaptic inputs distributed throughout the entire arbor. 5. These results are inconsistent with the findings of prior computational modeling studies of passive, dendritic current flow in A17 and starburst amacrine cells that synaptic inputs on distal dendritic branches are isolated electrically from the soma and that these branches form autonomous, functional subunits. 6. The majority of amacrine cells encountered displayed light-evoked and/or spontaneous action potentials. These action potentials often took the form of high-amplitude somatic and low-amplitude dendritic spikes. On average, spiking amacrine cells showed considerably larger dendritic fields than nonspiking amacrine cells. In fact, all amacrine cells with arbors greater than 436 microns, which formed 45% of the total population, displayed spike activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1993

Spatial distribution of Ca2+ influx in turtle Purkinje cell dendrites in vitro: role of a transient outward current.

1. Intracellular recordings were made from Purkinje cells in a slice preparation of the turtle cerebellum. Simultaneously, changes in [Ca2+]i in all regions of the cell were detected with high-speed fluorescence imaging of injected fura-2. Cells were stimulated either intrasomatically or synaptically. In addition, the cells were polarized locally with an external electrical field aligned parallel to the soma-dendritic axis. 2. The soma, smooth dendrites, and spiny dendrites displayed voltage-dependent changes in [Ca2+]i. Changes in the somatic region were correlated with Na+ spike firing and local depolarization. Small [Ca2+]i changes in the spiny dendrites were correlated with graded potentials and larger changes with Ca2+ action potentials. Individual Ca2+ spike transients sometimes occurred separately in different dendritic regions demonstrating localized firing. 3. The amplitude and spatial extent of spike-related [Ca2+]i transients were increased with intrasomatic depolarizing prestimulus membrane potentials and reduced by hyperpolarizing prestimulus potentials. This dependence and the latency to Ca2+ spike activation were strongly reduced by 4-aminopyridine (4-AP). These results suggest that a transient A-like current regulates the generation of Ca2+ spikes and the localization of Ca2+ influx in turtle Purkinje cell dendrites. 4. Both electric field depolarization and intrasomatic depolarization affected the generation of Ca2+ spikes and [Ca2+]i signals in a similar manner. Strong field stimulation could evoke focal depolarization at the tips of the spiny dendrites and cause local Ca2+ spike generation near the pial surface. When both stimuli were used, their effects were additive. 5. Climbing fiber (CF) or parallel fiber (PF) stimulation were associated with the generation of dendritic Ca2+ transients. In some experiments the PF-induced Ca2+ transients were confined to a small part of the spiny dendrites. The spatial distribution and the amplitude of these transients were influenced by somatic depolarization or field stimulation in a manner similar to their effect on directly evoked Ca2+ spikes and consistent with the involvement of a transient outward current in the control of the synaptically induced Ca2+ influx. 6. These results suggest that the intrinsic potassium conductances dynamically modulate spatial integration and influence the compartmentalization of Ca2+ spikes and [Ca2+]i changes in the dendrites.

Animals↗

PubMed1999

Voltage-dependent properties of dendrites that eliminate location-dependent variability of synaptic input.

We examined the hypothesis that voltage-dependent properties of dendrites allow for the accurate transfer of synaptic information to the soma independent of synapse location. This hypothesis is motivated by experimental evidence that dendrites contain a complex array of voltage-gated channels. How these channels affect synaptic integration is unknown. One hypothesized role for dendritic voltage-gated channels is to counteract passive cable properties, rendering all synapses electrotonically equidistant from the soma. With dendrites modeled as passive cables, the effect a synapse exerts at the soma depends on dendritic location (referred to as location-dependent variability of the synaptic input). In this theoretical study we used a simplified three-compartment model of a neuron to determine the dendritic voltage-dependent properties required for accurate transfer of synaptic information to the soma independent of synapse location. A dendrite that eliminates location-dependent variability requires three components: 1) a steady-state, voltage-dependent inward current that together with the passive leak current provides a net outward current and a zero slope conductance at depolarized potentials, 2) a fast, transient, inward current that compensates for dendritic membrane capacitance, and 3) both alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid- and N-methyl-D-aspartate-like synaptic conductances that together permit synapses to behave as ideal current sources. These components are consistent with the known properties of dendrites. In addition, these results indicate that a dendrite designed to eliminate location-dependent variability also actively back-propagates somatic action potentials.

