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* Mucosal Immunology Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129; and
Mucosal Immunity Section, National Institutes of Health, Bethesda, MD 20892
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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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. Dietary Ags are sometimes allergenic, but typically induce systemic nonresponsiveness (8). Experimentally, various microbial products can act as adjuvants and induce systemic and mucosal immune responses to coadministered protein Ags (9). Previous work from our laboratory (Mucosal Immunology Laboratory, Massachusetts General Hospital, Charlestown, MA) has shown that an ongoing enteric helminth infection can also act as an adjuvant to prime for an Ag-specific Th2 response to a model dietary Ag (10, 11). Like helminth infection, allergic diseases are associated with the increased production of IgE Abs. In this report, we examine whether the polarized Th2 response induced by intestinal helminth infection in early life influences the development of an allergic response to a dietary Ag. Although not all helminth infections migrate through the intestine, the helminth used in our study, Heligmosomoides polygyrus, has a strictly enteric life cycle. Using a model in which intragastric (i.g.)3 administration of peanut (PN) Ag in the presence of cholera toxin (CT) (a Th2-inducing mucosal adjuvant) results in the production of Ag-specific IgE and systemic symptoms of anaphylaxis (12), we have compared the response to Ag administered to helminth-infected mice to that seen after sensitization with Ag and CT alone. Our results show that helminth infection does not prime for a PN Ag-specific IgE response; only mice given PN Ag plus CT developed Ag-specific IgE and an allergic response. Moreover, the IgE-mediated anaphylactic response to Ag plus CT was greatly reduced in helminth infected mice, observations that parallel those made in clinical studies. The down-regulation of Ag-specific IgE observed in helminth-infected mice was accompanied by a reduction of Ag-specific T cells secreting IL-13. Treatment of infected mice with neutralizing Ab to IL-10 abrogated infection-mediated protection against allergic symptoms. Our results suggest a mechanistic explanation for the absence of Ag-specific IgE in helminth-infected mice and provide a new rationale for the ability of helminth infection to protect against allergy.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C3H/HeJ weanling mice (3-wk-old) were purchased from The Jackson Laboratory (Bar Harbor, ME) and maintained under specific viral pathogen-free conditions at an American Association for the Accreditation of Laboratory Animal Care accredited facility at Massachusetts General Hospital (Charlestown, MA). Infective, ensheathed, third-stage larvae of H. polygyrus were propagated as previously described and stored at 4°C until use. H. polygyrus-infected mice were inoculated orally with 200 third-stage larvae (10, 11).
PN Ag preparation
Ten grams of unshelled ground PN were homogenized in 25 ml PBS (pH 7.2). The suspension was stirred for 4 h and centrifuged at 18,000 x g for 30 min at 4°C to remove insoluble materials. The fatty layer was removed. The clear solution was centrifuged again under the same conditions. The supernatant was dialyzed overnight against distilled water with a 3–5 kDa MWCO membrane (Spectrum Laboratories, Houston, TX). Protein was determined by the Bio-Rad protein assay (Hercules, CA). The dialyzed PN proteins at a concentration of 2 mg of protein per milliliter are referred to as PN Ag. This solution was then sterile-filtered with a 0.22-µm Nalgene syringe filter, and stored at -20°C.
Sensitization with crude PN extract
H. Polygyrus-infected or noninfected female C3H/HeJ
mice were sensitized by weekly i.g. gavage with 5 mg of ground whole PN
per mouse (previously estimated to be equivalent to 1 mg of PN protein;
Ref. 12). Three different sensitization protocols were
used in this study (see Fig. 1
). In
protocol A, mice were sensitized with 5 mg of PN in PBS on days 7, 14,
21, 28, and 35 with or without CT (0.3 µg/g body weight; List
Biological Laboratories, Campbell, CA). In protocol B, mice were
sensitized with two doses of 5 mg PN in PBS on days 7 and 21 with or
without CT (10 µg per animal at a concentration of 1 mg/ml). In
protocol C, groups of infected and noninfected mice were treated with
three doses of neutralizing rat anti-mouse IL-10 mAb on days 7, 21,
and 28. mAb SXC-1 and SXC-2 were purified from ascites fluid as
previously described (13). At the indicated times, 0.75 mg
of each Ab was administered.
