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,
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Department of Cell Biology, Neurobiology, and Anatomy,
Department of Physiology,
The Burn and Shock Trauma Institute,
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Department of Microbiology and Immunology, and
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Department of Surgery, Loyola University Medical Center, Maywood, IL 60153
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Norepinephrine (NE)4 is a signaling molecule of the sympathetic nervous system that is released from sympathetic nerve terminals, which are found in all organ systems, including the primary and secondary lymphoid organs (5, 6, 7). Upon release from the nerve terminal, NE binds to high affinity ß2-adrenergic receptors (ß2AR) that are expressed on various immune cell populations. Previous studies at both protein and mRNA levels have shown that while B cells (8) and clones of CD4+ Th1 cells (9, 10)5 express a functional ß2AR, clones of Th2 cells do not, providing a mechanism by which NE can selectively regulate the function of specific immune cell populations. For example, depletion of NE in scid mice that were reconstituted with Ag-specific ß2AR-negative Th2 cell clones and ß2AR-positive B cells resulted in decreased serum levels of Ag-specific IgM and IgG1, splenic follicular cell expansion, and germinal center formation (8) in response to immunization compared with reconstituted NE-intact scid mice. Hence, it appears that NE stimulation of the ß2AR expressed on B cells is essential for maintaining an optimal Th2 cell-dependent Ab response in vivo.
However, for NE to influence immune cell function, it must be released at the immediate site of action, since it is either rapidly degraded by catechol-O-methyltransferase and monoamine oxidase, diffused into the circulation, or taken back up into the nerve terminal following release (reviewed in Ref. 11). Therefore, if NE is to influence the Th2-dependent Ab response in vivo, it is critical to determine whether mechanisms exist for enhancing the normal low level of NE release within the microenvironment in which immune cells are responding to a soluble protein Ag. Previous studies suggest that immune cell activation by either infectious challenge (12, 13, 14) or SRBC immunization (15, 16) results in a higher level of NE release in lymphoid organs. Importantly, in the previous SRBC studies investigating NE release, the rate of NE release was inferred from observations that SRBC administration resulted in lower tissue NE concentrations, and this observation could be interpreted as the result of either an enhanced level of NE release, a suppressed level of NE production, or a suppressed level of NE reuptake by the nerve terminal. However, Fuchs et al. (17) reported that immunization of mice with SRBC enhanced the concentration of the dopamine metabolite, 3,4-dihyroxyphenylacetic acid, in the spleen, which is a metabolic indication that the administration of SRBC enhanced NE production and release. Also, the soluble products released during infectious challenge, e.g., IL-1, have been shown to stimulate NE release (21), suggesting a role for macrophage-derived products in modulating NE release in lymphoid organs. Thus, while previous studies suggested that administration of an infectious organism, particulate Ag, or an inflammatory cytokine to mice stimulates NE release in lymphoid organs, no studies have shown that the administration of a soluble protein Ag plays a role in modulating NE release in the spleen or bone marrow.
One complication for studies designed to examine such an effect is that the frequency of Ag-specific Th and B cells that are able to respond to a specific soluble protein Ag is much lower than the frequency of cells that are able to respond to immunization with either an infectious organism or SRBC. If the release of cytokines from activated immune cells is important for triggering NE release via either a CNS-mediated (20, 21) or local (22) mechanism, such a low frequency of responding cells may restrict the level of cytokines released to such a degree that it is difficult to detect NE release during an Ag-specific response. To increase the frequency of responding Ag-specific Th2 and B cells, we used a model system in which scid mice (23), which normally lack T and B lymphocytes, were reconstituted with clones of KLH-specific Th2 cells and TNP-specific B cells isolated from the spleens of unimmunized mice. We have previously reported that immunization of reconstituted scid mice with the cognate Ag TNP-KLH results in MHC-restricted, Ag-specific Ab production, splenic follicular cell expansion, and germinal center formation in vivo (8).