Action Potentials↗

PubMed1999

Muscarinic control of dendritic excitability and Ca(2+) signaling in CA1 pyramidal neurons in rat hippocampal slice.

The cholinergic system is critically involved in synaptic models of learning and memory by enhancing dendritic [Ca(2+)](i) signals. Diffuse cholinergic innervation suggests subcellular modulation of membrane currents and Ca(2+) signals. Here we use ion-selective microelectrodes to study spread of carbachol (CCh) after focal application into brain slice and subcellular muscarinic modulation of synaptic responses in CA1 pyramidal neurons. Proximal application of CCh rapidly blocked the somatic slow afterhyperpolarization (sAHP) following repetitive stimulation. In contrast, the time course of potentiation of the slow tetanic depolarization (STD) during synaptic input was slower and followed the time course of spread of CCh to the dendritic tree. With distal application, augmentation of the somatic STD and of dendritic Ca(2+) responses followed spread of CCh to the entire apical dendritic tree, whereas the sAHP was blocked only after spread of CCh to the proximal dendritic segment. In dendritic recordings, CCh blocked a small sAHP, augmented the STD, and rather reduced dendritic action potentials. Augmentation of dendritic Ca(2+) signals was highly correlated to augmentation of the STD. The NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV) blocked approximately 55% of the STD in control and during CCh application. In conclusion, muscarinic suppression of the proximal sAHP can augment firing and thereby Ca(2+) responses. Dendritic augmentation of the STD by blockade of the sAHP and direct enhancement of N-methyl-D-aspartate (NMDA) receptor-mediated currents potentiates Ca(2+) signals even when firing is not affected due to suprathreshold input. In this way, subcellular muscarinic modulation may contribute to parallel information processing and storage by dendritic synapses of CA1 pyramidal neurons.

2-Amino-5-phosphonovalerate↗

PubMed2005

Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma.

To directly dissect the role of each immune component in human tumor immunopathogenesis, we have studied the interaction between dendritic cells and T cells in the tumor environment of patients with ovarian carcinoma. We previously reported that functional plasmacytoid dendritic cells, but not functionally mature myeloid dendritic cells, accumulated in tumor microenvironments. We now show that tumor ascites macrophage-derived dendritic cells induced tumor-associated antigen-specific CD8+ T cells with effector functions. Strikingly, tumor ascites plasmacytoid dendritic cells induced interleukin-10+ CCR7+ CD45RO+ CD8+ regulatory T cells. Four characteristics have been identified in tumor plasmacytoid dendritic cell-induced CD8+ regulatory T cells: (a) induction of CD8+ regulatory T cells is independent of CD4+ CD25+ T cells; (b) CD8+ regulatory T cells significantly suppress myeloid dendritic cell-mediated tumor-associated antigen-specific T cell effector functions through interleukin-10; (c) repetitive myeloid dendritic cell stimulation can recover CD8+ regulatory T cell-mediated poor T cell proliferation, but not T cell effector function; (d) CD8+ regulatory T cells express functional CCR7, and efficiently migrate with lymphoid homing chemokine MIP-3beta. Primary suppressive CCR7+ CD45RO+ CD8+ T cells are found in the tumor environment of patients with ovarian cancers. Thus, tumor-associated plasmacytoid dendritic cells contribute to the tumor environmental immunosuppressive network. Collectively, tumors manipulate tumor microenvironmental dendritic cell subset distribution and function to subvert tumor immunity. The data are relevant to understanding tumor immunopathology as well as reevaluating tumor immunotherapeutic strategies.

