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Department of Pediatrics, Stanford University, Stanford, CA 94305
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IgG2a
and low levels of IgE and IL-4. Neutralization of IL-12 activity at the
time of HKL administration blocked the enhancement of IFN- and
reduction of IL-4 production, indicating that IL-12, induced by HKL,
was responsible for the adjuvant effects on cytokine production. These
results suggest that HKL as an adjuvant during immunization can
successfully bias the development of Ag-specific cytokine synthesis
toward Th1 cytokine production even in the setting of an ongoing
Th2-dominated response. Thus, HKL may be clinically effective in
vaccine therapies for diseases such as allergy and asthma, which
require the conversion of Th2-dominated immune responses into
Th1-dominated responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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during Th1-dominated responses is associated with
vigorous cell-mediated immunity, with an induction of IgG2a and
inhibition of IgE synthesis (3, 4), and with resistance to
intracellular pathogens (1, 2). In contrast, the production of IL-4,
IL-5, and IL-10 during Th2-dominated responses is associated with
humoral immunity and protection from autoimmune pathology (5, 6, 7, 8).
Overproduction of Th2 cytokines by allergen-specific CD4+ T
cells also results in the development of allergic disease and asthma
(9, 10, 11, 12, 13, 14, 15, 16).
An important mechanism that influences the specific profile of the
cytokines produced by responding CD4+ T cells is the
cytokine environment present at the time of initiation of the immune
response. IL-12, a heterodimeric cytokine produced by macrophages and
dendritic cells, is potent in driving the development of Th1 cytokine
synthesis in naive and memory CD4+ T cells (17, 18, 19, 20, 21).
However, several in vivo studies have demonstrated that rIL-12 as an
adjuvant, while enhancing IFN- synthesis, paradoxically also
increases IL-4 and IL-10 synthesis in Ag-primed CD4+ T
cells in some cases (22, 23, 24, 25).
In this report, we studied the innate adjuvant activity of heat-killed
Listeria monocytogenes
(HKL)3 to provoke
Th1-dominated immune responses. Infection with L.
monocytogenes, a potent stimulator of the innate immune system,
induces production of high levels of IL-12 and results in cell-mediated
immunity against this intracellular bacterium. We used L.
monocytogenes as an adjuvant with the Ag keyhole limpet hemocyanin
(KLH) to generate a KLH-specific immune response characterized by high
Ag-specific IFN- production and large quantities of KLH-specific
IgG2a Ab. Moreover, vaccination with HKL and KLH reversed an
established Th2-dominated, KLH-specific immune response and resulted in
significant reductions in IL-4 and IL-10 synthesis, increases in
IFN- production, and reduction in KLH-specific IgE. Reduction in
IL-4 and IL-10 synthesis did not reduce the intensity of the
Ag-specific immune response, since T cell proliferation to KLH was not
reduced. Neutralization of IL-12 activity with anti-IL-12 mAb at
the time of boosting with Ag blocked reduction of IL-4 and enhancement
of IFN- production, indicating that HKL-induced IL-12 was
responsible for the adjuvant effects on cytokine production.
Taken together, these results suggest that employing a strong
nonspecific activator of IL-12 and IFN- production such as HKL as an
adjuvant during Ag-specific immunization can successfully bias the
development of Ag-specific cytokine synthesis toward Th1 cytokine
production in both primary and secondary immune responses. Reversal of
an established Th2-dominated response is particularly difficult and has
not been effectively achieved by previous protocols using recombinant
cytokines (22, 23, 25) or by agents that neutralize IL-4 (26). A
modified version of this technique may be useful in clinical situations
to induce appropriate cytokine synthesis during vaccination and in the
treatment of ongoing diseases such as allergy and asthma, which are
caused by heightened Th2 cytokine responses to exogenous allergens.
