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,
*
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
Department of Pediatrics, Walter Reed Army Medical Center, Washington, DC 20307;
Division of Immunology, Department of Medicine, University of Cincinnati, Cincinnati, OH 45267;
Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; and
¶ Immunology and Disease Resistance Laboratory, Animal and Natural Resources Institute, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD 20705
The opinions and assertions in this article are those of the authors and do not necessarily represent those of the Department of Defense.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-4
complexes (IL-4C) for 7 days. Separate groups of BALB/c mice
were drug-cured of initial infection and later reinfected and treated
with anti-IL-4R mAb, an antagonist of IL-4 and IL-13 receptor
binding, or with a control mAb. Segments of jejunum were mounted in
Ussing chambers, and short circuit current responses to acetylcholine,
histamine, serotonin, PGE2, and glucose were determined.
Although only modest changes in epithelial cell function were observed
during primary Hp infection, IL-4C or a secondary
Hp infection each induced more dramatic changes,
including increased mucosal permeability, reduced sodium-linked glucose
absorption, and increased Cl- secretory response to
PGE2. Some, but not all, effects of IL-4C and
Hp infection were dependent on enteric nerves.
Hp-induced changes in epithelial function were
attenuated or prevented by anti-IL-4R mAb. Thus, IL-4/IL-13 mediate
many of the effects of Hp infection on intestinal
epithelial cell function and do so both through direct effects on
epithelial cells and through indirect, enteric nerve-mediated
prosecretory effects. These immune system-independent effector
functions of IL-4/IL-13 may be important for host protection against
gastrointestinal nematodes. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To gain insight into the intestinal effects of IL-4 that might contribute to host protection against gastrointestinal nematode parasites, we compared the physiology of the intestine of normal mice treated with recombinant IL-4 to the effects of infection with a gastrointestinal nematode parasite Heligmosomoides polygyrus (Hp).4 In addition, we investigated the IL-4R dependence of the intestinal effects of Hp. Hp is an intestinal nematode parasite that is used in experimental rodent models to study immunologic mechanisms associated with parasite infection (7, 8, 9, 10). This trichostrongyloid parasite has a strictly enteral life cycle in which third-stage larvae are ingested by the host and invade the gastric and intestinal mucosa within 24 h (10). Hp larvae develop into mature adults that enter the gut lumen 8 days later and reside in the proximal third of the small intestine, surviving and laying eggs for months in immunocompetent hosts (10). Hp infections induce a type 2 cytokine profile characterized by elevated IL-4, IL-5, IL-9, IL-10, and IL-13 (7, 11). Although endogenously produced IL-4 limits the severity of primary Hp infections (Hp 1o), the production of this cytokine in a primary infection does not occur with sufficient rapidity to prevent the development of long-lived adult worms. However, treatment with exogenous IL-4 decreases worm egg production and induces expulsion (12). Secondary infections with Hp (Hp 2o) are much less severe than primary infection, and accelerated IL-4 production and increased IL-13 production have been linked to host protective immunity during reinfection (13).
Hp adults derive their nourishment from the intestinal
epithelium of the host (14) without causing mucosal
damage; therefore, we investigated the effects of IL-4 and
Hp on gut epithelium. To perform this evaluation, we
compared ion transport in normal mice, mice treated with a long-lasting
formulation of recombinant mouse IL-4/IL-4 complexes (IL-4C)
for 7 days, and Hp-infected mice. To determine the IL-4R
dependence of the Hp 2o-induced changes in
epithelial function, we also assessed epithelial cell function in
Hp-infected mice treated with an anti-IL-4R mAb to
antagonize the action of soluble IL-4/IL-13. Results of these studies
demonstrate that 1) exogenous IL-4C treatment and Hp
2o exert predominantly similar effects on
intestinal epithelial cell function that include a net increase in the
amount of fluid in the intestinal lumen and 2) most of the Hp
2o effects are mediated by IL-4R.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The effects of IL-4 were studied in female 8- to 12-wk-old
BALB/c mice (National Cancer Institute, Frederick, MD). Animals were
given vehicle or IL-4 as described previously (15), using
a long-lasting IL-4 formulation consisting of 10 µg IL-4 (IL-4C;
generous gift of Dr. R. Coffman, DNAX Research Institute, Palo
Alto, CA) mixed with 50 µg of 11B11, a neutralizing rat IgG1
anti-mouse IL-4 mAb (Verax, Lebanon, NH). The IL-4C increase the in
vivo half-life of IL-4 from <30 min to 
24 h (15). All
of the effects of IL-4C have been shown to result from slow release of
IL-4 from the complex rather than from any effects of the
anti-IL-4 mAb or to IgGFc or complement-mediated effects. To
control for the amount of Ab protein in the IL-4 complexes, a separate
group of BALB/c mice (n = 3–4) were given 60 µg (the
total amount of protein in the complexes) of GL113, a rat IgG1 isotype
control, every 3 days (days 0, 3, and 6) and studied on day 7. A single
injection of IL-4C that contains 10 µg of IL-4 stimulated
IL-4-dependent effects for at least 3 days. Injection of
immunocompetent BALB/c mice every 3 days with this dose of IL-4C cures
an established Hp infection within 7 days (12).