NE turnover analysis (24, 25) provides an estimate of dynamic changes in sympathetic nerve activity that cannot be gained by the determination of tissue NE concentration alone. This is because the rate of NE release is balanced by the rate of NE synthesis, resulting in constant tissue levels over a wide range of sympathetic nerve activity (24). In the previous studies that measured the effect of infectious challenge, particulate Ags, or inflammatory cytokines on the NE concentration in lymphoid organs, limited information was provided about the activity of sympathetic nerves and their release of NE. In addition, experimental conditions that induced detectable changes in tissue NE concentrations suggest that sympathetic nerve activity was so great that homeostatic balance was lost, NE release outstripped synthesis, and tissue levels of NE may have been exhausted. In addition, experimental conditions that do not induce detectable reductions in tissue NE concentrations provide little information about the level of NE release, except that the steady state dynamics of the nerve terminal were not interrupted. Hence, the lack of any observed changes in the tissue concentration of NE provides no information about the level of sympathetic nerve activity and the resulting level of NE release within the microenvironment in which the immune cells are responding to Ag challenge. Therefore, to more accurately measure the specific rate of NE release in immune organs, the present study was performed using a pulse-chase technique that measures the rate of disappearance of tissue [3H]NE over time. In addition, when experimental conditions induced a significant change in the rate of [3H]NE release over time, the rate of NE turnover was calculated.
To investigate the role of Ag-specific Th2 cells and B cells in evoking NE release in the spleen and bone marrow during a Th2-dependent immune response, a model system was used in which Ag-specific Th2 cells and B cells were adoptively transferred into scid mice (8). In this report we show that activation of Ag-specific Th2 cells and B cells by a soluble cognate Ag increases NE release in the spleen and bone marrow by 18 h following immunization. These results also show a critical role for an Ag-specific, MHC-restricted interaction between the Th2 cell and the B cell to precipitate the observed Ag-induced release of NE. Finally, since administration of the ganglionic blocker, chlorisondamine, only partially blocked the Ag-induced release of NE, the effect of immune cell activation on the level of NE release appears to be in part mediated by immune cell-derived factors acting on either the CNS, postganglionic nerve, or the local nerve terminal found within the microenvironment of the responding Th2 cells and B cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six-week-old female C.B.17/ICR scid and BALB/c mice were obtained from Taconic Farms (Germantown, NY). All mice were provided autoclaved pellets and water ad libitum. Mice were permitted 2 wk to acclimate to their environment before being manipulated and were used at 8 wk of age in all experiments. The scid mice were housed under a 12-h light, 12-h dark cycle in microisolater cages contained within a laminar flow system to maintain a specific pathogen-free environment.
Reagents and Abs
Picrylsulfonic acid (2,4,6-trinitrobenzenesulfonic acid), OVA, and fluorescein (FLU) were purchased from Sigma (St. Louis, MO). KLH was obtained from Calbiochem (La Jolla, CA). TNP-KLH and FLU-OVA were prepared at a haptenation ratio of 17–24 TNP or FLU molecules/KLH or OVA carrier molecule.
T cell clones
The Th2 cell clone BAC 3.2 was maintained as described previously (9). Viable cells were obtained before use by centrifugation over Lympholyte-M (Accurate, Westbury, NY) 8–14 days after Ag stimulation. Clones were maintained in IL-2-containing medium and were used at least 3 days after an exposure to IL-2. The BAC 3.2 clone was tested for the presence of Mycoplasma contamination (Life Technologies, Gaithersburg, MD) and was found to be negative.
TNP-specific B cell preparation
The procedures for enrichment of unprimed TNP-specific B
lymphocytes from spleens of nonimmunized mice were adapted from those
described by Snow et al. (26) as modified by Myers et al.
(27). All procedures were performed at 4°C, except for
RBC haptenation and enzyme treatment, which were performed at 37°C.
Briefly, horse RBCs (Colorado Serum, Denver, CO) were haptenated with
20 mg of 2,4,6-trinitrobenzene sulfonic acid/ml of packed RBCs. Spleen
cell/haptenated horse RBC suspensions were prepared, and
rosette-forming B lymphocytes were separated by velocity and density
sedimentation using a discontinuous Percoll gradient. The
lymphocyte-bound RBCs were removed by a mild trypsin-pronase treatment,
and the lymphocytes were collected over Lympholyte-M (Cedarlane,
Ontario, Canada). The lymphocytes recovered at the end of the procedure
were incubated overnight to allow for re-expression of
surface-associated molecules before additional experimentation.
Phenotypic and functional characterization of the unprimed TNP-specific
B cells have been presented previously, and the resultant cell
population contains 
85–90% TNP-specific B cells
(28).
