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Signaling Pathway1
Department of Immunology, University of Glasgow, Western Infirmary, Glasgow, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production. IFN- has
also been implicated as a mediator of T cell tolerance in other models
in vivo and in vitro, including that induced by aerosol administration
of protein. We show here that feeding tolerogenic doses of OVA primes
for IFN- production in the spleen of mice with a normal T cell
repertoire. However, depleting IFN- at the time of feeding OVA had
no effect on the induction of tolerance. In addition, tolerance was
induced normally in both IFN- receptor knockout
(IFN-R-/-) and IL-12 p40 knockout
(IL-12-/-) mice. This was the case for all components of
the systemic immune response and also with a variety of feeding
protocols, including those believed to induce distinct regulatory
mechanisms. We conclude that IL-12-dependent IFN--mediated
regulation does not play an essential role in oral
tolerance. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A variety of regulatory mechanisms have been implicated in oral
tolerance, including anergy and deletion of Ag-specific T lymphocytes,
as well as active suppressor mechanisms mediated by individual subsets
of T cells or cytokines (5, 7). Of these,
cytokine-dependent regulatory mechanisms would appear to be the most
suitable targets for modulation. A number of different cytokines have
been studied in oral tolerance, with most work focusing on the
production of Th2 cell-dependent mediators such as IL-4 and IL-10, or
on IL-10/TGF-ß-producing Th3 or Tr1 CD4+ T
cells (2, 7, 8, 9, 10, 11, 12, 13). However, IFN- produced by 
T
cells has been implicated as a mediator of the apparently analogous
model of tolerance induced by aerosol administration of Ag (14, 15). This would be consistent with several other models of
tolerance in vivo and in vitro, where the presence of T cell anergy is
accompanied by preservation of IFN- production and, in some cases,
can be prevented by neutralization of the cytokine
(16, 17, 18, 19, 20, 21).
Recent results suggest that the induction of oral tolerance may also be
associated with early priming of IFN- production. Feeding
tolerogenic doses of OVA to TCR transgenic mice, or recipients of TCR
transgenic cells, stimulates IFN- production in the gut-associated
lymphoid tissues (2, 11, 22). One interpretation of this
is that the early release of IFN- is required for subsequent
manifestations of tolerance, such as T cell anergy or active
suppression. Here we have investigated whether IFN--mediated events
are essential for oral tolerance in mice by examining the effects of
neutralizing IFN- in vivo and by inducing tolerance in mice lacking
the IFN- receptor or the IFN- inducing cytokine, IL-12. Our
results show that these pathways are not of central importance in the
induction or expression of oral tolerance, irrespective of the
immunoregulatory mechanism involved.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IFN-R-/- 129/Sv and BALB/c IL-12
p40-/- mice were obtained originally from Dr.
H. Bluethmann, Hoffmann La Roche, Basel, Switzerland, and Dr. J.
Magram, Hoffmann La Roche, Nutley, NJ, respectively, before being bred
and maintained in the animal facility at the University of Glasgow
under specific pathogen-free conditions. In experiments with
IL-12-/- mice, wild-type
(WT)3 BALB/c mice bred
in house were used, whereas in the studies of
IFN-R-/- animals, the
WT mice were 129/Sv obtained from Harlan Olac,
Bicester, Oxon, U.K. All mice were first used at 8–12 wk of
age.
Induction and assessment of oral tolerance
Mice were fed OVA (Fraction V, Sigma, Poole, U.K.) dissolved in saline via a stainless steel gavage needle, and 10 days after the last feeding they were immunized with 100 µg OVA in CFA (Sigma) into one footpad. Control mice received 0.2 ml saline orally. Systemic immune responses were assessed in vitro by measuring OVA-specific proliferative activity and cytokine production in draining popliteal lymph nodes (PLN) 2 wk after immunization and in vivo by measuring systemic delayed-type hypersensitivity (DTH) and serum Ab responses 21 days after immunization.
Induction of priming by feeding OVA
Mice were fed 25 mg OVA, and 1, 2, 3, 4, and 10 days later, spleens, mesenteric lymph nodes, and Peyer’s patches were removed for culture in vitro in the presence of 1 mg/ml OVA to assess OVA-specific proliferation and cytokine production.