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All mice were bled weekly, beginning at 1 wk after the initial
sensitization by PN. A week after the last sensitization, mice were
fasted overnight before two i.g. challenges with PN (10 mg per mouse
divided into two doses) at 30–40 min intervals. The mice were
continuously monitored for signs of allergic sensitization. Plasma and
serum were harvested from each mouse 30 min after the second challenge
with PN. Plasma samples were used for measuring histamine levels before
and after Ag challenge. In each experiment, there were 5–10 mice per
group. Three independent experiments were performed for feeding
protocol Fig. 1
A, two for Fig. 1B, and one for
Fig. 1C.
Measurement of serum total and PN-specific Abs
PN-specific IgE in the sera was measured by ELISA with modification from an assay previously described (14). The upper two rows of a 96-well plate (Maxisorp Immunoplates; Nalge Nunc International, Naperville, IL) were coated with purified goat anti-mouse IgE mAb (2 µg/ml; BD PharMingen, San Diego, CA) and were used to generate a standard curve. The remainder of the plate was coated with PN Ags (5 µg/ml). The plate was incubated at 4°C overnight, washed with PBS/0.05% Tween 20 and blocked with PBS/10% FCS. Diluted serum samples were dispensed in triplicate in the lower portion of the plate and incubated overnight at 4°C. IgE was detected with biotinylated rat anti-mouse IgE (BD PharMingen) and avidin alkaline phosphatase (Sigma-Aldrich, St. Louis, MO). The reaction was developed with the phosphatase substrate (Kirkegaard & Perry Laboratories, Gaithersburg, MD). The reaction was then stopped by the addition of 100 µl 5% EDTA to each well and absorbance was read at 405 nm (Molecular Devices, Menlo Park, CA). OD values were converted to nanograms per milliliter of IgE by comparison with standard curves of purified IgE (BD PharMingen) by linear regression analysis, and are expressed as the mean concentration of each group of mice ± SEM.
PN-specific IgG1 was determined by ELISA. The upper two rows of a 96-well (Immunolon II) plate were coated with a goat anti-mouse IgG1 (Southern Biotechnology Associates, Birmingham, AL) and used to generate a standard curve. The remainder of the plate was coated with PN Ag (5 µg/ml) and incubated overnight at 4°C. Following blocking and washing, the plates were incubated with diluted serum samples and standard mouse IgG1 (Southern Biotechnology Associates). Ag-specific IgG1 was detected using HRP-conjugated anti IgG1 Abs (Southern Biotechnology Associates) and substrate o-phenylenediamine (OPD; Zymed Laboratories, South San Francisco, CA). The plates were read in an ELISA plate reader at 492 nm.
Total IgE and IgG1 were measured by ELISA as described previously (10). All samples were assayed in triplicate; the limit of sensitivity of all of the ELISAs is <0.5 ng/ml.
Measurement of cytokine production of splenocytes (SPL) and mesenteric lymph node (MLN) cells in vitro
SPL from individual animals (5–10 per group) and pooled MLN (five animals per group) were prepared using a 70-µM nylon cell strainer (Falcon; BD Labware, Franklin Lakes, NJ). Single cell suspensions of SPL and MLN (1 x 106 cells/well) were cultured in 24-well plates (Costar, Cambridge, MA) in the presence or absence of PN (200 µg/ml) in complete DMEM (Life Technologies, Grand Island, NY) containing 10% FCS (HyClone Laboratories, Logan, UT), 10 mM HEPES, 2 mM L-glutamine, 100 U penicillin/ml, 100 µg of streptomycin/ml, 50 µM 2-ME, 0.1 mM nonessential amino acids, and 1 mM sodium pyruvate.
At 72 h after the initiation of the culture, culture supernatants
were collected for the assessment of IL-4, IL-5, IL-10, IL-13, and
IFN-
production by ELISA as described previously (10).
ELISA capture (BVD4-1D11, IL4; R4-6A2, IFN-; TRFK-5, IL-5; and
JESS-2A5, IL10) and biotinylated second Abs (BVD6-24G2, IL-4; XMG1.2,
IFN-; TRFK4, IL-5; and SXC-1, IL-10) were purchased from BD
PharMingen. Standard curves were obtained using recombinant murine
IFN-, IL-4 (Genzyme, Cambridge, MA), IL-10 (R&D Systems,
Minneapolis, MN), and IL-5 (BD PharMingen) and are expressed in
picograms per milliliter ± SEM. A DuoSet ELISA development kit
for the detection of murine IL-13 was purchased from R&D Systems.