Cell transfer and immunization
All animals received both KLH-specific BAC 3.2 Th2 cells and TNP-specific B cells. Each cell type was prepared for adoptive transfer at 2 x 106 cells in 50 µl of PBS. T and B cell dilutions were prepared separately and were combined only at the time of injection. Cells were injected i.v. into the lateral tail vein in a total volume of 100 µl of PBS. One week after cell reconstitution, mice received primary immunizations i.p. with 100 µg of TNP-KLH, FLU-OVA, or saline delivered in the adjuvant TiterMax Gold (CytRx, Norcross, GA), which does not induce nonspecific inflammatory cytokine production. In addition, all mice received 25 µCi of [3H]NE (Amersham Pharmacia Biotech, Piscataway, NJ) i.p. in 200 µl of saline plus 0.01% ascorbate either at the time of or 17 h following Ag administration. In some experiments mice received an i.p. injection of the ganglionic blocker, chlorisondamine (5 mg/kg in saline; Sigma). Spleen, bone marrow, and heart samples were collected from the mice either 1 or 8 h following [3H]NE administration and were stored at -80°C until time of analysis. Bone marrow samples were immediately mixed with HCl and then stored at -80°C until the time of analysis.
NE and [3H]NE analysis
Tissue samples were homogenized in 1.0 ml of cold 0.4 M
perchloric acid using a Polytron tissue homogenizer (Brinkmann
Instruments, Westbury, NY) and centrifuged. The supernatant was
adjusted to pH 8.4 with 1 M Tris buffer (pH 10) and was mixed with
activated acid-washed alumina. The alumina was washed with water, and
alumina-bound NE was eluted with 0.2 M acetic acid. The concentration
of NE in the elute was measured by electrochemical detection following
HPLC separation (HPLC and EC systems from BioAnalytical Systems, West
Lafayette, IN). The recovery of NE from alumina was 85% efficient.
Aliquots of alumina elutes (0.1 ml) were mixed in 5.0 ml of
scintillation cocktail (Bio-Safe II, RPI, Mount Prospect, IL) and
counted for 3H in a scintillation counter (LS
6500, Beckman Instruments, Fullerton, CA). The specific activity of the
[3H]NE (cpm per nanogram of NE) was calculated
as the quotient of [3H]NE present in the tissue
and the total tissue NE content.
Data analysis and statistics
To determine NE turnover rates (rate constant x tissue NE), the specific activity of tissue NE ([3H]NE per picograms of NE) after radiolabeled injection was plotted as a function of time. The decay of specific activity is a first-order function, a straight line with a negative slope, and decay lines were calculated by the method of least squares (29). The rate constant represents the fraction of the NE pool replaced per unit time (h-1). Rate constants (k) were calculated from the slope of logarithm of the specific activity vs time relationship (0.434 [k] = slope). Data are expressed as the mean ± SEM. Differences between the slopes of the regression lines were tested by Student’s t test, using the pooled SE of sample regression (30). p < 0.05 was accepted as achieving statistical significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine whether immunization of mice with a soluble protein
Ag influences the rate of NE release from sympathetic nerve
terminals, the rate of NE release was determined in the spleen,
bone marrow, and heart following immunization of mice with a soluble
protein Ag. One week following cell reconstitution with KLH-specific
Th2 cells and TNP-specific B cells, scid mice were immunized
with TNP-KLH at time zero and administered 25 µCi of
[3H]NE 1 h before tissue sample collection
at the first of two time points spanning an 8-h period. Tissue samples
were collected either at 1 and 8 h or at 18 and 24 h
following immunization for NE turnover analysis. The rate of NE release
is reflected by the slope of the line resulting from plotting the
specific activity of tissue NE ([3H]NE per
picograms of NE) as a function of time following immunization and is
independent of the relative NE specific activity of each group. No
significant difference was observed in the rate of NE release (Fig. 1
and Table I) 1–8 h following Ag exposure in the
spleen, bone marrow, and heart compared with that in adjuvant-only
controls. Interestingly, the level of NE specific activity was
significantly lower in all bone marrow samples compared with that in
the heart and spleen, and this observation is consistent with a
previous report (12). However, the mechanism responsible
for this lower level of specific activity is currently unknown, but it
may involve factors such as local blood flow rates and patterns,
differences in local nerve terminal uptake mechanisms, or differences
in the level of sympathetic innervation (31).