In our current experiments, mice were injected i.v. on days 0, 3, and 6
with IL-4C in 0.1 ml of normal saline (n = 5) or with
an equal volume of normal saline (n = 7). Mice were
studied 7 days after the initial injection.
Infective, ensheathed third-stage Hp larvae (specimens on file at the U.S. National Parasite Collection, U.S. National Helminthological Collection, Beltsville, MD; collection no. 81930) were propagated and stored at 4°C until used. BALB/c mice were inoculated orally with 200 larvae using a ball-tipped feeding needle, and infected and age-matched controls were studied 12 days later (Hp 1o). A group of Hp 1o-infected mice was treated for 7 days with IL-4C as described above. Separate groups of Hp 1o-infected BALB/c mice were cured with the antihelminthic drug, pyranthal tartrate, 3 wk after inoculation. These groups were reinfected orally with 200 larvae (day 0) 12–20 days later (day 0 of Hp 2o). On days 0 and 4 of the Hp 2o, BALB/c mice were injected i.v. with either 0.2 ml (15) of a rat IgG2a that blocks the IL-4R chain (m1, anti-IL-4R; n = 5) or with an isotype-matched control Ab (16), GL117 (5 mg) (n = 5). Infected and uninfected BALB/c mice treated with GL117 or m1 were studied 10 days after the second Hp inoculation.
Ussing chambers
Four 1-cm segments of mucosa were stripped of muscle and mounted in Ussing chambers that exposed 0.126 cm2 to 10 ml of Krebs’ buffer. Agar-salt bridges and electrodes were used to measure potential difference. Every 50 s, the tissues were short-circuited at 1 V (DVC 1000 voltage clamp; World Precision Instruments, Sarasota, FL) and the short circuit current (Isc) continuously monitored. In addition, every 50 s the clamp voltage was adjusted to 1 V for 10 s to allow calculation of tissue resistance using Ohm’s law.
Following the 15-min equilibration period, basal Isc, representing the net ion flux before stimulation, and tissue resistance, a measure of tissue permeability, were measured. After a second 15-min period, concentration-dependent changes in Isc were determined for the cumulative addition of acetylcholine, histamine, or PGE2 to the serosal side of the intestine. To determine whether IL-4C-induced alterations were due to an effect on the epithelial cell or were mediated by nerves, responses to PGE2 and histamine were compared in the presence and absence of tetrodotoxin (TTX, 1 µM), a potent neurotoxin that blocks nerve conduction by blocking sodium channels in nerves. After the peak response to the final concentration of each secretagogue was recorded, the Krebs’ buffer on each side of the chamber was replaced and the tissue was allowed to equilibrate for 30 min. Upon re-equilibration, concentration-dependent changes in Isc were measured in response to the cumulative addition of glucose to the mucosal side. Responses from all glucose-treated tissue segments from an individual mouse were averaged to yield a mean response per animal.
Histology
Segments of mid-jejunum, 12 cm proximal to the ileocecal
junction, were removed and prepared for histological evaluation. Tissue
samples were rinsed promptly in saline and immediately fixed in 10%
buffered formalin. The tissue was embedded in paraffin, sectioned
transversely (5 µm), and stained with H&E or Giemsa. For
visualization of mast cells, tissue samples were prepared as described
previously (2). Briefly, segments of mid-jejunum were
excised, slit longitudinally, laid flat with the mucosal surface up,
rolled around a 1-in-long wood applicator stick, placed immediately in
Carnoy’s solution, and fixed overnight. Tissues were then transferred
to 90% ethanol, embedded in paraffin, and sectioned (5 µm).
