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Department of Immunophysiology, Institute of Physiology, Philipps-University, 35039 Marburg, Germany
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This work is based on the hypothesis that sympathetic nerves regulate the uptake of circulating cells by the spleen by affecting splenic blood flow and that the quantity of cells sequestered depends on whether changes in noradrenergic transmission occur at local or systemic levels. Fluorescently labeled lymphoid cells were injected into rats, and organ blood flow was measured by the microsphere method. Increased retention of cells in the spleen paralleled by increased blood flow was detected after local denervation of this organ or administration of bacterial endotoxin. A comparable enhanced splenic blood flow was observed after general sympathectomy. However, the redistribution of blood perfusion during general vasodilatation resulted in deviation of leukocyte flow from the spleen, thus resulting in reduced uptake of cells by this organ. These results indicate that, although the uptake of cells by the spleen depends on arterial blood supply, enhanced perfusion does not always result in increased cell sequestration because general vasodilatation reduces cell uptake by this organ and even overrides stimulatory effects of endotoxin.
norepinephrine; sympathetic innervation; heart minute volume
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE FUNCTION OF THE MAMMALIAN spleen is intensely interwoven with the detection of antigenic material circulating in blood, and splenectomy increases the risk of overwhelming infections or septic complications (3, 23). In contrast to other lymphoid organs, the spleen lacks significant afferent lymphatic vessels and blood flow represents the predominant route for the influx of cells and antigens. Two characteristic findings indicate the interdependence between splenic perfusion and cell uptake: 1) the flow per gram of tissue is 10 times higher than that of resting skeletal muscle and nearly as high as the blood flow of heart muscle, and 2) the rate of lymphocyte circulation into the spleen equals the total number of cells flowing into all other lymphatic and nonlymphatic organs (15, 16, 27).
It is remarkable that a strong interdependence between cell and blood
supply coexists with a dense splenic noradrenergic innervation. If the
content of norepinephrine (NE) is taken as reflection of the degree of
noradrenergic sympathetic innervation, the spleen belongs to the most
densely sympathetically innervated organs (5, 12), and the
NE turnover rate is four to six times higher than that of the liver or
lung. Most splenic noradrenergic nerve fibers have
vasoconstrictor function and reduce blood flow. Therefore, the high
splenic perfusion rate observed under basal conditions and during
immune responses is surprising, but it can be explained by our
laboratory's previous observations that locally released cytokines,
such as interleukin (IL)-1
, exert a tonic inhibition on the
noradrenergic vasoconstrictor tonus (18). An
increase in splenic blood flow mediated by a cytokine-inhibited NE
release by sympathetic nerves may be a main mechanism influencing
lymphoid cell uptake from the circulating cell pool
(19). In addition, it is expected that the special
morphological structure of the spleen guides cells and antigenic
material from the circulation into the resident pool. The analysis of
how lymphocytes enter into splenic cell compartments suggests local
regulatory influences either during the phase of cell uptake or during
homing into specific areas (2, 26). However, these local
mechanisms will still depend on the supply of lymphoid cells by blood
circulation and on the particular structure of the spleen. Until now,
the role of hemodynamic forces that determine splenic perfusion and
cell uptake in this organ was not systematically investigated in vivo, and it is not known whether adhesion molecules can interfere or even
override noradrenergic influences on splenic perfusion and blood cell
supply. The experiments reported here tested the hypothesis that
noradrenergic regulation of vascular blood flow plays a significant, but not exclusive, role for the splenic extraction of immune cells from
the circulating pool.