Finally, no significant differences were observed in the
tissue concentration of NE between mice receiving either Ag or
adjuvant-only injections (Table I). Thus, these results suggest that Ag
administration did not significantly alter the rate of NE release in
the spleen, bone marrow, and heart at 1–8 h following Ag exposure. The
possibility existed that activation of the Ag-specific Th2 and B cell
populations was responsible for altering the rate of NE release via a
mechanism that was triggered at times later than 8 h following Ag
exposure. For example, APC require at least 8–12 h for Ag homing,
uptake, processing, and presentation to a Th cell in vivo
(32, 33, 34); thus, immune cell-derived soluble products may
not be produced within 8 h of immunization. Therefore, the rate of
NE release was determined in the spleen, bone marrow, and heart 18–25
h following immunization. As shown in Fig. 2A and Table II, immunization of mice with the cognate
Ag TNP-KLH significantly enhanced the rate of NE release in the spleen
(p < 0.01) compared with that in adjuvant-only
controls. Even though NE specific activity was lower in mice
receiving TNP-KLH, this exerted no influence on measurement of the rate
of NE release (24, 25).
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A,
inset, and Table II) and bone marrow (Fig. 2B and
Table II) compared with that in adjuvant-only controls. Interestingly,
Ag administration enhanced the rate of NE release in the heart to
varying levels. Finally, and most importantly with regard to previous
findings, Ag administration had no significant effect on the total
amount of NE in the tissues (Table II), indicating that Ag stimulation
did not impair the mechanisms responsible for maintaining the local
stores of NE within the tissue. Thus, administration of the soluble
protein Ag TNP-KLH to scid mice reconstituted with
KLH-specific Th2 cell clones and TNP-specific B cells significantly
enhanced the rate of NE release and NE turnover in the spleen and bone
marrow 18–25 h after Ag exposure. Role of Ag-specific Th2 cells and B cells in stimulating the Ag-induced release of NE
To determine whether Ag-induced activation of Th2 cells and B
cells in our model system was critical for inducing the measured
increase in NE release in the spleen and bone marrow, scid
mice were reconstituted with KLH-specific Th2 cell clones and
TNP-specific B cells and immunized with the cognate Ag TNP-KLH, the
noncognate Ag FLU-OVA, or adjuvant only, using TiterMax Gold adjuvant,
which does induce nonspecific inflammatory cytokine production. As
shown in Fig. 3A and Table III, immunization of mice with FLU-OVA
failed to significantly increase the rates of NE release and NE
turnover in the spleen in comparison to adjuvant-only controls.
Similarly, in the bone marrow (Fig. 3B and Table III),
administration of FLU-OVA also failed to significantly enhance the
rates of NE release and NE turnover in comparison to adjuvant-only
controls. As in previous experiments, administration of either TNP-KLH
or FLU-OVA had no significant effect on the tissue concentration of NE
in the spleen, bone marrow, or heart (Table III). Thus, immunization of
mice with the cognate Ag TNP-KLH, but not the noncognate Ag FLU-OVA,
significantly enhanced the rate of NE release and NE turnover in the
spleen and bone marrow.
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The NE-containing sympathetic nerve terminals that innervate
immune organs originate from cell bodies located in local sympathetic
ganglia lying close to the spinal cord. The function of these ganglia
is to receive input signals from nerves that originate in the CNS.
Therefore, any signal from the CNS destined for delivery to immune
organs via sympathetic innervation must travel through the local
sympathetic ganglion, for example, the splanchnic ganglion for the
spleen. On the other hand, it has also been proposed that NE release
from sympathetic nerve terminals may be regulated by stimulation of
cytokine receptors expressed on sympathetic nerve terminals
(22). In this case, NE release in the spleen and bone
marrow would be regulated locally, as opposed to regulated by signals
originating from the CNS, thus eliminating the requirement for the high
levels of cytokine necessary to precipitate alterations in CNS
activity. To investigate the role of signals from the CNS in mediating
the Ag-induced increase in the rate of NE release and turnover in the
spleen and bone marrow, some mice received injections of the ganglionic
blocker chlorisondamine (5 mg/kg) at the time of
[3H]NE administration to interrupt signal
transmission through sympathetic ganglia. As shown in Fig. 4A and Table IV, administration of chlorisondamine
partially blocked the Ag-induced enhancement of the rated of NE release
and NE turnover compared with those in mice receiving TNP-KLH alone. In
addition, chlorisondamine partially blocked the Ag-induced enhancement
of the rates of NE release and NE turnover in the bone marrow in
comparison to mice receiving TNP-KLH only. In contrast, chlorisondamine
(Fig. 4C) completely blocked the cognate Ag-induced increase
in the rates of NE release and turnover (Table IV) in the heart in
comparison to adjuvant-only controls. Finally, administration of
chlorisondamine had no effect on tissue NE content (Table IV). Thus,
ganglionic blockade partially prevents the Ag-induced enhancement of
the rates of NE release and NE turnover in the spleen and bone
marrow.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
Interestingly, administration of a noncognate Ag that is not recognized
by either the Ag-specific Th2 cell clones or B cells used to
reconstitute the scid mice in our model system failed to
enhance NE release in the spleen or bone marrow. Finally,
administration of the ganglionic blocker, chlorisondamine, partially
prevented the Ag-induced activation of NE release and turnover in the
spleen and bone marrow.