Neutralization of IFN- in vivo
To deplete mice of IFN- during the induction of oral
tolerance, mice were injected twice with 0.5 mg hamster IgG
anti-mouse IFN- (R46A2, a gift of Celltech, Slough, U.K.) 1 day
and 1 h before and 2 days after feeding 25 mg OVA. Control mice
received 0.2 ml normal hamster serum, diluted 1:4 to obtain a
concentration of 0.5 mg IgG.
Measurement of systemic immunity in vivo
As described previously (23), DTH responses were assessed by measuring the specific increment in footpad thickness 24 h after s.c. challenge of immunized mice with 100 µg heat-aggregated OVA in 50 µl saline using skinfold calipers, whereas the levels of OVA-specific total IgG, IgG1, and IgG2a isotypes in serum were measured by ELISA. In all assays, serial dilutions of a standard hyperimmune serum were included for calculation of the activity of test samples. The levels of total IgG are expressed as the percent activity of the hyperimmunized serum or as micrograms per ml IgG Ab, whereas IgG1 and IgG2a Ab levels are expressed as the titer obtained from determining the dilution of test serum which gave an OD equivalent to 5% of that found with the standard serum (23).
Measurement of OVA-specific proliferation and cytokine production in vitro
Single-cell suspensions were prepared in RPMI 1640 (Life Technologies, Gaithersburg, MD) by rubbing through a stainless steel mesh and passing the resulting suspension through Nitex mesh (Cadisch, London, U.K.). After three washes, the cells were resuspended at 106 cells/ml and cultured in 200-µl aliquots in flat-bottom 96-well tissue culture plates (Costar, Nucleopore, High Wycombe, U.K.) in RPMI 1640 containing 10% FCS, 100 U/ml penicillin, 100 mg/ml streptomycin, 50 mg/ml Fungizone, 2 mM L-glutamine, 25 mM HEPES, 50 mM 2-ME (all Life Technologies), either alone or with 1 mg/ml OVA. Proliferation was assessed by addition of 1 µCi/well [3H]TdR for the last 18 h of culture. Cell-bound DNA was harvested on filter mats, and [3H]TdR incorporation was measured on a Betaplate counter. To measure cytokine production, 4 x 106 lymph node cells in 1-ml aliquots were cultured in 24-well tissue culture plates (Costar) either in medium alone or with 1 mg/ml OVA. Supernatants were harvested after 2–4 days and stored at -20°C until assayed. Cytokine production was quantified by sandwich ELISA techniques described in detail elsewhere (23), using appropriate pairs of capture and biotinylated detecting Abs (all PharMingen, San Diego, CA). Ab binding was detected with extravidin-peroxidase (Sigma) and tetramethylbenzidine as described above. Cytokine concentrations in test supernatants were determined with reference to a standard curve constructed using serial dilutions of recombinant cytokines.
Statistical analysis
Results are represented as the mean ± SEM where indicated and were analyzed by Student’s t test, except for Ab levels, which were compared by the Wilcoxon rank sum test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production in vivo
Recent studies with TCR transgenic animals have suggested that
feeding tolerogenic doses of Ag primes for the production of IFN- in
the intestine-associated lymphoid tissues (2, 11, 22). To
determine whether IFN- production is also primed during the
induction of oral tolerance in normal animals, we fed BALB/c mice 25 mg
OVA and assessed the ability of lymphoid cells to respond to
restimulation with OVA in vitro.
Spleen cells from mice fed OVA 1, 2, or 3 days previously produced
elevated levels of IFN- compared with saline-fed controls (Fig. 1
). OVA-specific IFN- production was
absent at later times. Spleen cells taken from mice fed OVA 1 or 2 days
before also showed low levels of OVA-specific proliferative activity
and IL-3 production when restimulated in vitro (data not shown),
confirming the presence of T cell priming in normal mice fed a
tolerogenic dose of OVA. A similar pattern of IFN- priming was also
seen in the mesenteric lymph node of OVA-fed mice, but not in the
Peyer’s patches. No OVA-specific IL-2, IL-4, IL-5, or IL-10 could be
detected at any time after feeding (data not shown). Despite this
evidence of T cell priming and Ag-specific IFN- production soon
after feeding OVA, Ag-fed mice were already tolerant to systemic
challenge with OVA/CFA, as shown by reduced IFN- responses in
draining lymph nodes when challenged with OVA/CFA 1, 2, or 4 days after
feeding (OVA-specific IFN- levels: 22 ± 4, 6 ± 2*,
7 ± 1*, 3 ± 2* ng/ml in saline-fed controls, fed 25 mg OVA
on day -1, day -2, day -3, and day -4, respectively; *,
p < 0.01). Other systemic responses were also tolerant
in all OVA-fed mice (data not shown).