We studied the influence of increased splenic vascular perfusion induced by either local denervation or general sympathectomy on lymphoid cell uptake by the spleen of normal and endotoxin-stimulated rats. The results obtained show that, although both procedures result in comparable increases in splenic blood perfusion, only local denervation produces a net increased influx of lymphoid cells into the spleen.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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General Procedures
Male inbred Wistar-Koyoto rats (300-350 g body wt) were housed in single cages and kept at a 12:12-h day-night cycle with water and standard pellets available ad libitum. Surgery was performed while the animals were under general anesthesia with pentobarbital sodium (60 mg/kg Narcoren). Animals were placed during surgery and experiments on a heating plate regulated to maintain core temperature between 36.5 and 37°C.Determinations of Blood Flow
The procedure for the determination of organ blood flow with the microsphere technique is similar to standard, previously reported techniques (14, 21). Briefly, fluorescent-dye labeled polystyrene microspheres [excitation/emission 450/480 nm, diameter 15.5 µm (± 2%); Molecular Probes (MoBiTec, Göttingen, Germany)] were injected at 0.2 ml/min into the left ventricle at a dose of 450,000 spheres per animal. Simultaneously, a reference probe (
ref) was withdrawn from the abdominal aorta
at the same flow velocity through the femoral artery, and blood flow in
spleen, liver, heart, and skeletal muscle (ti) was
determined by using the following equation
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The heart minute volume was determined with an ultrasonic flow probe (model T206, blood flowmeter, Transonic Systems, Ithaca, NY) in animals that were not used for organ perfusion and cell uptake studies. The flow probe was placed around the thoracic aorta, and, after closure of the the chest and stabilization of blood gases and peripheral arterial resistance, blood flow was digitally registered at 80-kHz real-time display throughput (Dataq Instruments, Akron, OH).
In all animals, arterial blood pressure was measured via a catheter implanted in the femoral artery combined with a Statham pressure transducer; arterial PO2 and PCO2 were measured by electrochemical detection (Gas Check AVL, Bad Homburg), and core temperature was monitored with a thermistor probe in the abdominal cavity.
Labeling Procedure for Splenocytes
Splenocyte suspensions were prepared from inbred donor rats and labeled under sterile conditions with a PKH fluorescent cell linker kit (107 cells/ml in a 2 µM staining solution for 2 min; excitation/emission of PKH 551/567 nm; Sigma Chemical, St. Louis, MO). These cell suspensions were used because they mainly consist of lymphocytes; they need a minimum of purification steps. Before injection into the recipient, the number of dead cells was determined with trypan blue; the suspensions normally contained 6-10% dead cells; suspensions with <15% dead cells were also used. Cells (108 per kg body wt) were infused into the left ventricle over a period of 2 min in a volume of 1 ml, and the catheter was subsequently rinsed with 0.5 ml saline.Evaluation of Splenic Cell Uptake
A piece of spleen was used to evaluate the uptake of labeled cells and the amount of trapped fluorescent spheres. The number of labeled cells per 100,000 splenocytes was determined from cytocentrifuge preparations of recipient spleen cell suspensions by using a fluorescent microscope. Because this step is critical for subsequent calculations, determinations were performed in parallel by two independent observers. Twelve cytocentrifuge preparations were evaluated from each cell suspension. Uptake of fluorescent cells was expressed either as the percentage of the number of injected cells, or per spleen or per 100,000 splenocytes.Determination of IL-1 in the Spleen
concentration in the
supernatant was determined by using a commercially available kit for
determination of rat IL-1 (Endogen, Woburn, MA).
Experiments
Control group. The uptake of fluorescent cells under baseline conditions was evaluated 15 min, 6 h, and 24 h after the injection of labeled cells (6 animals per time point). Blood flow was measured in the same animals 15 min or 6 h after cell injection, and the infusion of microspheres started 3 min before the spleen was removed.
Effect of vasodilatation induced by cutting the splenic nerve.
The effect of local vasodilatation on fluorescent cell uptake into the
spleen was evaluated by surgically interrupting splenic sympathetic
nervous supply 5 days before the experiments were started as described
previously (18). At this time, animals were recovered from
the operation, as shown by their normal weight gain and
corticosterone blood levels (see Table
1).
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Effect of vasodilatation by depletion of sympathetic noradrenergic stores. Because, under clinical conditions, pharmacological interventions can affect not only splenic but also sympathetic nerve endings in other organs, general noradrenergic transmission was interrupted by depleting noradrenergic stores with reserpine (10 mg/kg ip; 24 h before the experiment). Six animals treated with reserpine and six animals injected with the vehicle alone were studied in parallel at the same points of time as in the other studies.
Effect of endotoxin on splenic cell uptake. Endotoxin [lipoplysaccharide (LPS)] from Escherichia coli (026:B6; TCA extract; Sigma Chemical; 10 µg/kg body wt) was dissolved in isotonic sodium chloride solution and injected into the tail artery in awake animals. Six hours later, labeled cells were injected as described above, and cell uptake was determined at the same time intervals as in the other experimental groups.