Amino Acid Sequence↗

PubMed2000

Dendritic alterations of cerebellar Purkinje neurons in postnatally lead-exposed kittens.

Many investigations have sought to determine the effect of lead exposure on the development of the cerebellum. This study addresses the effects of postnatal lead exposure in kittens on dendritic development of Purkinje cells. Golgi-Cox filled cells were used to measure dendritic branching patterns, spine density, height, width and distance from the cerebellar surface. The results revealed a significant increase in spine density and altered patterns of dendritic branching. Complex dendritic branching was evident with a progressive shift in peak branching peripherally. Lead-exposed Purkinje cells showed early sprouting with subsequent pruning. At 5 weeks of age dendritic branches on experimental cells were increased along the entire dendritic extent. Control Purkinje cells showed initial sprouting with subsequent pruning. Normal developmental growth spurts and lead-induced effects were evident on dendritic height, width and distance from the surface. Cerebella stained with hematoxylin and eosin and cresyl violet acetate showed no evidence of vascular damage or other pathologies. These findings corroborate the evidence of hyperspiny dendritic formation representing an important mechanism of neuronal plasticity. In regard to morphological effects of lead on rodents, the hyperspiny Purkinje cell dendrites and patterns of dendritic growth in lead-treated kittens offer an alternative interpretation of neurobehavioral findings of lead-burdened children. The results are discussed with reference to other aspects of lead exposure and neural development.

Animals↗

PubMed2001

Generation of dendritic cells from leukaemia cells of a patient with acute promyelocytic leukaemia by culture with GM-CSF, IL-4 and TNF-alpha.

Dendritic cells are potent antigen-presenting cells derived from CD34+ haemopoietic stem cells. Dendritic cells have been reported to be generated from cells in granulocytic lineage as well as monocytes, blood dendritic cell precursors and lymphoid progenitors. In order to explore the differentiation pathway of dendritic cells from granulocytic cells and the applicability of leukaemia-derived dendritic cells for anti-leukaemic immunotherapy in acute leukaemia of granulocytic origin, we tried to generate dendritic cells from leukaemia cells of a patient with acute promyelocytic leukaemia (APL). Leukaemia cells were cultured with GM-CSF, IL-4 and TNF-alpha for 10 days. Azurophilic granule-containing cells with marked cytoplasmic projections were generated in the culture. FACS analysis of these cultured cells revealed the generation of CD1a+, CD83+, CD80+, CD86+, CD40+ and HLA-DR+ cells. The leukaemic origin of these dendritic-like cells was demonstrated by in situ hybridization of magnetic-bead-sorted CD1a+ dendritic cells using the DNA probes of t(15;17). Cells generated by culturing leukaemia cells were demonstrated to have a potent antigen-presenting function in allogeneic mixed leucocyte cultures. These findings show the plausibility of the previously reported pathway of dendritic cell maturation through granulocytic cells and suggest the possibility of anti-leukaemic immunotherapy using leukaemia-derived dendritic cells even in patients with acute promyelocytic leukaemia.

Adult↗

PubMed1988

Intrathyroidal dendritic cells.