Such therapies, which alter the underlying immunologic processes, could
potentially provide a cure for such diseases, which currently are
treated only symptomatically.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/cByJ mice were obtained from The Jackson Laboratory (Bar Harbor, ME). Animal protocols used in this study were approved by the Stanford University Committee on Animal Welfare.
Antigens
KLH was obtained from Calbiochem (San Diego, CA).
Immunizations
BALB/c mice were immunized in the footpads with KLH (100 µg/mouse) emulsified in CFA or in IFA with or without HKL (108 bacteria/mouse). CFA contains the same oil base as does IFA, but CFA also contains killed mycobacteria. In some experiments, BALB/c mice were first primed in the footpads with KLH (10 µg) adsorbed to 2 mg of alum (Al(OH)3), a priming method that invokes a strong Th2 response. After 4 wk, mice were treated with KLH (100 µg) in either CFA or IFA with or without HKL (108 bacteria). After an additional 10 days, all mice received another dose of KLH (100 µg) in PBS.
Monoclonal Abs
Anti-IFN- mAb R46A2 (HB170, American Type Culture Collection,
Manassas, VA) and anti-IL-4 mAb (11B11) (generously provided by
Drs. J. Ohara and B. Paul, National Institutes of Health, Bethesda,
MD), were prepared from serum-free culture supernatants by ammonium
sulfate precipitation. Anti-IL-2 mAb S4B6 and anti-IFN- Ab
XMG1.2 were obtained from Dr. T. Mosmann (University of Alberta,
Edmonton, Canada). Anti-IL-4 mAbs BVD4-1D11 and BVD6-24G2 were obtained
from M. Howard (DNAX Research Institute, Palo Alto, CA). Each of these
Abs was purified from ascites by ammonium sulfate precipitation and
ion-exchange chromatography. Anti-IL-10 mAb SXC.1 (M. Howard) was
purified by ammonium sulfate precipitation followed by Sepharose 4B
chromatography. Anti-IL-10 mAb 2A5 was purchased from PharMingen (San
Diego, CA). Neutralizing anti-IL-12 mAb C17.8 (a generous gift of
Dr. G. Trinchieri, Wistar Institute, Philadelphia, PA) was
purified from ascites by affinity chromatography. Anti-IL-12 mAb
C15.6.8 (a generous gift of Dr. G. Trinchieri), which recognizes an
independent epitope of the IL-12 p40 chain, was purified from ascites
by affinity chromatography. Anti-38C13 idiotype mAb 4G10 (rat IgG2a)
(27) was obtained from S. Levy and used as an isotype control.
Treatment of mice with anti-cytokine Abs
BALB/c mice were injected i.p. with 1 mg of mAbs C17.8 (for
IL-12 depletion), XMG1.2 (for IFN- depletion), or 4G10 (rat IgG2a
control) in 0.5 ml PBS on the day before, the day of, and 3 days
following immunization with KLH in IFA or KLH in IFA with HKL.
Medium
Cells were cultured in DMEM (Life Technologies, Grand Island, NY), which was supplemented as described previously (28) and contained 5 x 10-5 M 2-ME and 10% FBS (HyClone Laboratories, Logan, UT).
Restimulation of lymph node (LN) cells in vitro
Draining LN were removed at 7 days after priming or booster
immunization and depleted of resting B cells by adherence to goat
anti-mouse Ig-coated plates; cells (4 x 105) were
restimulated in vitro with KLH at 1 or 10 µg/ml as indicated in the
figure legends. B cells are depleted from the LN before culture because
they consume cytokines, particularly IL-4, produced by the T cells.
Cultures were set up in 96-well microtiter plates in 150 µl of
medium. Supernatants were harvested after 4 and 5 days for the
determination of IL-4, IL-10, and IFN- levels. Cytokine levels for
each sample were measured in triplicate by ELISA. Proliferation was
assessed by pulsing cultures overnight with [3H]thymidine
after 36 h of culture.