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IFN. We therefore
examined whether IFN- is an essential component of orally induced
tolerance.
Oral tolerance is not influenced by neutralizing IFN- in vivo
In the first experiments, we determined whether oral tolerance
could be induced in the absence of IFN- by administering a
neutralizing anti-IFN- mAb around the time of feeding a
tolerogenic dose of OVA. As expected, BALB/c mice treated with an
isotype control Ab and fed OVA had significantly reduced systemic DTH
and serum IgG Ab responses compared with saline-fed controls (Fig. 2, a and b). In
parallel, these animals had significant tolerance of IgG2a Ab
production (Fig. 2d). Saline-fed mice given anti-IFN-
Ab had markedly reduced systemic immune responses compared with
isotype-treated controls. However, systemic DTH (Fig. 2a)
and serum IgG Ab (Fig. 2b) responses were tolerized
significantly in mice fed 25 mg OVA and treated with anti-IFN-.
Furthermore, the lower levels of IgG1 and IgG2a Ab production were also
both significantly suppressed in OVA-fed, IFN--depleted mice (Fig. 2, c and d).
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in the
induction of oral tolerance by feeding a high dose of Ag. However,
because it remained possible that neutralization of IFN- by the Ab
in these experiments was incomplete or that IFN- is critical for
later phases of oral tolerance, we investigated the induction of
tolerance in IFN-R-/- mice. In addition, we
attempted to exclude the possibility that the use of high dose Ag might
obscure a subtle defect in oral tolerance by feeding a lower dose of 2
mg OVA as well as 25 mg OVA.
Induction of oral tolerance in IFN-R-/- mice
Wild-type 129/Sv mice fed OVA showed dose-dependent suppression of
subsequent DTH and proliferative responses after feeding OVA (Fig. 3, a and c).
Ag-specific production of IFN-, IL-3, IL-5, and IL-10 showed similar
dose-dependent tolerance in OVA-fed mice (Fig. 4). In addition, WT mice fed both doses
of OVA had significantly reduced IgG1 and IgG2a Ab responses compared
with saline-fed controls (Table I),
although only the mice fed 25 mg OVA had tolerance of total IgG
production (Fig. 3b).
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R-/- animals had markedly
reduced DTH responses compared with WT controls, and these responses
were reduced almost to background levels by feeding either low or high
dose OVA (Fig. 3
a). OVA-specific total IgG responses were
comparable in WT and IFN-R-/- control mice
after immunization (Fig. 3b), whereas OVA-specific IgG1 and
IgG2a responses were significantly lower in saline-fed
IFN-R-/- mice (Table I). Feeding 2 or 25 mg
OVA significantly inhibited all these humoral responses in
IFN-R-/- mice. OVA-specific proliferative
responses of saline-fed IFN-R-/- mice were
significantly higher than those of WT controls, perhaps reflecting a
normally cytostatic role for IFN- in this phenomenon (Fig. 3c). However, feeding either 2 or 25 mg OVA before
immunization resulted in marked suppression of the proliferative
responses of IFN-R-/- cells, to levels
equivalent to those seen in tolerant WT mice (Fig. 3c).
OVA-specific production of IFN- was virtually negligible in cultures
of saline-fed IFN-R-/- cells, whereas IL-5
was produced in levels comparable with that of WT controls and
OVA-specific IL-3 and IL-10 were significantly enhanced (Fig. 4).
Despite these differences in the baseline cytokine levels in
IFN-R-/- and WT mice, feeding OVA to
IFN-R-/- mice before immunization markedly
suppressed the production of all the cytokines. If anything, the
tolerance of these cytokines was greater in
IFN-R-/- mice than in WT controls.
Taken together, these results show that oral tolerance of in vivo and
in vitro responses is induced normally in the absence of endogenous
IFN- function, with no defect in either its scope or its
susceptibility.