Deparaffinized sections were rehydrated and stained with Alcian blue
and safranin O. The number of mucosal mast cells (MMC) present in the
lamina propria and mucosa was determined in 50 consecutive high power
fields (magnification, x397) in each section by an investigator
unaware of the treatment group.
Solutions and drugs
Krebs buffer contained 4.74 mM KCl, 2.54 mM CaCl2, 18.5 mM NaCl, 1.19 mM NaH2PO4, 1.19 mM MgSO4, and 25 mM NaHCO3 on each side. Tissues were allowed to equilibrate for 15 min in Krebs’ buffer containing 12 mM glucose on the serosal side and 10 mM mannitol on the mucosal side. All drugs were obtained from Sigma (St. Louis, MO) unless stated otherwise. Stock solutions were prepared as follows: PGE2 was dissolved in 100% ethanol (1 µM) and stored at -70°C, TTX was dissolved in citrate buffer to a stock solution of 1 mM, and acetylcholine was dissolved in ultrapure water (1 µM) and frozen. On the day of the experiment, histamine was dissolved in water, and appropriate dilutions of histamine, PGE2, acetylcholine, glucose, and TTX were made using distilled water.
Data analysis
Statistical analysis was performed using one-way ANOVA to compare basal Isc and resistance. Cumulative dose responses were compared using multiple MANOVA with post hoc analysis for multiple comparisons. A value of p < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Initial studies evaluated the effects of IL-4C treatment of normal
BALB/c mice on 1) baseline net intestinal epithelial cell ion flux
(Isc) and resistance; 2) glucose absorption; and
3) PGE2-, acetylcholine-, and
histamine-stimulated epithelial secretion. Responses in G113-treated
mice were not significantly different from those in vehicle-treated
mice except that G113 significantly increased basal
Isc, a measure of net ion flux (Table I
) and the response to glucose
placed on the mucosal (luminal) side of the epithelium (Fig. 1A). Administration of IL-4C
to BALB/c mice increased basal Isc when compared
with vehicle control but not when compared with GL113. In contrast,
IL-4C significantly reduced tissue resistance, an index of tissue
permeability (Tables II and III). In addition, treatment of
BALB/c mice with IL-4C for 7 days significantly reduced sodium-linked
glucose absorption (Fig. 1A). This effect of IL-4C is even
more dramatic when compared with the response after GL113
administration. In contrast, IL-4C increased responses to
PGE2 (Fig. 1B) and histamine (Fig. 1C) added to the serosal side of the epithelium. Thus,
effects of IL-4C were not attributed to nonspecific actions of 11B11
protein in the complexes. The effects of IL-4C were specific in that
responses to acetylcholine were unchanged (Fig. 1D).
Isc responses to glucose added to the mucosal
side are due to substrate-linked sodium absorption, whereas
Isc responses to agonists placed on the serosal
side can be attributed to chloride secretion (17). Thus,
in vivo treatment with IL-4C increases basal net ion flux across the
tissue and tissue permeability, decreases nutrient-stimulated ion
absorption, and enhances the prosecretory effects of the mast
cell-produced mediators, PGE2 and histamine.
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PGE2 and histamine can act on epithelial
cells or on enteric nerves. To determine whether
IL-4C-induced alterations were due to an effect on the
epithelial cell or were neurally mediated, responses to
PGE2 and histamine were compared in the presence
and absence of the neurotoxin, TTX (Fig. 2, A and B). In
normal BALB/c mice, there were no differences between responses to
PGE2 in the presence or absence of TTX (Fig. 2A), indicating that the baseline response to
PGE2 is independent of nerves. In contrast, the
response of normal mice to histamine was reduced approximately one-half
by TTX (Fig. 2B); thus, a portion of the response to
histamine in these mice resulted from a direct effect of histamine on
the epithelium, and another portion was mediated by nerves. IL-4C
treatment increased Isc responses to
PGE2 in the absence of TTX, but had no effect on
responses in the presence of TTX. In contrast, IL-4C increased
responses to histamine in the presence and absence of TTX. These
observations suggest that the IL-4C-induced increase in chloride
secretion to PGE2 is completely dependent on
nerves, whereas the increased response to histamine involves both
neurally dependent and independent effects on epithelial cell
secretion.