Statistics
The data were compared by ANOVA and Scheffé's test. All values are reported as means ± SE from six rats, and statistical significance was set at P < 0.05.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Relation Between Splenic Blood Flow and Cell Uptake
Blood flow of the spleen was measured under basal conditions and after interruption of noradrenergic innervation. Basal flow was 73.5 ± 8.65 ml · 100 g
1 · min1. This value approached
myocardial perfusion (91 ± 8.00 ml · 100 g1 · min1) and was nearly 20 times
higher than the perfusion of skeletal muscle at rest (3.8 ± 0.6 ml · 100 g1 · min1), as
measured in the same animal and under the same experimental conditions.
Because the spleen has a high basal blood flow value, it was important
to determine whether it can be increased after interruption of the
noradrenergic innervation. The results showed that despite high resting
flow, the ablation of the noradrenergic innervation led to a
significant increase: 276.7 ± 10.6 ml · 100 g1 · min1 after local surgical
denervation (P < 0.001), and 265 ± 10.6 ml · 100 g1 · min1 after
depletion of noradrenergic presynaptic stores (P < 0.001; Fig. 1). The increase in flow
indicates that the noradrenergic sympathetic innervation of the spleen
has profound influence on establishing the level of splenic perfusion.
Sham-operated and untreated animals exhibited no significant
differences of splenic blood flow.
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Next, we wanted to know whether an increased local perfusion favors the
accumulation of injected cells in the spleen. Both 15 min and 6 h
after the injection of labeled cells, a higher sequestration of
injected cells (Fig. 2A),
higher number of cells retained per spleen (Fig. 2B), and
higher number of cells retained per 100,000 splenocytes (Fig.
2C) were observed in the denervated spleen compared with the
controls. Even after 24 h, more cells accumulated in the
denervated spleen compared with the sympathetically innervated organ.
These results suggest the possibility of parallel changes between
spleen perfusion and cell uptake, which was corroborated by the
experiments described below.
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Cell Sequestration into the Spleen Is Favored by an Increased Splenic Perfusion Induced by Bacterial Endotoxin
Studies in which LPS was used were included because this cytokine raises blood flow and can favor the adhesion of leukocytes on endothelial cells. If adhesion is additive to the effect of perfusion, a higher cell uptake into the spleen, which exceeds the effect of increased perfusion, would be expected. However, Fig. 3 indicates parallel changes between the level of splenic perfusion and cell uptake. A positive correlation between local perfusion and the degree of cell extraction from circulation is described by a second-order polynomial equation (y = 1 × 105x2 + 0.008x + 0.074, R2 = 0.74;
Fig. 3).
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Because, as our laboratory reported before (19), IL-1
is the main mediator of the increase in splenic blood flow induced by
LPS, the production of this cytokine in the spleen of rats subject to
either local or general denervation was evaluated. LPS administration
significantly increased IL-1 in the spleen, but the increase was
comparable in control or local and systemic denervated rats (IL-1
ng/spleen: none + vehicle = 2.57 0.35; none + LPS 28.9 6.32; sham operated + vehicle = 5.7 0.55; sham + LPS = 27.9 3.85; local splenic denervated + LPS = 19.37 3.19; systemically denervated + LPS = 24.1 5.8; 4-6 rats
per group). The IL-1 content in the spleen of rats from all groups
that received LPS differed significantly from the controls
(P < 0.05); the different denervation procedures did
not significantly affect LPS-induced IL-1 content.