Normal induction of oral tolerance in IL-12-/- mice
To confirm that the induction of tolerance did not require the
function of IFN- in vivo and to examine the proposed regulatory role
for the IFN--inducing cytokine IL-12, we examined the effects of
feeding OVA to IL-12-/- mice.
In the first experiment, we examined the tolerance induced by a single
high dose feed of 25 mg OVA. Compared with wild-type BALB/c mice,
saline fed IL-12-/- mice had normal DTH, serum
IgG (Fig. 5, a and
b), IgG1, and IgG2a Ab responses (Table II) in vivo when challenged with OVA/CFA
10 days later, as well as normal OVA-specific proliferative responses
(data not shown). However, saline-fed IL-12-/-
mice had somewhat higher OVA-specific IL-5 production than control
BALB/c mice and, as anticipated, produced no IFN- (Fig. 5, c and d). With the exception of the defective
IFN- response in IL-12-/- animals, both
groups of mice showed identical patterns of tolerance, with significant
suppression of systemic OVA-specific DTH, total IgG, IL-5 (Fig. 5),
IgG1, IgG2a (Table II), and proliferative responses (data not shown) in
mice fed 25 mg OVA before immunization.
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a), total IgG Ab responses
(Fig. 6b), and proliferation (Fig. 6c). IgG1 Ab
responses were also significantly suppressed in both WT and
IL-12-/- mice fed OVA in either regimen, as
were IgG2a responses in the IL-12-/- mice
(Table III). WT mice had markedly reduced
IgG2a production after feeding either 1 x 2 mg or 5 x 1 mg
OVA, although this attained statistical significance only in mice fed
multiple low doses of Ag (Table III). WT mice fed OVA by either regimen
had significantly suppressed OVA-specific IFN- production, but as
before, no group of IL-12-/- mice had any
OVA-specific IFN- production in vitro (data not shown). Once again,
saline-fed IL-12-/- mice had enhanced
OVA-specific IL-5 production compared with WT controls, but these
exaggerated responses were dramatically reduced by feeding single or
multiple low doses of OVA, similar to the effects in WT animals (Fig. 6d).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. This conclusion is not
dependent on the feeding regimen used and is despite the fact that
IFN- production is primed during the induction phase of tolerance.
Our findings contrast with evidence that IFN- is important in other
models of peripheral tolerance and support the view that an
IFN--dependent regulatory mechanism does not play an essential role
in oral tolerance to protein Ags.
Conflicting evidence has been presented recently on the role of IFN-
in oral tolerance, with one study in
IFN-R-/- mice reporting normal induction of
tolerance after feeding multiple low doses of keyhole limpet hemocyanin
(KLH) (25), whereas another found defective tolerance in
IFN--/- mice fed a single high dose of OVA
(26). Here we have reexamined these discrepancies using a
combination of experimental approaches and by assessing a much wider
range of systemic immune responses and more feeding regimens than used
in previous studies. We show first that neutralizing IFN- at the
time of feeding had no effect on the tolerance induced by feeding a
single high dose of OVA. This regimen of Ab treatment was chosen
because we found IFN- production to be primed very soon after
feeding this dose and we had previously used the same Ab in a similar
protocol to inhibit IFN--dependent intestinal immunopathology in
vivo (27). Although we therefore considered it likely that
the Ab treatment was effective in neutralizing cytokine function at the
most appropriate time, we thought it important to confirm the results
by examining tolerance induction in the complete absence of IFN-
function during the entire induction and effector phases. Thus, we used
IFN- R-/- mice to prevent functional
signaling by the cytokine and IL-12-/- mice to
ensure an absence of IFN--producing Th1 cells (28, 29, 30).
In both cases, feeding OVA resulted in an entirely normal state of
tolerance identical in scope and intensity with that observed in WT
animals. Importantly, the pattern of susceptibility of Th1- and
Th2-dependent immune responses was entirely normal in both kinds of
knockout (KO) mice fed single high or low doses of Ag, or using a
multiple low dose feeding regimen, protocols that are believed to
induce distinct regulatory mechanisms, clonal anergy/deletion, and
active regulation, respectively (6, 7, 31, 32). Together,
these results support the view that IFN- is not essential for any of
these tolerogenic processes.