The presence, marker pattern, and ultrastructure of antigen-presenting dendritic cells were studied in normal thyroid glands from 9 subjects (6 obtained at surgery; 3 at autopsy) and in the thyroid glands form 13 patients with Graves' hyperthyroidism, 10 patients with simple nontoxic goiter, and 1 patient with Hashimoto's disease (all obtained at surgery). The immunohistochemical characterization of the cells was carried out using the monoclonal antibodies OKIa (class II MHC determinants), RFD1 and L25. These latter monoclonal antibodies react strongly with active dendritic cells in T-cell areas of secondary lymphoid organs (the interdigitating cells in lymph nodes and spleen). Antigen-presenting dendritic cells were defined as cells with an eccentric reniform nucleus, long cytoplasmic protrusions, and strong membrane-bound class II MHC positivity combined with little or no cytoplasmic acid phosphatase activity. According to these criteria normal human thyroid tissue contained a few dendritic cells; they were localized outside the thyroid follicles. These dendritic cells in normal thyroid tissue lacked the marker molecules identified by the monoclonal antibodies RFD1 and L25. In fact, the majority of the dendritic cells were strongly positive for the C3bi receptor (identified by the monoclonal antibody FK 24), which indicates a more monocyte/macrophage character of the cell. In Hashimoto's goiter, Graves' disease, and sporadic nontoxic goiter (which we consider an autoimmune thyroid disease) the numbers of dendritic cells were higher compared to those in the normal gland, and these dendritic cells were clearly positive for RFD1 and L25. The cells were often seen in contact with a few intrathyroidal lymphocytes, forming small lymphoid cell clusters. They were also found in the T-cell zones of larger well organized intrathyroidal lymphoid structures (focal thyroiditis). On ultrastructural examination the dendritic cells in Graves' glands, Hashimoto's goiter, and sporadic nontoxic goiter were similar to the interdigitating cells present in secondary lymphoid organs. The data suggest active involvement of dendritic cells in the immune process in the thyroids of patients with autoimmune thyroid disease.

Adult↗

PubMed2007

Projections of Drosophila multidendritic neurons in the central nervous system: links with peripheral dendrite morphology.

Neurons establish diverse dendritic morphologies during development, and a major challenge is to understand how these distinct developmental programs might relate to, and influence, neuronal function. Drosophila dendritic arborization (da) sensory neurons display class-specific dendritic morphology with extensive coverage of the body wall. To begin to build a basis for linking dendrite structure and function in this genetic system, we analyzed da neuron axon projections in embryonic and larval stages. We found that multiple parameters of axon morphology, including dorsoventral position, midline crossing and collateral branching, correlate with dendritic morphological class. We have identified a class-specific medial-lateral layering of axons in the central nervous system formed during embryonic development, which could allow different classes of da neurons to develop differential connectivity to second-order neurons. We have examined the effect of Robo family members on class-specific axon lamination, and have also taken a forward genetic approach to identify new genes involved in axon and dendrite development. For the latter, we screened the third chromosome at high resolution in vivo for mutations that affect class IV da neuron morphology. Several known loci, as well as putative novel mutations, were identified that contribute to sensory dendrite and/or axon patterning. This collection of mutants, together with anatomical data on dendrites and axons, should begin to permit studies of dendrite diversity in a combined developmental and functional context, and also provide a foundation for understanding shared and distinct mechanisms that control axon and dendrite morphology.

Animals↗

PubMed1994

Regulation of motor neuron dendrite growth by NMDA receptor activation.

Spinal motor neurons undergo great changes in morphology, electrophysiology and molecular composition during development. Some of this maturation occurs postnatally when limbs are employed for locomotion, suggesting that neuronal activity may influence motor neuron development. To identify features of motor neurons that might be regulated by activity we first examined the structural development of the rat motor neuron cell body and dendritic tree labeled with cholera toxin-conjugated horseradish peroxidase. The motor neuron cell body and dendrites in the radial and rostrocaudal axes grew progressively over the first month of life. In contrast, the growth of the dendritic arbor/cell and number of dendritic branches was biphasic with overabundant growth followed by regression until the adult pattern was achieved. We next examined the influence of neurotransmission on the development of these motor neuron features. We found that antagonism of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor inhibited cell body growth and dendritic branching in early postnatal life but had no effect on the maximal extent of dendrite growth in the radial and rostrocaudal axes. The effects of NMDA receptor antagonism on motor neurons and their dendrites was temporally restricted; all of our anatomic measures of dendrite structure were resistant to NMDA receptor antagonism in adults. These results suggest that the establishment of mature motor neuron dendritic architecture results in part from dendrite growth in response to afferent input during a sensitive period in early postnatal life.