Cytokine ELISA
Plates with 96 wells were coated overnight with primary
anti-cytokine capture Ab, washed, and blocked, and dilutions of
supernatants or standards were added. Dilutions of culture supernatant
were incubated overnight at 4°C; after washing, the wells were
incubated with biotin-conjugated anti-cytokine-detecting mAb. After
a 2-h incubation, the plates were washed, and a horseradish peroxidase
(HRP)-streptavidin conjugate (Southern Biotechnology Associates,
Birmingham, AL) was added. The plates were incubated for an additional
hour, and o-phenylenediamine (OPD) substrate was added after
washing. After developing, the OD was determined at 492 nm. The amount
of cytokine in each supernatant was extrapolated from the standard
curve. The Ab pairs used were as follows (listed by
capture/biotinylated detection): IFN-, R4-6A2/XMG1.2; IL-12,
C17.8/C15.6; IL-10, 2A5/SXC.1; and IL-4, 11B11/BVD6-24G2. The standards
were recombinant cytokine curves generated in 1/2 dilutions from 20 to
0.156 ng/ml for IFN-, 4000 to 30 pg/ml for IL-12, 20 to 0.1 ng/ml
for IL-10, and 10 to 0.15 U/ml for IL-4. One unit of IL-4 is equivalent
to 50 pg.
Measurement of anti-KLH Ab isotypes
Mice were bled at the time of sacrifice, and KLH-specific Ab was measured using a modified Ag-specific ELISA. For measurement of KLH-specific IgG1 and IgG2a, plates were coated overnight with 2 µg/ml of KLH. After washing and blocking, serial diluted sera were added to the plates. Following overnight incubation, the plates were developed using HRP-conjugated goat anti-IgG subclass-specific Abs (Southern Biotechnology Associates). After additional washing, OPD substrate was added, the plates were developed, and the OD was determined at 492 nm. The concentration of anti-KLH Ab was estimated using standard curves constructed by coating wells with 1 µg/ml of goat anti-mouse IgG1 or anti-IgG2a (Southern Biotechnology Associates) and adding polyclonal mouse Ig standards of the pertinent subclass. Determination of KLH-specific IgE was performed by ELISA using rat anti-mouse IgE mAb EM95 (0.5 µg/ml) to coat plates. After the samples were applied and incubated overnight, plates were washed, and biotinylated KLH (5 µg/ml) was added. After 3 h, plates were washed, and HRP-conjugated streptavidin (Southern Biotechnology Associates) was added. Plates were developed with OPD substrate, and the OD was determined at 492 nm.
Preparation of HKL
A clinical isolate of L. monocytogenes was kindly provided by Dr. L. Tompkins and B. Allen (Stanford University). A heat-killed preparation of bacteria (HKL) was prepared by growing nutrient broth cultures (Difco, Detroit, MI) overnight at 37°C on a rotator. Cultures in log-phase growth were harvested, centrifuged, and washed three times in PBS. The recovered bacteria were resuspended in PBS and incubated at 80°C for 1 h. After two additional washes in PBS, the absence of viable colonies was confirmed by lack of growth on nutrient agar plates. Bacteria concentration was enumerated by comparing the absorbance of a serial dilution of HKL at 570 nm with a standard dilution of a known concentration of Listeria that had been enumerated previously by counting the outgrowth of colonies from serial dilutions of bacteria plated on nutrient agar. The HKL was kept at -80°C.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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but
inhibits IL-4 and IL-10 production
We investigated the ability of HKL to act as a Th1-inducing
adjuvant in vivo. The HKL activates a potent innate immune response
characterized by the induction of IL-12, which induces rapid production
of IFN-, but inhibits the synthesis of IL-4 in NK cells and
CD4+ T cells (17, 20, 29, 30). For these experiments, we
immunized BALB/c mice in the footpads with KLH (100 µg) plus HKL
(108 bacteria) in IFA. Control mice received KLH in IFA or
in CFA. At 7 days postimmunization, draining LN were removed, and LN
cells were restimulated with KLH in vitro. Figure 1
shows that HKL induced the development
of LN cells with a strongly biased Th1-like cytokine pattern,
characterized by production of large quantities of IFN- and very low
levels of IL-4. The level of IFN- was significantly greater and the
levels of IL-4 were significantly lower than the quantities produced by
LN cells from mice that had received KLH in IFA or KLH in CFA.