IL-13 was assayed according to the manufacturer’s instructions and is
expressed in picograms per milliliter ± SEM.
Assessment of hypersensitivity reaction
Anaphylactic symptoms were evaluated for 30–40 min after the second challenge dose by using a scoring system that was modified slightly from previous reports (12): 0, no symptoms; 1, scratching and rubbing around the nose and head; 2, puffiness around the eyes and mouth, diarrhea, pilar erecti, reduced activity, and/or decreased activity with increased respiratory rate; 3, wheezing, labored respiration, and cyanosis around the mouth and the tail; 4, no activity after prodding or tremor and convulsion; and 5, death.
Measurement of plasma histamine levels
Plasma samples taken 1 day before PN challenge and 30 min after the last PN challenge were used to determine the histamine level as previously described (15). Histamine levels were determined by using an enzyme immunoassay kit (Immunotech, Marseille, France), as described by the manufacturer. Histamine concentrations were calculated by comparison with a reference standard curve provided by the manufacturer.
Statistical differences in serum Ab levels were determined using a two-tailed Student’s t test with StatView software (Abacus Concepts, Berkeley, CA). A p value < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is well-established that i.g. sensitization of mice
using PN and CT, a Th2-inducing mucosal adjuvant, leads to a
predominant PN-specific IgE response that mimics the clinical and
immunologic characteristics of PN allergy in humans (12).
We have previously shown that helminth infection, like CT, acts as a
Th2-inducing mucosal adjuvant (10, 11). In this report, we
have examined the relationship between enteric helminth infection and
the development of food allergy. Three different challenge
protocols were used (Fig. 1). In the first set of experiments, the
kinetics of PN-specific and total IgE and IgG1 isotypes in the serum of
HP/PN mice was compared with that of PN/CT mice using protocol
A. As shown in Fig. 2, A and C, H. polygyrus infection is
associated with a vigorous polyclonal IgE and IgG1 serum Ab response in
both HP/PN mice and HP/PBS controls. Total IgE levels increased in the
two infected groups in a comparable fashion, peaking on day 21
postinfection. In the HP/PN group, total IgE levels increased
again after day 28 (Fig. 2A). Total IgG1 levels
also increased markedly in the HP/PN group and the HP/PBS controls
following infection with H. polygyrus. No apparent
difference was observed between the two infected groups (Fig. 2C). Although there was little difference in total IgE or
IgG1 isotype production between HP/PN and the control HP/PBS, there was
a clear difference when the HP/PN group was compared with the
noninfected PN/CT mice as can be seen from Fig. 2, A and
C. It is evident that only PN/CT sensitization in the
noninfected mice induces a PN-specific IgE and IgG1 response, despite
elevated serum total IgE and IgG1 levels in helminth-infected mice (see
Fig. 2, B and D). Interestingly, some of the mice
that received PN alone also responded with increased total as well as
PN-specific IgG1 levels whereas other mice in the same group did not
respond. In the HP/PN group, H. polygyrus infection failed
to induce a PN-specific IgE response in the presence of PN Ags.
However, the parasite-infected mice did mount a PN-specific IgG1
response similar to that seen in mice fed PN alone.
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Ag-specific IgE plays a central role in the pathogenesis of
allergic disorders. Cross-linking of high-affinity receptors (Fc
R1)
on mast cells and basophils by allergen-specific IgE leads to the
release of mediators that cause allergic reactions (16).