2-Amino-5-phosphonovalerate↗

PubMed2006

Branch-specific Ca2+ influx from Na+-dependent dendritic spikes in olfactory granule cells.

Two-photon laser scanning microscopy was used to correlate electrical events detected with whole-cell somatic recordings to Ca2+ transients in dendrites of olfactory bulb granule cells. A subset of spontaneous subthreshold depolarizing events recorded at the soma were shown to correspond to suprathreshold dendritic, Na-dependent action potentials [APs; dendritic spikes (D-spikes)]. These potentials were blocked by intracellular QX-314 (lidocaine N-ethyl bromide), hyperpolarizing current injection at the soma, and by partial inhibition of AMPA/kainate receptors with 0.75 microM DNQX. They were affected only slightly by 100 microM NiCl2. The majority of D-spikes recorded at the soma had a time to peak of <4 ms, comparable with somatic APs, a nonexponential decay, and amplitudes between 3 and 21 mV. Somatically recorded APs produced Ca2+ transients that were observed in spines and dendrites in all parts of the cell. Ca2+ transients from D-spikes were restricted to subsets of distal dendrites and their associated spines but were absent from the soma and dendrite within approximately 50-80 microm of the soma. Ca2+ transients in different branches could be correlated with different-sized D-spikes. D-spike and backpropagating AP-induced Ca2+ transients summed in dendrites, provided the interval between them was >5-6 ms. Generation of a D-spike in a particular dendrite <5-6 ms before a somatic AP blocked backpropagation of the somatic AP into that dendrite. The temporally specific interplay between D-spikes and backpropagating APs may play a role in regulating feedback and feedforward inhibition of groups of mitral cells synapsing on different granule cell dendrites.

Action Potentials↗

PubMed2006

Dendritic calcium spikes are tunable triggers of cannabinoid release and short-term synaptic plasticity in cerebellar Purkinje neurons.

Understanding the relationship between dendritic excitability and synaptic plasticity is vital for determining how dendrites regulate the input-output function of the neuron. Dendritic calcium spikes have been associated with the induction of long-term changes in synaptic efficacy. Here we use direct recordings from cerebellar Purkinje cell dendrites to show that synaptically activated local dendritic calcium spikes are potent triggers of cannabinoid release, producing a profound and short-term reduction in synaptic efficacy at parallel fiber synapses. Enhancing dendritic excitability by modulating dendritic large-conductance calcium-activated potassium (BK) channels improves the spread of dendritic calcium spikes and enhances cannabinoid release at the expense of spatial specificity. Our findings reveal that dendritic calcium spikes provide a local and tunable coincidence detection mechanism that readjusts synaptic gain when synchronous activity reaches a threshold, and they reveal a tight link between the regulation of dendritic excitability and the induction of synaptic plasticity.

Action Potentials↗

PubMed1993

S100 positive dendritic cells in human lung tumors associated with cell differentiation and enhanced survival.

Antigen presenting S100 positive dendritic cells have been quantified in normal trachea, lung, bronchial lymph nodes, 130 lung tumors and in 100 lymph nodes regional to tumor. Dendritic cells are rarely seen as intraepithelial components of the normal bronchial mucosa, but are more commonly observed in the perivascular lymphoid tissue of the submucosa and in the alveolar septae of normal lung parenchyma (6 +/- 4.85 cells/HPF). The density of these dendritic cells is marked in histologically normal bronchial lymph nodes. Bronchioalveolar (Alveolar II), well and moderately differentiated squamous cell carcinomas contain the highest density of S100 positive dendritic cells, while small cell lung cancer and poorly differentiated squamous cell carcinoma show the lowest density. Regional lymph nodes to lung tumors with lymphocytic predominance and active germinal centres show the highest density of dendritic cells, while unstimulated lymph nodes contain the lowest number of S100 positive dendritic cells. Tumor infiltrating lymphocytes are marked in and around lung tumors with the higher density of dendritic cells. Survival of patients whose tumors contain high density of S100 positive dendritic cells is more favourable compared to tumors with low density of these cells. It is concluded that the density of the antigen presenting S100 dendritic cells in lung tumors is related to subtype, and tumor differentiation. A high dendritic cell density is associated with enhanced patient survival.