Furthermore, the cells from mice immunized with KLH plus HKL produced
much lower quantities of IL-10, demonstrating the shift from a Th2-like
to a Th1-like cytokine profile. These data indicate that HKL is a
potent Th1 cytokine-inducing adjuvant in vivo.
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). LN cells from mice primed with KLH in
IFA, KLH in CFA, or KLH plus HKL in IFA all proliferated to the same
extent when stimulated with a wide range of Ag concentrations. Thus,
addition of HKL as an adjuvant to KLH did not alter the intensity of
the KLH-specific immune response. The similar dose-dependent
proliferation between groups primed under different conditions and the
lack of significant cytokine production in the absence of Ag indicated
that priming with HKL has a minimal effect on the specificity of the
response to KLH.
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We subsequently examined the capacity of HKL to enhance Th1
cytokine synthesis in established Th2 cytokine-dominated immune
responses. In these experiments, BALB/c mice were first primed with KLH
(10 µg/mouse) adsorbed to alum (2 mg/mouse), which is known to
provoke Ag-specific Th2-dominated immune responses (31, 32). After 4
wk, mice were immunized in the footpads with KLH (100 µg/mouse) plus
108 HKL in IFA, KLH in CFA, or KLH in IFA. After an
additional 10 days, all mice received a s.c. booster immunization of
KLH (100 µg) in no adjuvant to mimic persistent although nonbiasing
in vivo antigenic stimulation. The draining LN were removed 7 days
later, and the cells were cultured in vitro with KLH. Figure 3 shows that HKL as an adjuvant was
extremely effective in enhancing IFN- and in reducing IL-4 and IL-10
synthesis in the draining LN cells compared with controls. There was a
slight reduction in IL-4 production in mice receiving CFA as an
adjuvant compared with mice receiving IFA as an adjuvant, but the
reduction in IL-4 production was much greater in mice receiving HKL as
an adjuvant. In addition, HKL was much more effective than CFA in
reducing IL-10 synthesis. Finally, the proliferative responses in all
groups were similar, with negligible proliferation in the absence of in
vitro Ag (data not shown). Taken together, these data demonstrate that
HKL can act as a potent Th1 cytokine-inducing adjuvant and also reduce
preexisting Th2 cytokine production in an Ag-specific manner.
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production is mediated by
IL-12
Since HKL is a potent inducer of IL-12 production, and since IL-12
is known to inhibit production of IL-4 and enhance production of
IFN- (18, 19, 20, 33), we asked whether the effects of HKL as an
adjuvant on cytokine production were mediated primarily by IL-12. Mice
were first primed with KLH in alum to induce a Th2-dominated immune
response. As in the experiments shown in Figure 3
, the mice were
vaccinated with KLH plus HKL in IFA or with KLH in IFA. Some mice
received three i.p. injections of the anti-IL-12 mAb C17.8: one
dose just before boosting with KLH plus HKL (4 wk after priming),
another dose on the day of boosting, and the final dose at 3 days after
boosting. Figure 4A shows that
the treatment of the KLH-primed mice with KLH plus HKL, as expected,
greatly enhanced IFN- production and greatly reduced IL-4 production
in LN cells taken from these mice. Neutralization of IL-12 in such mice
with anti-IL-12 mAb reversed the enhanced IFN- production and
the reduction in IL-4 production, indicating that IL-12 mediated much
of the in vivo effects of HKL on cytokine production. Although IL-12
was critical for enhanced IFN- and reduced IL-4 production, the
presence of IFN- was not important in regulating cytokine synthesis
by HKL, since neutralization in vivo of IFN- with an
anti-IFN- mAb, XMG1.2, had a minimal effect on ex vivo IFN-
and IL-4 synthesis (Fig. 4A). The effects of HKL on Th2
cytokine production involved other factors in addition to IL-12,
since the reduction in IL-10 production by HKL was not reversed by
treatment with anti-IL-12 mAb. These findings indicate that the
effects of HKL as an adjuvant on IL-4 and IFN- production are
mediated by IL-12 and not by the enhanced levels of IFN-; however,
IL-12-independent mechanisms are also implicated, particularly in
reducing IL-10 synthesis.