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Experiments were performed in mice infected with Hp to
determine whether any of the IL-4-induced changes in epithelial cell
function are due to endogenous IL-4/IL-13 production induced during
gastrointestinal nematode infection. The effects of Hp
1o resembled those of IL-4C treatment in that
both significantly reduced responses to glucose (Fig. 1
A vs
Table II), but differed in that Hp 1o had
no effect on basal Isc or resistance (data not
shown), or Isc responses to acetylcholine,
histamine, or PGE2 (Table II). Hp
2o, which induces a more rapid IL-4 response and
a greater IL-13 response than Hp 1o
(9), more closely resembled the effects of IL-4C treatment
than Hp 1o. In addition to decreasing the
response to glucose (Fig. 1A), Hp
2o significantly reduced tissue resistance and
elevated basal Isc (Table I), and the
Isc response to PGE2 (Fig. 1B). However, the effects of Hp
2o and IL-4C differed in that Hp
2o had no effect on responses to histamine (Fig. 1C) and significantly decreased the
Isc response to acetylcholine (Fig. 1D). Treatment of Hp
1o-infected mice with IL-4C over 7 days
significantly increased the number of MMC (Fig. 3), enhanced the response to
PGE2, and further reduced the response to glucose
(Table II), effects that more closely approximate Hp
2o. The failure of IL-4C treatment of Hp
1o-infected mice to increase the
Isc response to histamine (Table II) indicates
that Hp 1o suppresses responsiveness to
histamine, perhaps by inducing chronic mast cell degranulation that
could desensitize histamine receptors.
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If some of the changes in epithelial cell function observed in
Hp 2o mice result from the effects of IL-4
or IL-13, then treatment of infected mice with anti-IL-4R mAb,
which blocks the effects of both cytokines, should block the effects of
Hp 2o. Treatment of Hp
2o-infected mice with a blocking anti-IL-4R
mAb blunted the Hp 2o-induced increase in
basal Isc and restored resistance to control
levels (Table I). In Hp
2o-infected mice, anti-IL-4R mAb
also blocked the increased response to PGE2 (Fig. 1B), and attenuated the inhibition of the
Isc change to the highest concentration of
acetylcholine (Fig. 1D). However, not all effects of
Hp 2o on epithelial cell function could be
attributed to IL-4/IL-13. In Hp
2o-infected mice, the anti-IL-4R
mAb enhanced the Isc response to histamine (the
same effect as was induced by IL-4C in uninfected mice, Fig. 1C) and failed to reverse depressed glucose absorption (Fig. 1A).
Neural dependence of Hp 2o effects on epithelial cell function
To ascertain whether Hp 2o-induced
alterations in epithelial cell function had a similar neural dependence
as those induced by IL-4C treatment, Isc
responses to PGE2 and histamine were compared in
the presence and absence of TTX (Fig. 4).
The effects of Hp 2o resembled those of
IL-4C in that both induced considerable, neurally mediated increases in
the Isc responses to PGE2.
However, the inhibitory effect of TTX was even greater in Hp
2o-infected mice than in IL-4C-treated mice
(compare Figs. 2A and 4A). The effect of Hp
2o on responses to histamine also differed from
the effect of IL-4C (compare Figs. 2B and 4B).
Unlike IL-4C, Hp 2o had no effect on the
magnitude of the Isc response to histamine, but
infection increased the neural dependence of this response. Inhibition
of IL-4/IL-13 effects with anti-IL-4R mAb prevented the Hp
2o-induced increase in the neural dependence of
the response to both PGE2 and histamine (Fig. 4, A and B).
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There was no damage to the intestinal mucosa in response to either
Hp 1o or Hp
2o; however, there was evidence of patchy
lifting of epithelial surface cells, and goblet and Paneth cells were
more prominent than in uninfected or IL-4C-treated mice (data not
shown). The number of MMC was significantly elevated by Hp
1o and was increased further by Hp
2o (Fig. 3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Differences between Hp 1o and Hp 2o also implicate IL-4/IL-13 with changes in intestinal epithelial cell function as well as host protection. Although some alterations in intestinal epithelial function occurred during Hp 1o, changes were considerably more marked during Hp 2o. This difference may result from the more rapid production of IL-4 and the increased production of IL-13 observed during Hp 2o (9). Consistent with this possibility is the observation that administration of exogenous IL-4C to Hp 1o-infected mice increased MMC, enhanced responses to PGE2, and further reduced glucose absorption, making these changes resemble those observed during Hp 2o. The increase in rapidity and magnitude of the IL-4/IL-13 response during Hp 2o has also been tied to host protection against Hp. The reduced fecundity and adult worm survival characteristic of Hp 2o are not observed in mice treated with anti-IL-4R mAb (13) and, administration of IL-4C to Hp 1o-infected mice cures infection (12).