Prominent among these is histamine, an intracellular mediator of the
immediate hypersensitivity response that exerts potent effects on
various target tissues. Plasma histamine levels provide a measure of
mast cell and basophil degranulation. To determine how H.
polygyrus infection and CT affect the plasma histamine response
(and to examine whether this measure of systemic anaphylaxis correlates
with the Ag-specific IgE response), we examined the difference in
plasma histamine levels from samples taken 1 day before and 30 min
after i.g. PN challenge. The greatest change in plasma histamine levels
was observed in the PN/CT mice (Fig. 3A). No difference in
histamine levels was noted in the naive (PBS), control (PBS/CT and PN),
and infected (HP/PN and HP/PN/CT) mice. The elevated plasma histamine
levels observed in the PN/CT group correlated with the symptoms of
systemic anaphylaxis (anaphylactic shock, labored respiration, marked
decrease in activity) as indicated by the systemic anaphylaxis scores
shown in Fig. 3B (see Materials and Methods). PN
challenge elicited anaphylactic shock for one mouse in the PN/CT group
within 5–10 min of the first challenge. On an individual basis, a
striking association was found between PN-specific IgE levels, the
clinical symptoms of allergy as evaluated by systemic anaphylaxis
scores, and the difference in the histamine level before and after
challenge with PN.
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Based on our previous observations, we hypothesized that helminth
infection would predispose toward the development of a Th2-biased
immune response to PN Ag. We thought we might be able to uncover a PN
responsive T cell population among lymphocytes derived from the spleen
or MLN of HP/PN mice upon Ag rechallenge in vitro. To address
this issue, we analyzed PN-induced Th1 and Th2 cytokines from
PN-stimulated SPL and MLN cells from HP/PN/CT, or PN/CT (Fig. 4). PN Ag restimulation elicited the
secretion of elevated levels of IL-13 (Fig. 4A), IL-5 (Fig. 4B), and IL-10 (Fig. 4C) from spleen cells taken
from PN/CT mice compared with mice that received PN alone. Only minimal
secretion of IL-4 (not shown) or IFN- (Fig. 4D) above
background levels was detectable in these assays. When spleen cells
from HP/PN mice were restimulated with PN Ag in vitro, the levels of
PN-induced IL-5 and IL-10 detected in the culture supernatant were
similar to those seen in mice fed PN alone. Interestingly, however, the
amount of PN-specific IL-13 produced by spleen cells from
helminth-infected PN-sensitized mice was significantly lower than that
produced by cells from PN/CT mice (Fig. 4A,
p < 0.0001). The absence of a PN-specific IL-13
response upon in vitro Ag restimulation correlated with the inability
of the helminth-infected, PN-sensitized mice to mount a PN-specific IgE
response (Fig. 2). In contrast to spleen cells, in vitro restimulation
of MLN cells from PN/CT mice did not elicit an appreciable Th2 response
(data not shown).
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Our first set of experiments showed that mice fed repeatedly with
PN Ag plus the Th2 inducing mucosal adjuvant CT developed a PN-specific
IgE response and symptoms of systemic anaphylaxis. By contrast, feeding
PN Ag to mice with an ongoing enteric helminth infection (which also
induces a polarized Th2 response) did not elicit an Ag-specific IgE
response or any symptoms of a systemic allergic response. In a second
series of experiments (Fig. 1, protocol B), we examined the
effect of helminth infection on the allergic response to PN plus CT.
Fig. 5A shows that the marked
rise in total IgE that follows H. polygyrus infection
(HP/PBS) was unchanged by i.g. administration of PN plus CT (HP/PN/CT).
A clear but variable Ab response to PN alone was noted, and
administration of PN plus CT to noninfected mice elicited both a marked
PN-specific IgE and IgG1 response as well as signs of systemic
anaphylaxis, as in the previous experimental protocol. Fig. 5B shows that significantly lower levels of PN-specific IgE
were detectable after oral sensitization of HP/PN/CT compared with
PN/CT mice. HP/PN/CT mice showed a significant decrease in
PN-specific IgE (p < 0.01 and 0.001 at 14
and 21 days after infection, respectively) compared with PN/CT
mice.
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A) and systemic anaphylaxis
scores (Fig. 6B) were also reduced in PN/CT
helminth-infected mice. Although enteric helminth infection induced an
exuberant polyclonal IgG1 and IgE response, the production of
PN-specific IgE (and concomitant anaphylactic symptoms) was
down-regulated by infection in the HP/PN/CT group.