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Next, we asked whether the isotype and subclass distribution
of anti-KLH Ab were altered by treatment with HKL. Mice were first
primed with KLH in alum to generate a Th2-dominated immune response and
then treated with KLH plus HKL. After an additional boost with Ag at
5.5 wk (same protocol as in Figs. 3 and 4), serum was collected, and
KLH-specific Ab responses were determined by isotype- and IgG
subclass-specific ELISA. Mice treated with KLH plus HKL showed enhanced
anti-KLH IgG2a Ab responses (2.5- to 2.8-fold enhancement in three
experiments) and reduced anti-KLH IgE responses (59.6–79.6%
reduction in four experiments) as compared with control mice treated
with KLH (Fig. 5). Levels of anti-KLH
IgG1 Ab in KLH plus HKL-treated mice were reduced from those of
KLH-treated mice (38%, 47%, and 72% reduction in three experiments)
(Fig. 5). The increase in KLH-specific IgG2a by HKL treatment was
dependent upon the presence of IL-12 and IFN-, since neutralization
of these cytokines blocked the effects. In contrast, the reduction in
both IgE synthesis and KLH-specific IgG1 was only partially dependent
upon the presence of IL-12 and IFN-, since neutralization of IL-12
and IFN- only partially restored IgE and IgG1 synthesis. These
results demonstrating the effects of HKL on Ab isotype and IgG subclass
production are consistent with the idea that HKL as an adjuvant can
convert a Th2-dominated immune response into Th1-dominated one, and
that the mechanisms by which HKL performs this conversion involve in
part IL-12 and IFN-.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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L. monocytogenes, a Gram-positive, intracellular,
facultative bacterium, elicits a strong, classical, cell-mediated
immune response that is characterized by the presence of potent
Ag-specific CD8 killer cells (34, 35, 36). In the infected cell,
Listeria escapes from the phagosome/endosome and replicates
in the cytoplasm, preferentially shunting listerial Ags into the MHC
class I-restricted pathway of Ag processing (37). The cytoplasmic
localization of the bacteria permits Listeria to be an
effective vector for tumor and viral Ags and function as a tumor/viral
vaccine (38, 39, 40, 41). However, Listeria also rapidly activates
innate immunity and induces high levels of IL-12. This results in high
IFN- production in NK cells and stimulates the induction of strongly
polarized Th1 CD4 T cells (17, 18).
Our study exploits the capacity of Listeria to induce IL-12
in APCs as a means to alter the cytokine profile of ongoing immune
responses and limit a Th2-dominated immune response in BALB/c mice.
IL-12, which is induced by HKL, plays a critical role in regulating
cytokine synthesis in primed CD4 T cells. We reported recently that the
amount of IFN- and IL-4 produced by primed CD4 T cells upon
restimulation in vitro depended upon the quantity of IL-12 present in
culture, primarily produced by APCs (42). We showed that macrophages
from BALB/c mice, which are predisposed to high IL-4 and high IgE
synthesis, produced less IL-12 than did DBA/2 macrophages during
Ag-driven interactions with CD4 T cells, resulting in higher IL-4 and
less IFN- production by T cells from BALB/c than MHC identical
(H-2d) DBA/2 mice. This observation suggested that enhanced
IFN- and reduced IL-4 production in primed BALB/c T cells could be
induced if greater IL-12 production by APCs could be mobilized by
adjuvants such as HKL.