Direct effects of IL-4/IL-13 appear to account for some, but not all,
of the Hp-induced effects on epithelial cell function.
Hp 2o, but not IL-4C, reduced secretory
responses to acetylcholine. However, the Hp
2o-induced changes in responses to
acetylcholine, as well as the infection-induced change in response to
PGE2, were prevented or attenuated by treatment
with anti-IL-4R mAb, indicating an indirect dependence on
IL-4/IL-13. Thus, IL-4/IL-13 appears to be necessary and sufficient for
some Hp infection-induced responses and necessary, but not
sufficient, for other intestinal epithelial responses to Hp
infection. The failure of IL-4 treatment to completely reproduce the
effects of Hp infection on intestinal epithelial function
indicates that IL-4 cannot be the only worm-associated factor that has
an effect on the gut. In fact, previous studies demonstrate increases
in several cytokines, including IL-3, IL-5, IL-9, IL-10, TNF-, and
IL-13 in the intestines of worm-infected mice (18). It is
also likely that worm infection stimulates the production of multiple
chemokines, additional proinflammatory cytokines such as IL-1
and
GM-CSF, and inflammation-limiting cytokines, such as TGF-. Given
this abundance of worm-associated mediators that may directly or
indirectly influence intestinal epithelial function, it is, in fact,
surprising that a single cytokine, IL-4, reproduces the gut epithelial
effects of worm infection as well as it does.
Hp infection and IL-4C also induced one effect, a decreased Isc response to glucose, which was not blocked by anti-IL-4R mAb in Hp 2o-infected mice. Possibly anti-IL-4R mAb failed to block this effect because the effect had already been induced by the limited quantities of IL-4/IL-13 produced during an initial Hp infection. Alternately, because even small quantities of IL-4/IL-13 decrease the Isc response to glucose, it is possible that anti-IL-4R mAb does not block this receptor sufficiently during Hp 2o to inhibit IL-4/IL-13 effects on this response. IL-4C also induced some effects, such as increased histamine-stimulated ion secretion, which were not observed in Hp-infected mice. Possibly, mast cell degranulation during Hp infection releases sufficient histamine to partially desensitize epithelial cell histamine receptors.
The effects of IL-4C and Hp 2o on secretory responses differed in their neural dependence. In normal mice, almost all of the responses to PGE2 were attributable to a direct effect because treatment with the neurotoxin, TTX, failed to block the responses to PGE2. Approximately half of the responses to histamine were due to a direct effect because TTX only partially inhibited the responses. The enhanced Cl- secretion observed in response to PGE2 induced by both Hp 2o and IL-4C was entirely mediated by a nerve-dependent mechanism. IL-4C induced both direct and indirect, neurally mediated increases in the intestinal epithelial response to histamine. Hp 2o had no effect on the total response to histamine, but dramatically inhibited the direct effect of histamine, rendering the response to this mediator almost entirely dependent on nerves. Because the Hp 2o-induced changes were prevented by anti-IL-4R mAb, the Hp 2o-induced shift to neural dependence of the PGE2- and histamine-induced secretory responses must require IL-4/IL-13. As noted already, increased mast cell degranulation in Hp 2o-infected mice might explain the decreased direct effect of histamine on intestinal epithelium in these mice. Mast cells may also be involved in the increased neurally mediated effects. The close approximation of mast cells and nerves may cause mast cell degranulation to increase the excitability of neurons that regulate epithelial cell function. In this regard, histamine has been implicated as a paracrine messenger that enhances the excitability of submucosal neurons in Ag-sensitized colon (19).
In vitro studies are consistent with our observation that IL-4 also has direct effects on intestinal epithelial cells. Colgan et al. (20) showed that exposure of the human T84 epithelial cell line to human rIL-4 for 48 h decreased resistance, similar to that observed in mice in the present in vivo study. However, results of the in vitro study differed from our in vivo observations. IL-4 treatment in vitro inhibited Cl- secretory responses, in association with diminished cystic fibrosis transmembrane regulator Cl- channel activity (20, 21), whereas our in vivo results show that IL-4 increases Cl- secretory responses to PGE2 and histamine, but does not affect responses to acetylcholine. It is possible that the direct antisecretory effects of IL-4 via receptors on intestinal epithelial cells that are seen in vitro can be modulated or transcended in vivo by the neurally mediated prosecretory activity of IL-4. This could be a function of IL-4-induced MMC hyperplasia (2, 13).