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To examine how the helminth-induced Th2 response might
influence allergic sensitization to orally administered PN plus CT,
spleen cells from both infected and noninfected mice sensitized with PN
plus CT were harvested and stimulated with PN in vitro (Fig. 7). As expected, a marked PN-specific
IL-13 (Fig. 7A), IL-5 (Fig. 7B), and IL-10 (Fig. 7C) response was induced by restimulation of spleen cells
from PN/CT (PN allergic) mice in vitro. In HP/PN/CT mice, the
PN-specific response for each of these cytokines was reduced to the
levels seen in mice fed PN alone. This helminth-induced reduction of
the PN-specific cytokine response was most striking for IL-13
(Fig. 7A). Spleen cells from helminth infected
PN-CT-sensitized mice produced 5-fold less IL-13 than that made by
noninfected PN-CT fed mice (mean ± SEM, 2360 ± 145 compared
with 650 ± 120 pg/ml, respectively; p < 0.001).
This was associated with the production of background levels of
PN-specific IgE (Fig. 5).
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Although well-known for their induction of a prototypic Th2 type
of response, chronic infection with helminthic parasites is also
accompanied by the induction of potent immunoregulatory mediators,
particularly IL-10 (5, 6, 7). Recent epidemiological studies
have suggested that helminth-induced IL-10 may play a protective role
against allergic disease. Accordingly, we treated PN-sensitized
helminth-infected mice with neutralizing Abs to IL-10 according to the
protocol shown in Fig. 1C. Anti-IL-10 treated
helminth-infected mice made much higher levels of PN-specific IgE than
nontreated mice (Fig. 8B,
p > 0.001). Interestingly, anti-IL-10 treatment
did not increase the PN-specific IgE response in noninfected mice
sensitized with PN plus CT. Anti-IL-10 treatment also did not alter the
total or PN-specific IgG1 response (Fig. 8, C and
D). In accordance with its ability to increase the levels of
PN-specific IgE, anti-IL-10 strikingly abrogated the
helminth-induced down-regulation of plasma histamine levels and
systemic anaphylaxis scores in PN plus CT-sensitized mice (Fig. 9).
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, A–C) upon restimulation
with PN in vitro. These cytokine responses were not influenced by in
vivo treatment of PN/CT mice with neutralizing Ab to IL-10.
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, HP/PN/CT mice produced lower levels of IL-13 and IL-10. Treatment with
neutralizing Ab to IL-10 partially restored the PN-specific IL-13
response in these mice. Interestingly, PN-sensitized, helminth-infected
mice treated with neutralizing Ab to IL-10 produced about 3-fold less
IL-10 upon restimulation with PN Ag in vitro. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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An interesting characteristic of the parasite-induced IgE and IgG1
response is that it is mainly polyclonal, i.e., most of this Ab is not
specific for nematode Ags (21). Previous studies in humans
and mice have suggested that allergic responses are suppressed by
helminth infection. For example, in a study that examined the effects
of anti-helminthic treatment on the allergic reactivity of children
in a tropical slum, Lynch et al. (22) noted an inverse
correlation between the levels of total and Ag-specific IgE. They
suggested that the polyclonal parasite-induced IgE response suppressed
the production of Ag-specific IgE and blocked anaphylactic symptoms by
saturating high-affinity receptors for IgE (FcR1) on mast cells and
basophils. Parasite-induced suppression of allergic reactivity was
reversed by anti-helminthic treatment. More recently, Wang et al.
(23) showed that, in a murine model, helminth infection
could result in an increased Ag-specific Th2 cytokine response in the
bronchiolar lavage fluid accompanied by an apparent reduction in
Ag-specific IgE. The authors speculated that high levels of total serum
IgE suppressed the synthesis of Ag-specific IgE in the lungs. This
would presumably lead to a reduction in anaphylactic symptoms, although
it was not measured in this report.
Our studies demonstrate a clear correlation between the induction of
Ag-specific IgE and the development of systemic anaphylaxis. By
examining the cytokine response to Ag restimulation in vitro we have
shown that, in our model, the inability to induce an allergic response
to PN Ag in helminth-infected mice is linked to their inability to make
PN-specific IL-13. IL-4 and IL-13, the prototypic mediators of the Th2
cytokine response, are produced in abundance both in response to
infection with helminthic parasites and during the course of an
allergic reaction (5, 24). Both are also central to the
regulation of class switching to IgE (25). In keeping with
our previous experience with in vitro restimulation assays, the
production of Ag-specific IL-4 was difficult to detect in our cultures
(10). Therefore, we cannot make any conclusions regarding
its role in our model. IL-4 and IL-13 share some biological activities
as well as a common receptor subunit, the IL-4R
chain
(25). IL-13 also specifically binds two other cell surface
proteins, IL-13R1 and IL-13R2. Although IL-4 and IL-13 often work
synergistically, a role for IL-13 in the induction of an
IL-4-independent IgE response has been demonstrated by the generation
of IL-13 transgenic mice (26). IL-13 transgenic mice make
higher levels of IgE than their wild-type littermates and continue to
produce IgE when crossed to IL-4-deficient mice (26).