Our finding that IFN- plays no role in the induction or expression
of oral tolerance contrast with other models of T cell tolerance in
vivo and in vitro in which initial priming of IFN- production
precedes an unresponsive state that requires the presence of the
cytokine (17, 19, 20). In addition, it has been suggested
that the tolerance induced by aerosol administration of OVA is
dependent on IFN--producing T cells (14, 15). Although
this could reflect the involvement of distinct regulatory mechanisms in
tolerance induced by different routes, others have failed to find an
essential role for IFN- in peripheral tolerance (33).
The mechanisms underlying such immunoregulatory effects of IFN- have
also not been elucidated. It is more difficult to reconcile our
findings with those of Kweon et al. (26) who reported a
defect in oral tolerance in IFN--/- mice fed
high dose OVA. The defects in tolerance reported by these authors were
generally small, with a significant loss of tolerance observed mainly
in systemic B cell responses, whereas T cell-dependent responses such
as DTH, proliferation, and cytokine production were tolerized
effectively in the KO mice (26). Furthermore, others have
supported our findings by reporting normal oral tolerance of Ab and
cytokine production induced by feeding multiple low doses of KLH to
IFN-R-/- mice (25). It is
possible that the apparent discrepancy between the susceptibilities of
IFN-R-/- and
IFN--/- mice to the induction of oral
tolerance could reflect differences between these animals in immune
function. Nevertheless, the fact that IFN- and its receptor form a
unique receptor-ligand pair makes this idea seem unlikely.
An intriguing finding of our work was the IFN- production which was
primed in the spleen soon after feeding a tolerogenic dose of Ag. This
has now been described in the local and peripheral lymphoid tissues of
Ag-fed animals in a number of normal and TCR transgenic models
(2, 11, 22, 26, 34), and it is consistent with the idea
that early IFN- production is part of the process of partial T cell
activation that occurs in many forms of T cell tolerance and that may
precede the onset of T cell anergy (16, 17, 18, 19, 20, 21). Several
pieces of evidence support the view that a similar process occurs in
oral tolerance, including the fact that there is rapid but transient
activation of Ag-specific T cells throughout the immune system of
animals fed tolerogenic doses of Ag (Fig. 1 and Refs. 2, 11, 34, 35, 36, 37). In addition, the induction of oral tolerance is favored by
presentation of Ag in the absence of adequate costimulation (1, 38), conditions that frequently lead to partial T cell
activation and clonal anergy (16, 39). However, our
current results indicate that the priming of IFN- production may be
an epiphenomenon of partial T cell activation, rather than tolerance
induction, and suggest that the two processes may not be linked
mechanistically.
Recent studies have shown that exogenous IL-12 can prevent the induction of tolerance and act as a mucosal adjuvant (40) and can also partially reverse T cell anergy in vivo after parenteral administration of soluble peptide (41). However, we show here that tolerance to single high doses or multiple low doses of Ag was normal in IL-12-/- mice, confirming and extending our preliminary findings of normal oral tolerance to high dose KLH in IL-12-/- mice (42). Although a study published while our manuscript was in preparation indicates that all aspects of oral tolerance to a single high dose of OVA are normal in Stat4-/- mice that lack IL-12 signaling (43), ours is the first detailed examination of peripheral tolerance in the absence of IL-12. We conclude that IL-12 has no immunoregulatory role in oral tolerance to protein Ags in normal animals, irrespective of the mechanism involved, or dose of Ag fed. In addition, the normal tolerance in the absence of IL-12 demonstrates that oral tolerance of Th2 responses is not dependent on cross-regulation by Th1 cells, which do not develop in IL-12-/- animals. This contrasts with results reported in certain models in which Th2 responses can be suppressed by nasal administration of Ag (14, 15) but is analogous to the situation in which oral tolerance of Th1 responses does not require classical Th2 cells, as shown by studies in IL-4-/- mice (23, 44). Also, our study indicates that IL-12 is also not required for the uptake and processing events that underlie the ability of protein Ags to induce tolerance via the intestine.
It has been hypothesized that IFN- or IL-12 and TGF-ß play
mutually exclusive roles in determining the immune consequences of oral
administration of Ag (2). According to this view,
IL-12-dependent production of IFN- occurs during active
immunity/inflammation, whereas TGFß is associated with the induction
of tolerance and is inhibited by IFN- (or IL-12). However, our own
and other (26) studies show directly that tolerance to
systemic challenge developed at the precise time when priming of
IFN- production could be observed, indicating that the two processes
are not necessarily exclusive. Further evidence against the idea that
oral tolerance is dependent on an IL-12/IFN- TGF-ß counterbalance
is our observation that IL-12-/- mice did not
show enhanced susceptibility to tolerance induction, even when a low
dose feeding regimen was used, a protocol that is believed to
selectively induce TGF-ß-secreting regulatory cells (6).