Bronchi↗

PubMed1999

Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens.

OBJECT: An approach toward the treatment of intracranial gliomas was developed in a rat experimental model. The authors investigated the ability of "professional" antigen-presenting cells (dendritic cells) to enhance host antitumor immune responses when injected as a vaccine into tumor-bearing animals. METHODS: Dendritic cells, the most potent antigen-presenting cells in the body, were isolated from rat bone marrow precursors stimulated in vitro with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4. Cultured cell populations were confirmed to be functional antigen-presenting cells on the basis of expressed major histocompatibility molecules, as analyzed by fluorescence-activated cell sorter cytofluorography. These dendritic cells were then pulsed (cocultured) ex vivo with acid-eluted tumor antigens from 9L glioma cells. Thirty-eight adult female Fischer 344 rats harboring 7-day-old intracranial 9L tumors were treated with three weekly subcutaneous injections of either control media (10 animals), unpulsed dendritic cells (six animals), dendritic cells pulsed with peptides extracted from normal rat astrocytes (10 animals), or 9L tumor antigen-pulsed dendritic cells (12 animals). The animals were followed for survival. At necropsy, the rat brains were removed and examined histologically, and spleens were harvested for cell-mediated cytotoxicity assays. The results indicate that tumor peptide-pulsed dendritic cell therapy led to prolonged survival in rats with established intracranial 9L tumors implanted 7 days prior to the initiation of vaccine therapy in vivo. Immunohistochemical analyses were used to document a significantly increased perilesional and intratumoral infiltration of CD8+ and CD4+ T cells in the groups treated with tumor antigen-pulsed dendritic cells compared with the control groups. In addition, the results of in vitro cytotoxicity assays suggest that vaccination with these peptide-pulsed dendritic cells can induce specific cytotoxic T lymphocytes against 9L tumor cells. CONCLUSIONS: Based on these results, dendritic antigen-presenting cells pulsed with acid-eluted peptides derived from autologous tumors represent a promising approach to the immunotherapy of established intracranial gliomas. which may serve as a basis for designing clinical trials in patients with brain tumors.

Animals↗

PubMed2002

Signaling of layer 1 and whisker-evoked Ca2+ and Na+ action potentials in distal and terminal dendrites of rat neocortical pyramidal neurons in vitro and in vivo.

Dendritic regenerative potentials play an important role in integrating and amplifying synaptic inputs. To understand how distal synaptic inputs are integrated and amplified, we made multiple simultaneous (double, triple, or quadruple) and sequential (4-12 paired) recordings from different locations of single tufted layer 5 pyramidal neurons in the cortex in vitro and studied the spatial and temporal properties of their dendritic regenerative potential initial zone. Recordings from the soma and from trunk, primary, secondary, tertiary, and quaternary tuft branches of the apical dendrite of these neurons reveal a spatially restricted low-threshold zone approximately 550-900 microm from the soma for Ca2+-dependent regenerative potentials. Dendritic regenerative potentials initiated in this zone have a clearly defined threshold and a refractory period, and they can propagate actively along the dendrite before evoking somatic action potentials. The detailed biophysical characterization of this dendritic action potential initiation zone allowed for the further investigation of dendritic potentials in the intact brain and their roles in information processing. By making whole-cell recordings from the soma and varied locations along the apical dendrite of 53 morphologically identified layer 5 pyramidal neurons in anesthetized rats, we found that three of the dendritic potentials characterized in vitro could be induced by spontaneous or whisker inputs in vivo. Thus layer 5 pyramidal neurons of the rat neocortex have a spatially restricted low-threshold zone in the apical dendrite, the activation or interaction of which with the axonal action potential initiation zone is responsible for multiple forms of regenerative potentials critical for integrating and amplifying sensory and modulatory inputs.