Conversely, reduced levels of IgE have been reported in IL-13-deficient
mice, suggesting that IgE levels are responsive to both an increase and
a decrease in the expression of IL-13 (27). Moreover, the
role of IL-13 in the development of anaphylactic symptoms is
well-documented (28, 29). Sensitization of mice in which
IL-13 is overexpressed in lymphoid cells results in the enhanced
production of Ag-specific IgE and the rapid induction of fatal
anaphylaxis (28). In asthma models, IL-13 has also been
shown to be particularly important for the induction of the bronchial
constriction and the smooth muscle cell contraction that characterizes
the airway symptoms of an allergic response (30).
Recent epidemiological studies have suggested that the ability of helminth infection to protect against allergic disease is linked to its induction of immunoregulatory cytokines (5, 6, 7). In one study, various immunological parameters were measured to explain the reduced skin test reactivity to a ubiquitous allergen (house dust mites) observed in helminth-infected children in Gabon (31). Only high-level production of parasite-induced IL-10 significantly correlated with reduced skin test reactivity, even in the face of an equivalent allergen-specific IgE response. Other studies have also suggested that enhanced production of IL-10 by PBL is a characteristic feature of chronic helminth infection (32, 33). In our model, treatment of helminth-infected mice with neutralizing Abs to IL-10 dramatically abrogated the infection’s protective effect against allergic sensitization to PN plus CT. Both the anaphylactic symptoms and the PN-specific IgE response in the anti-IL-10-treated mice were similar to or greater than those seen in mice that received PN and CT alone. Therefore, our data provide compelling evidence for the ability of helminth-induced immunoregulatory cytokines to alter an allergic response.
The precise mechanism by which helminth-induced IL-10 protects against allergic symptoms is not yet clear. Although we have noted a strong correlation between the induction of a PN-specific IgE response and the detection of PN-specific IL-13 in vitro, some PN-specific IL-13 is detectable in cultures prepared from mice where both the IgE response and anaphylactic symptoms are clearly reduced. This suggests that there are other cytokines involved in the regulation of the IgE response in this model. Some evidence suggests that IL-10 can down-regulate allergic hyperreactivity via direct effects on both DC (34, 35) and mast cells (36). However, no study has yet demonstrated a mechanism by which helminth-induced immunoregulation directly affects the induction of allergic disease. Recent hypotheses have focused on a role for anti-inflammatory cytokines in down-regulating the effector phase of the allergic response by blocking, for example, mast cell degranulation (6). We show, in this report, that chronic helminth infection can block the induction of allergen-specific IgE by influencing the behavior of the Ag-specific Th cells that are required for this response. This reduction in allergen-specific IgE correlated with the abrogation of anaphylactic symptoms. We speculate that, in our model, the effects of parasite-induced immunoregulation (mediated, at least in part, via IL-10) occur at the level of allergen presentation by APCs, presumably DC. Interestingly, a prominent role for regulatory cells secreting IL-10 has also been attributed to the gut-associated lymphoid tissue which is exposed to chronic stimulation via both the commensal bacterial flora and food Ags (9). Taken together, our data are consistent with a model in which parasite-induced immunoregulation abrogates the production of allergen-specific IgE. We have shown that helminth infection primes for a Th2 response to an orally administered Ag but fails to induce atopy. Our results demonstrate that, in a murine model, helminth infection protects against the development of allergy.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Cathryn Nagler-Anderson, Mucosal Immunology Laboratory, Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital East, Building 114, 16th Street, Charlestown, MA 02129. E-mail address: nagler_a{at}helix.mgh.harvard.edu
3 Abbreviations used in this paper: i.g., intragastric; PN, peanut; CT, cholera toxin; SPL, splenocyte; MLN, mesenteric lymph node.