We demonstrated that HKL as an adjuvant is very effective in reversing
cytokine synthesis in primed CD4+ T cells and in reducing
ongoing IgE synthesis. Although rIL-12 can reduce in vitro IgE
synthesis (43) and in vitro IL-4 synthesis (20, 44), administration of
rIL-12 in vivo results in more limited effects, particularly during
ongoing Th2-dominated immune responses. In such secondary responses,
IL-4 synthesis is often resistant to the effects of rIL-12 (22, 25); in
fact, rIL-12 may increase IL-4 synthesis (22, 25), perhaps by inducing
a rebound increase in IL-10 synthesis (23). In parasite models,
treatment with rIL-12 can resolve ongoing Leishmania
infection in susceptible BALB/c mice, but only when used in combination
with the anti-parasite drug antimony (45) or if rIL-12 treatment is
started within 14 days of challenge (46). In our system, administration
of KLH plus rIL-12 (20 µg) to mice primed with KLH in alum failed to
decrease IL-4 or IgE synthesis and resulted in increased production of
IL-10 and IFN- (data not shown). In contrast, HKL as an adjuvant in
our in vivo model system was effective in reducing ongoing IgE and IL-4
synthesis. This effect was due to the induction of endogenous IL-12
production by HKL, since neutralization of IL-12 activity with a mAb
abolished the effect of the HKL. Administration of an anti-IFN-
mAb did not affect the activity of HKL, suggesting that HKL functioned
independently of IFN-.
There are several possible reasons why HKL is much more effective than
rIL-12 in reducing ongoing Th2-dominated immune responses. HKL, in
contrast to IL-12, reduces IL-10 synthesis (Fig. 3), which may result
in enhanced IL-12 production. Furthermore, it is possible that the
adjuvant effects of HKL are localized to sites of antigenic
stimulation, whereas the effects of rIL-12, which diffuses rapidly into
the systemic circulation, are more widespread in the host, less
Ag-specific, and appear to evoke sustained NK cell activation. The
restriction of the effects of HKL plus Ag to Ag-specific cells may be
similar to that observed with fusion proteins consisting of Ag
genetically linked to IL-12. Such fusion proteins are similarly
effective in reducing IL-4 and IgE synthesis as HKL plus Ag and appear
to limit the effects of IL-12 to Ag-specific cells (47).
Another reason for the effectiveness of HKL as an adjuvant is that HKL
may induce the production of several cytokines in addition to IL-12,
such as IL-18, which is 10-fold more potent than IL-12 in inducing
IFN- (48) and also extremely effective in reducing IgE synthesis in
B cells. HKL as an adjuvant may function similar to naked DNA
containing unmethylated CpG motifs, which appear to induce production
of IL-12 and IL-18. Plasmids containing such motifs and cDNA for
allergen, when injected intramuscularly, are effective in reversing
Th2-dominated immune responses (49, 50). However, HKL plus Ag may
provide more consistent and potent immune responses. The magnitude of
such responses with HKL is comparable with that seen with CFA, which is
much greater than that seen with plasmid DNA vaccination (51). Since
the difference between CFA and IFA is the presence of killed
mycobacterium, administration of KLH with HKL was more effective in
reversing Th2 responses than administration of KLH with mycobacterium.