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(19). Since peripheral
administration of both cytokines has also been shown to evoke CNS
activation (35, 36), it is likely that such experimental
results involved macrophage activation, macrophage-derived cytokine
modulation of CNS activity, and subsequent increased sympathetic nerve
activity. If such a mechanism was involved in our reconstituted
scid mouse model system, we would expect administration of a
noncognate soluble protein Ag to induce alterations in the rate of NE
release in the spleen and bone marrow, since this Ag would be processed
by professional APC other than B cells. However, this expectation was
not realized, suggesting that nonspecific activation of macrophages or
other members of the innate immune system by a soluble protein Ag was
not sufficient to induce alterations in NE release within the spleen
and bone marrow when using our model system. More importantly, Ag
administration induced NE release only when mice were challenged with
the specific cognate Ag (TNP-KLH) recognized by both the Th2 cell
clones and B cells present in our model system, suggesting that the
production of inflammatory cytokines is not essential for NE release to
occur. Thus, these findings suggest that macrophage activation and
inflammatory cytokine production are not responsible for the soluble
protein Ag-induced increase in sympathetic nerve activation and that a
cognate interaction between Th2 cells and B cells is necessary for
immunization-induced enhancement of NE release by a currently
undetermined mechanism.
The capacity of immune cell-derived cytokines to influence sympathetic
nerve activity was originally suggested by an early study showing that
peripheral administration of cytokines stimulates increased nerve
activity in both the hypothalamus and brainstem (37).
Recently, this study was further supported by the findings that
cytokine receptors are present on various types of peripheral nerves,
including sensory nerves (38), sympathetic nerves
(39, 40), sympathetic ganglia (41, 42), and
vagal nerve paraganglia (4), all of which are found
outside the CNS. Therefore, the presence of cytokine receptors on
peripheral nerves provides a potential mechanism by which local immune
cell-derived cytokines produced in the periphery may transmit signals
to the CNS or the peripheral nerve directly (see model in Fig. 5).
Importantly, administration of the ganglionic blocker, chlorisondamine, completely blocked any effect of Ag administration on NE release in the heart, suggesting that the dose of chlorisondamine used in the current studies was sufficient to block ganglionic transmission. However, chlorisondamine only partially blocked the Ag-induced enhancement of NE release and turnover in the spleen and bone marrow, suggesting a role for signals originating above, as well as at the preganglionic cell body in regulating nerve activity in this model. One possible explanation of these results is that the immune cell-derived signals, which are most likely cytokines, do not act locally to enhance local NE release, but instead bind to cytokine receptors at an unknown site before the ganglion, e.g., on the preganglionic nerve terminal, to influence sympathetic nerve activity within the spleen and bone marrow. However, it is also possible that these cytokines might bind to their specific receptors on the local nerve terminal within the splenic or bone marrow microenvironment to initiate signals that must then be transmitted to either the CNS or the local ganglion before another signal is transmitted back to the local nerve terminal inducing NE release. This possibility is supported by two of the present findings. First, Ag administration induced a lower level of NE release in the heart compared with that in the spleen and bone marrow. Second, chlorisondamine completely blocked the Ag-induced alterations in sympathetic nerve activity in the heart. Since chlorisondamine failed to completely block the Ag-induced enhancement of sympathetic nerve activity in the spleen and bone marrow, it is possible that local cytokine production not only serves to initiate an afferent signal from the site of the immune response, but, in addition, modulates local nerve activity by binding to cytokine receptors on local nerve terminals or the postganglionic cell body. Of course, it is also possible that immune cell-nerve terminal interactions may occur after Ag exposure to induce NE release, a possibility that is testable using our model system. Thus, while signals from the ganglion represent a significant regulatory influence on sympathetic nerve activity in response to a specific cognate Ag, which is blocked by chlorisondamine, local cytokine receptor stimulation may also enhance NE release, which cannot be blocked by chlorisondamine. Thus, there may be multiple levels of cytokine-induced regulation of local sympathetic nerve activity and NE release within immune organs. The model system used in the present study will now help us to dissect the multiple levels of regulation of this immune cell-modulating neurotransmitter.