This is despite our earlier finding of increased TGF-ß production in
IL-12-/- mice (40). Others have
also reported that the oral tolerance in
Stat4-/- mice was not associated with an effect
on TGF-ß (43). Thus, the susceptibility of mice
defective in IL-12 or IFN- does not necessarily correlate with
differences in TGF-ß production. This conclusion contrasts with the
ability of anti-IL-12 Ab to cause parallel increases in both oral
tolerance and TGF-ß production in TCR transgenic mice fed OVA, as
well as in mice fed soluble Ag to prevent hapten-induced intestinal
immunopathology (2, 11, 24). Thus, the interactions among
IL-12, IFN-, and TGF-ß in the regulation of intestinal immune
responses warrant further investigation in additional models.
In conclusion, our study indicates that IFN- and IL-12-dependent
regulation of systemic immunity and other cytokines are not necessary
for oral tolerance. However, priming of IFN- production appears to
be a characteristic feature of the early mucosal immune response to Ag.
Why this occurs and whether it is a unique property of the mucosal
immune system remains to be clarified, as is the ultimate fate of the
cells responsible. Elucidation of these processes will help our
understanding of the induction and regulation of immune responses in
these important tissues.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. A. Mowat, Department of Immunology, University of Glasgow, Western Infirmary, Glasgow, U.K. G11 6NT. E-mail address:
3 Abbreviations used in this paper: WT, wild-type; PLN, popliteal lymph nodes; DTH, delayed-type hypersensitivity; KO, knockout; KLH, keyhole limpet hemocyanin.
Received for publication April 19, 1999. Accepted for publication August 13, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TGF-ß responses regulate the occurrence of mucosal inflammation. Immunol. Today 18:61.[Medline]
T cells down-regulate primary IgE responses in rats to inhaled soluble protein antigens. J. Immunol. 154:4390.[Abstract]
T cells. Science 265:1869. plays a critical role in induced cell death of effector T cells: a possible third mechanism of self-tolerance. J. Exp. Med. 172:1735. is critical for long-term allograft survival induced by blocking the CD28 and CD40 ligand T cell costimulation pathways. J. Immunol. 160:2059.. J. Exp. Med. 186:71.-receptor-deficient mice exhibit impaired gut mucosal immune responses but intact oral tolerance. Immunology 92:60.[Medline]
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/+ T cells or interferon (IFN)- in a murine model of allergen sensitization. J. Exp. Med. 187:721.This article has been cited by other articles:
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  K. Akadegawa, S. Ishikawa, T. Sato, J. Suzuki, H. Yurino, M. Kitabatake, T. Ito, T. Kuriyama, and K. Matsushima Breakdown of Mucosal Immunity in the Gut and Resultant Systemic Sensitization by Oral Antigens in a Murine Model for Systemic Lupus Erythematosus J. Immunol., May 1, 2005; 174(9): 5499 - 5506. [Abstract] [Full Text] [PDF]
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W. W. J. Unger, F. Hauet-Broere, W. Jansen, L. A. van Berkel, G. Kraal, and J. N. Samsom Early Events in Peripheral Regulatory T Cell Induction via the Nasal Mucosa J. Immunol., November 1, 2003; 171(9): 4592 - 4603. [Abstract] [Full Text] [PDF]
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P. M. Cobelens, A. Kavelaars, A. Vroon, M. Ringeling, R. van der Zee, W. van Eden, and C. J. Heijnen The {beta}2-Adrenergic Agonist Salbutamol Potentiates Oral Induction of Tolerance, Suppressing Adjuvant Arthritis and Antigen-Specific Immunity J. Immunol., November 1, 2002; 169(9): 5028 - 5035. [Abstract] [Full Text] [PDF]
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, p < 0.05
vs WT control; *, p < 0.01 vs appropriate saline
fed Controls; 26>*, p < 0.001;
¶, p < 0.01,
¶¶,
p < 0.001 vs saline-fed WT controls).