The effectiveness of HKL as an adjuvant in reducing Th2-dominated immune responses and reducing Ag-specific IgE synthesis suggests that it may be clinically useful in the treatment of diseases caused by heightened allergen-specific Th2 responses, such as allergy and asthma. Allergen immunotherapy, which is currently performed by vaccination with aqueous extracts of allergen, is used as an effective therapy for these two diseases (52, 53), although treatment failures are frequent. Since disease improvement with allergen immunotherapy is associated with the reduction of allergen-specific IL-4 synthesis (54), and since HKL is potent in reducing Ag-specific Th2-dominated immune responses and Ag-specific IgE synthesis, modification of conventional allergen immunotherapy to include adjuvants such as HKL may render allergen immunotherapy much more efficacious. Preliminary data in our laboratory also suggest that immunotherapy with HKL as an adjuvant can reduce allergen-induced airway hyperreactivity (G. Hansen et al., unpublished observations) and may be more effective than intratracheal rIL-12 (55) in such a model. Safety issues with Listeria may not be of major concern, since killed rather than live Listeria is effective; in addition, even live Listeria is not a particularly invasive organism, and is a pathogen primarily in immunosuppressed patients or in the setting of pregnancy. Therefore, HKL may be an effective adjuvant for allergen immunotherapy, eliciting rapid innate immune system activation and production of Th1-inducing and Th2-reducing cytokines on vaccination.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Dale T. Umetsu, Department of Pediatrics, Room H307, Stanford University, Stanford, CA 94305-5208. E-mail address:
3 Abbreviations used in this paper: HKL, heat-killed Listeria monocytogenes; KLH, keyhole limpet hemocyanin; LN, lymph node(s); HRP, horseradish peroxidase; OPD, o-phenylenediamine.
Received for publication April 8, 1998. Accepted for publication June 11, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production and diminishes interleukin 4 inhibition of such priming. Proc. Natl. Acad. Sci. USA 90:10188. production during differentiation of human T helper (Th) cells and transient IFN- production in established Th2 cell clones. J. Exp. Med. 179:1273. synthesis in primed CD4 lymphocytes. Int. Immunol. 8:1511. production by T cells. Nature 378:88.[Medline]
. Proc. Natl. Acad. Sci. USA 93:2879.This article has been cited by other articles:
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S. D. Hurst, B. W. P. Seymour, T. Muchamuel, V. P. Kurup, and R. L. Coffman Modulation of Inhaled Antigen-Induced IgE Tolerance by Ongoing Th2 Responses in the Lung J. Immunol., April 15, 2001; 166(8): 4922 - 4930. [Abstract] [Full Text] [PDF]
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T.-J. Huang, P. A. MacAry, P. Eynott, A. Moussavi, K. C. Daniel, P. W. Askenase, D. M. Kemeny, and K. F. Chung Allergen-Specific Th1 Cells Counteract Efferent Th2 Cell-Dependent Bronchial Hyperresponsiveness and Eosinophilic Inflammation Partly Via IFN-{{gamma}} J. Immunol., January 1, 2001; 166(1): 207 - 217. [Abstract] [Full Text] [PDF]
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H. N. Shi, H. Y. Liu, and C. Nagler-Anderson Enteric Infection Acts as an Adjuvant for the Response to a Model Food Antigen J. Immunol., December 1, 2000; 165(11): 6174 - 6182. [Abstract] [Full Text] [PDF]
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Y. Shibata, L. A. Foster, J. F. Bradfield, and Q. N. Myrvik Oral Administration of Chitin Down-Regulates Serum IgE Levels and Lung Eosinophilia in the Allergic Mouse J. Immunol., February 1, 2000; 164(3): 1314 - 1321. [Abstract] [Full Text] [PDF]
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G. Hansen, V. P. Yeung, G. Berry, D. T. Umetsu, and R. H. DeKruyff Vaccination with Heat-Killed Listeria as Adjuvant Reverses Established Allergen-Induced Airway Hyperreactivity and Inflammation: Role of CD8+ T Cells and IL-18 J. Immunol., January 1, 2000; 164(1): 223 - 230. [Abstract] [Full Text] [PDF]
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 L. Cohn, R. J. Homer, N. Niu, and K. Bottomly T Helper 1 Cells and Interferon {gamma} Regulate Allergic Airway Inflammation and Mucus Production J. Exp. Med., November 1, 1999; 190(9): 1309 - 1318. [Abstract] [Full Text] [PDF]
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