Systemic Vasodilatation Interferes with Local Cell Supply
The vasodilatation observed in the spleen after systemic depletion of noradrenergic stores was similar to the effect of local denervation (Fig. 1). Both procedures induced comparable reductions of the splenic NE content, but only systemic denervation affected the content of the neurotransmitter in other organs, such as the kidney (Table 1). Accordingly, although local denervation increased blood flow only in the spleen, the abrogation of general noradrenergic vasoconstrictor tonus induced higher blood flow also in other sympathetically controlled organs. This effect was followed by a significant increase of the heart minute volume to maintain arterial blood pressure at normal levels (Table 1).The redistribution of the heart minute volume between peripheral organs
included increased blood flow in large parenchymatous organs. For
example, liver blood flow rose from 3.7 ± 0.5 to 10.1 ± 1.4 ml/min, i.e., by 6.4 ml/min (Fig. 4);
skeletal muscle flow increased from 3.8 ± 0.6 to 45.0 ± 11.4 ml · 100 g1 · min1. As
already shown in Fig. 1, systemic NE depletion also resulted in an
increase of splenic blood flow of ~200%, but this increase was low
(only 1.5 ml/min) compared with that observed in other organs when
expressed in absolute terms (from 0.8 ± 0.1 to 2.3 ± 0.6 ml/min). Thus the larger proportion of the heart minute volume was
deviated during general vasodilatation to the liver and to other large
parenchymatous organs. This rise was particularly evident in the
skeletal muscle because, when it is considered that 40% of the animal
body weight is represented by this tissue, the increment of muscle
perfusion is 34.6 ml/min (~1,100%).
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A plot of cell uptake vs. splenic perfusion (Fig.
5) showed that increases of splenic cell
sequestration are observed in accordance with the rise of spleen
perfusion induced by local denervation, as has been already shown in
Fig. 3 for individual experiments. However, after general
vasodilatation, fewer cells were retained, although the flow was
similarly high as in locally denervated organs (P < 0.001). LPS-treated recipients exhibited higher cell uptake into the
spleen than sham-injected animals. Splenic cell uptake is in
LPS-treated rats further augmented by local denervation of the spleen.
In contrast, after general vasodilatation, fewer cells were retained in
the spleen of animals treated with LPS. These results indicate that the
cardiovascular system not only determines the random conditions for the
distribution of cells to the spleen but may even interfere with the
favoring effects of LPS on splenic cell uptake.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Our results demonstrate that the uptake of circulating lymphocytes
by the spleen is favored by a selective, local increase in splenic
perfusion induced by splenic denervation and by the bacterial endotoxin
LPS. Furthermore, we report here that general vasodilatation induces
opposite effects on immune cell uptake by the spleen. With respect to
LPS, it should be mentioned that the increase in blood perfusion
induced by doses of the endotoxin that do not cause shock is restricted
to the spleen without affecting other lymphoid organs, and this effect
is mediated by the capacity of locally released IL-1 to inhibit the
sympathetic tonus (19). Because cytokines released after
endotoxin administration can promote the expression of adhesion
molecules on endothelial cells, it can be expected that LPS stimulates
cell uptake by that mechanism (22, 28). The spleen has no
high endothelial venules, but adhesion molecules, such as integrins and
selectins, are expressed in the extracellular matrix of the splenic
meshwork, and they may be upregulated by cytokines induced by LPS and
contribute to the high capacity of the spleen to sequestrate cells from
the blood (15, 16). IL-1 is equally produced in the
spleen in locally and systemically denervated or normal innervated
spleens, and differences in cell uptake cannot be explained by
differences in IL-1 production. However, the results reported here,
although corroborating that splenic cell uptake is favored by LPS,
indicate that hemodynamic influences also play a relevant role in the
capacity of the spleen to uptake circulating cells.
We studied splenic cell uptake instead of determining the circulation half-time of injected cells. This approach was chosen because the number of circulating lymphoid cells depends on a large number of factors, including redistribution of cells between marginating, adhering, or emigrating pools. Furthermore, the measurement of half-times of circulating cells provides no information about where cells are homing, whereas the determination of cells accumulating in the different organs gives a better indication of local cell uptake. Because it has been shown in vivo that removal of sympathetic noradrenergic transmission has no measurable influence on the size of splenic cell compartments, the rate of cell proliferation, or apoptosis (6), it is unlikely that these processes would influence the number of cells uptaken by the spleen. The interruption of the noradrenergic transmission is frequently used to detect autonomic nervous influences on immune functions (for reviews, see Refs. 5, 16). The nearly complete abrogation of the noradrenergic vasoconstrictor influence, most likely mediated by inhibition of NE release after administration of LPS to animals with an intact innervation, results in an increase in blood flow that is close to that induced by sympathectomy (19, 20). Thus the effect of denervation can be considered as a situation reflecting what would occur under more physiological conditions. An increase in blood flow similar to that caused by denervation is also noticed during local inflammatory processes and in the local hyperemia that precedes specific immune responses. Our results indicate that, under these conditions, the locally increased blood flow would direct the cells to the sites of immune defense.