Action Potentials↗

PubMed1999

Cellular and humoral immune responses in patients with metastatic renal cell carcinoma after vaccination with antigen pulsed dendritic cells.

PURPOSE: Dendritic cells are the most potent stimulators of immune responses including antitumor responses. We performed a pilot study of cultured antigen loaded dendritic cells in patients with metastatic renal cell carcinoma. MATERIALS AND METHODS: Dendritic cells were obtained by culturing plastic adherent mononuclear cells from peripheral blood for 5 days in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4. Day 5 dendritic cells were loaded with cell lysate from cultured autologous tumor cells and with the immunogenic protein keyhole-limpet hemocyanin (KLH) which serves as a helper antigen and as a tracer molecule. During the antigen pulse dendritic cells were activated with a combination of tumor necrosis factor-alpha and prostaglandin E2. Dendritic cells were administered by 3 intravenous infusions at monthly intervals. Cellular and humoral immune responses to KLH and cell lysate were measured in vitro before and after the vaccinations. RESULTS: Preparation of 12 dendritic cell vaccines from patients with advanced renal cell carcinoma was successful. Treatment with fully activated CD83+ dendritic cells was well tolerated with moderate fever as the only side effect. Potent immunological responses to KLH and, most importantly, against cell lysate could be measured in vitro after the vaccinations. CONCLUSIONS: Our data demonstrate that a dendritic cell based vaccine can induce antigen specific immunity in patients with metastatic renal cell carcinoma. Dendritic cell based immunotherapy represents a feasible, well tolerated and promising new approach for the treatment of advanced renal cell carcinoma.

Aged↗

PubMed2000

The HIV-2 genotype and the HIV-1 syncytium-inducing phenotype are associated with a lower virus replication in dendritic cells.

During sexual transmission, HIV infects the mucosal dendritic cells and is transferred to CD4 T cells. Whether HIV variants of a particular genetic (sub)type or phenotype selectively infect dendritic cells (DC) or are preferentially transferred to T cells remains highly controversial. To avoid the cumbersome use of primary dendritic cells, in vitro dendritic cell models were generated from precursors, either hematopoietic progenitor cells (HPC) or monocytes (MO). Productive infection in the dendritic cells and transfer of the virus to T cells was assessed for a range of HIV variants. HPC-derived dendritic cells (HPC-DC) were more susceptible to HIV-1 than to HIV-2 isolates. The HIV-1 group O strains were more productive in HPC-DC than group M, but amongst the latter, no subtype-related difference was observed. Both non-syncytium-inducing (NSI) and SI HIV isolates and lab strains could productively infect HPC-DC, albeit with a different efficiency. Adding blocking antibodies confirmed that both CCR-5 and CXCR-4 co-receptors were functional. Biological HIV-1 clones of the NSI/R5 phenotype infected more readily HPC-DC than SI/X4 clones. MO-derived dendritic cells were, however, more exclusive in their preference for NSI/R5 clones. Some HIV variants, that did not grow readily in HPC-DC alone, could be rescued by adding resting or pre-activated T cells. The present data show that HIV-2 isolates and SI clones replicate less in model-DC, but no preference for a particular HIV-1 subtype was evident. Co-culture with T cells could "correct" a limited growth in dendritic cells. Clearly, both intrinsic dendritic cell susceptibility and enhancement by T cells are explained only partly by HIV genotype and phenotype. The in vitro dendritic cell models seem useful tools to further unravel interactions between HIV, DC, and T cells.

CCR5 Receptor Antagonists↗