Received for publication March 4, 2002. Accepted for publication July 15, 2002.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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but not by a Th1 to Th2 shift. Int. Immunol. 12:623.This article has been cited by other articles:
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I. A. Khan, R. Hakak, K. Eberle, P. Sayles, L. M. Weiss, and J. F. Urban Jr. Coinfection with Heligmosomoides polygyrus Fails To Establish CD8+ T-Cell Immunity against Toxoplasma gondii Infect. Immun., March 1, 2008; 76(3): 1305 - 1313. [Abstract] [Full Text] [PDF]
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T. Setiawan, A. Metwali, A. M. Blum, M. N. Ince, J. F. Urban Jr., D. E. Elliott, and J. V. Weinstock Heligmosomoides polygyrus Promotes Regulatory T-Cell Cytokine Production in the Murine Normal Distal Intestine Infect. Immun., September 1, 2007; 75(9): 4655 - 4663. [Abstract] [Full Text] [PDF]
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 R. Fischer, J. R. McGhee, H. L. Vu, T. P. Atkinson, R. J. Jackson, D. Tome, and P. N. Boyaka Oral and Nasal Sensitization Promote Distinct Immune Responses and Lung Reactivity in a Mouse Model of Peanut Allergy Am. J. Pathol., December 1, 2005; 167(6): 1621 - 1630. [Abstract] [Full Text] [PDF]
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 M. S. Wilson, M. D. Taylor, A. Balic, C. A.M. Finney, J. R. Lamb, and R. M. Maizels Suppression of allergic airway inflammation by helminth-induced regulatory T cells J. Exp. Med., November 7, 2005; 202(9): 1199 - 1212. [Abstract] [Full Text] [PDF]
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M. M. Hunter, A. Wang, C. L. Hirota, and D. M. McKay Neutralizing Anti-IL-10 Antibody Blocks the Protective Effect of Tapeworm Infection in a Murine Model of Chemically Induced Colitis J. Immunol., June 1, 2005; 174(11): 7368 - 7375. [Abstract] [Full Text] [PDF]
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N. E. Mangan, R. E. Fallon, P. Smith, N. van Rooijen, A. N. McKenzie, and P. G. Fallon Helminth Infection Protects Mice from Anaphylaxis via IL-10-Producing B Cells J. Immunol., November 15, 2004; 173(10): 6346 - 6356. [Abstract] [Full Text] [PDF]
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O. Liesenfeld, I. R. Dunay, and K. J. Erb Infection with Toxoplasma gondii Reduces Established and Developing Th2 Responses Induced by Nippostrongylus brasiliensis Infection Infect. Immun., July 1, 2004; 72(7): 3812 - 3822. [Abstract] [Full Text] [PDF]
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M. E. H. Bashir, S. Louie, H. N. Shi, and C. Nagler-Anderson Toll-Like Receptor 4 Signaling by Intestinal Microbes Influences Susceptibility to Food Allergy J. Immunol., June 1, 2004; 172(11): 6978 - 6987. [Abstract] [Full Text] [PDF]
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 G. Wohlleben, C. Trujillo, J. Muller, Y. Ritze, S. Grunewald, U. Tatsch, and K. J. Erb Helminth infection modulates the development of allergen-induced airway inflammation Int. Immunol., April 1, 2004; 16(4): 585 - 596. [Abstract] [Full Text] [PDF]
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 J V Weinstock, R Summers, and D E Elliott Helminths and harmony Gut, January 1, 2004; 53(1): 7 - 9. [Full Text]
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A. Boitelle, H. E. Scales, C. Di Lorenzo, E. Devaney, M. W. Kennedy, P. Garside, and C. E. Lawrence Investigating the Impact of Helminth Products on Immune Responsiveness Using a TCR Transgenic Adoptive Transfer System J. Immunol., July 1, 2003; 171(1): 447 - 454. [Abstract] [Full Text] [PDF]
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X.-M. Li, K. Srivastava, J. W. Huleatt, K. Bottomly, A. W. Burks, and H. A. Sampson Engineered Recombinant Peanut Protein and Heat-Killed Listeria monocytogenes Coadministration Protects Against Peanut-Induced Anaphylaxis in a Murine Model J. Immunol., March 15, 2003; 170(6): 3289 - 3295. [Abstract] [Full Text] [PDF]
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