The fact that splenic blood flow increases in a comparable magnitude both after local and general interruption of noradrenergic sympathetic transmission and after LPS, but that only local denervation or LPS administration results in increased splenic cell uptake, may be related to the particular function of the spleen, which can be considered as a filter inserted in the arterial circulation. This view is briefly discussed below.
There are still controversial results about adhesion and recognition of circulating leukocytes at the endothelial lining of blood vessels and about the effects of NE and sympathetic nerves on these processes (4, 10, 11, 17, 24, 26). An argument against cell sorting at the site of entrance into the spleen is the finding that memory cells and cytotoxic effector T lymphocytes are migrating in comparable numbers into the spleen, whereas they are differentially extracted from the circulating pool into other lymphoid organs (25).
Our results indicate that the absolute level of splenic perfusion (ml/min) is not the only variable determining the number of cells that are trapped by the spleen, because it also depends on the distribution of blood flow within peripheral organs. We showed that normal spleen perfusion represents ~2% of the total heart minute volume and that it increases to ~4% after local denervation. After general interruption of sympathetic noradrenergic transmission, the spleen receives ~2% of the heart minute volume, i.e., not more than when sympathetic innervation is intact. This may explain why during general vasodilatation not more cells are taken up by the spleen than under control conditions, despite the fact that splenic perfusion is higher than under basal conditions. The increased blood flow in large parenchymatous organs may diminish the chance of circulating lymphocytes to contact the splenic meshwork. After contacting endothelial cells, only 4-6 of 10 lymphocytes emigrate from the bloodstream (9), and prolonged circulation through extrasplenic pathways during general vasodilatation may further reduce splenic cell uptake. Such a prolonged extrasplenic circulation might be also relevant for the dynamics of uptake of particulate antigenic material.
The present data may have clinical implications. Vasodilating drugs and
physiological or pathophysiological conditions leading to general
vasodilatation would reduce splenic uptake of cells or circulating
antigenic material and therefore interfere with the protective function
of the spleen. For example, during physical stress, blood flow
decreases preferentially in the spleen because it is one of the most
densely noradrenergically innervated peripheral organs, whereas other
organs are not affected so much or are even more perfused, such as
skeletal muscle at work (7, 8). The present results
predict that, under this condition, the contact of circulating cells
with splenic tissue is reduced. Such interpretation is supported by
recent experiments showing that after prolonged 
-adrenergic
stimulation, the number of leukocytes increases in blood circulation
and decreases in the spleen (24).
It can be concluded from our results that after the redistribution of the heart minute volume during intense muscular work, i.e., in a condition where NE levels increase and skeletal muscle vasodilatation prevails, not only cell uptake, but also trapping of circulating antigenic material in the spleen, is reduced. This condition may contribute to the impairment of immune defense observed after exhausting physical training, a situation during which the blood flow of the muscle is increased because of high metabolic demands but splenic blood flow is reduced because of sympathetic activation (13).
In conclusion, our results stress the relevance of hemodynamic forces controlled by the sympathetic nervous system for cell and antigen uptake by the spleen. Immune processes that cause only a local increase in blood flow would favor splenic cell uptake and immune defense. On the contrary, general vasodilatation would interfere with the capacity of the spleen to extract cells from the circulation and thus interfere with splenic immune functions.
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ACKNOWLEDGEMENTS |
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We appreciate the expert technical assistance of Sigrid Petzoldt in the performance of the studies.
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FOOTNOTES |
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This work was supported by a grant from the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 297, Project B2) to H. Rogausch and A. del Rey.
Address for reprint requests and other correspondence: H. O. Besedovsky, Philipps-Univ. Marburg, Institute of Physiology, Deutschhausstrasse 2, D-35037 Marburg, Germany (E-mail: besedovs{at}mailer.uni-marburg.de)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published September 27, 2002;10.1152/japplphysiol.00411.2002
Received 10 May 2002; accepted in final form 26 September 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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), animals
that received endotoxin (10 µg/kg body wt) 6 h before cell
injection (
), and animals in which the spleen was
surgically denervated (
). Solid symbols represent the
mean of the respective experimental groups.