Currently, it is not known whether the production of specific cytokines
by Th2 and/or B cells mediates the Ag-induced enhancement of NE
release. If cytokines are involved in our model system, the most likely
source of the cytokines is the Th2 cell clone, which characteristically
produces the cytokines IL-4, IL-5, IL-6, and IL-10 (9, 43). In light of this possibility, the current findings may not
occur in mice reconstituted with Th1 cell clones that
characteristically produce IFN-
and IL-2 (9, 44). One
possible mediator of the Ag-induced increase in sympathetic nerve
activity may be IL-6 produced by the Th2 cell clones used in this model
system. Although IL-6 does not affect the uptake of
[3H]NE into sympathetic nerve terminals
(22), IL-6 does exert concentration-dependent effects on
sympathetic nerve activity. For example, 1 ng/ml of IL-6 stimulated, 10
ng/ml of IL-6 had no effect, and 100 ng/ml IL-6 inhibited
[3H]NE release from sympathetic nerve terminals
within 2 h of cytokine exposure. Thus, IL-6 may either enhance,
inhibit, or have no effect on NE release in our model system. However,
if similar findings are observed in animals reconstituted with Th1 cell
clones, they would suggest that the critical signal responsible for
influencing sympathetic nerve activity is produced by both Th1 and Th2
cells, such as IL-3 (44) or TNF- (45).
Finally, it is also possible that the B cell is the critical source of
the immune cell-derived cytokine signals mediating the effects of Ag
administration on NE release, thus eliminating the association of a Th
cell subset specificity with the response.
The current study supports the overall hypothesis that local immune responses generate important signals that regulate nervous system function. Since both in vitro and in vivo findings conclude that signaling mediators derived from the nervous system regulate immune cell function (reviewed in Ref. 46), it is not surprising that the peripheral immune system may transmit signals to the nervous system via local cytokine production or cell-cell interactions. By this type of mechanism, the CNS may differentially regulate immune cell function in the periphery depending on the intensity of the response to a specific Ag or the health of the entire body, such as during times of stress, disease, or trauma. Such actions of the CNS may influence the function of immune cells participating in responses above a certain threshold of intensity, whereas local immune system or nervous system mechanisms may be sufficient for regulating responses of lower intensity. If this should be the case, then bidirectional communication between the immune system and the nervous system would be critical in maintaining immune homeostasis in vivo.
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Acknowledgments |
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Footnotes |
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2 A.P.K. and Y.T. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Stephen B. Jones, The Burn and Shock Trauma Institute, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153.
4 Abbreviations used in this paper: NE, norepinephrine; ß2AR, ß2-adrenergic receptor; KLH, key hole limpet hemocyanin; TNP, trinitrophenyl; FLU, fluorescein.
5 A. P. Kohm, N. Morley, M. A. Swanson, and V. M. Sanders. Selective expression of ß2-adrenergic receptor mRNA in CD4+ Th1 cells, but not Th2 cells. Submitted for publication.
Received for publication February 15, 2000. Accepted for publication April 26, 2000.
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D. J. Kasprowicz, A. P. Kohm, M. T. Berton, A. J. Chruscinski, A. Sharpe, and V. M. Sanders Stimulation of the B Cell Receptor, CD86 (B7-2), and the {beta}2-Adrenergic Receptor Intrinsically Modulates the Level of IgG1 and IgE Produced per B Cell J. Immunol., July 15, 2000; 165(2): 680 - 690. [Abstract] [Full Text] [PDF]
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, mice immunized with TNP-KLH. Each
point represents the mean ± SEM for specific activity of organs
from six mice per experiment; r values are the
calculated least square regression coefficients using raw data points
for each line. See Table I
, mice receiving the irrelevant Ag FLU-OVA. Each point represents
the mean ± SEM for specific activity of organs from six mice per
experiment; r values are the calculated least square
regression coefficients using raw data points for each line. The
p values are indicated when the slope is significant.
See Table III