In conclusion, our results show that IL-4 increases secretion and reduces glucose absorption, all of which act to increase the net movement of fluid and ions into the gut lumen. Although the ability of IL-4/IL-13 to decrease mucosal barrier function may be due to a direct effect on the epithelial cell, the prosecretory effects of IL-4 are partially neurally mediated and may involve an interaction between nerves and mast cells. These IL-4/IL-13 effects are responsible for most, but not all, of the actions of Hp infection on intestinal epithelial cell function. However, the effects of IL-4/IL-13 on the intestine are not limited to effects on epithelium. A neurally mediated, IL-4-dependent increase in in vitro intestinal smooth muscle contractility has also been observed in Hp 2o-infected mice (22). The ability of IL-4/IL-13 to augment both epithelial cell secretion and smooth muscle contractility suggests that these cytokines may promote worm expulsion by contributing to the "weep and sweep" response of the host to gastrointestinal nematode infection.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Terez Shea-Donohue, Department of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799. E-mail address: tshea{at}usuhs.mil
3 Abbreviations used in this paper: Hp, Heligmosomoides polygyrus; Hp 1o, primary Hp infection; Hp 2o, secondary Hp infection; IL-4C, IL-4/IL-4 complexes; Isc, short circuit current; MMC, mucosal mast cell; TTX, tetrodotoxin.
Received for publication December 26, 2000. Accepted for publication June 13, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity 8:255.[Medline]
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M. Morimoto, M. Morimoto, J. Whitmire, S. Xiao, R. M. Anthony, H. Mirakami, R. A. Star, J. F. Urban Jr, and W. C. Gause Peripheral CD4 T Cells Rapidly Accumulate at the Host:Parasite Interface during an Inflammatory Th2 Memory Response J. Immunol., February 15, 2004; 172(4): 2424 - 2430. [Abstract] [Full Text] [PDF]
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A. Zhao, J. McDermott, J. F. Urban Jr, W. Gause, K. B. Madden, K. A. Yeung, S. C. Morris, F. D. Finkelman, and T. Shea-Donohue Dependence of IL-4, IL-13, and Nematode-Induced Alterations in Murine Small Intestinal Smooth Muscle Contractility on Stat6 and Enteric Nerves J. Immunol., July 15, 2003; 171(2): 948 - 954. [Abstract] [Full Text] [PDF]
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 J. R. McDermott, R. E. Bartram, P. A. Knight, H. R. P. Miller, D. R. Garrod, and R. K. Grencis Mast cells disrupt epithelial barrier function during enteric nematode infection PNAS, June 24, 2003; 100(13): 7761 - 7766. [Abstract] [Full Text] [PDF]
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L. Spencer, L. Shultz, and T. V. Rajan T Cells Are Required for Host Protection against Brugia malayi but Need Not Produce or Respond to Interleukin-4 Infect. Immun., June 1, 2003; 71(6): 3097 - 3106. [Abstract] [Full Text] [PDF]
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M. J. Ekkens, Z. Liu, Q. Liu, J. Whitmire, S. Xiao, A. Foster, J. Pesce, J. VanNoy, A. H. Sharpe, J. F. Urban, et al. The Role of OX40 Ligand Interactions in the Development of the Th2 Response to the Gastrointestinal Nematode Parasite Heligmosomoides polygyrus J. Immunol., January 1, 2003; 170(1): 384 - 393. [Abstract] [Full Text] [PDF]
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K. B. Madden, L. Whitman, C. Sullivan, W. C. Gause, J. F. Urban Jr., I. M. Katona, F. D. Finkelman, and T. Shea-Donohue Role of STAT6 and Mast Cells in IL-4- and IL-13-Induced Alterations in Murine Intestinal Epithelial Cell Function J. Immunol., October 15, 2002; 169(8): 4417 - 4422. [Abstract] [Full Text] [PDF]
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 S. d. Fleming, B. W. Starnes, J. G. Kiang, A. Stojadinovic, G. C. Tsokos, and T. Shea-Donohue Heat stress protection against mesenteric I/R-induced alterations in intestinal mucosa in rats J Appl Physiol, June 1, 2002; 92(6): 2600 - 2607. [Abstract] [Full Text] [PDF]
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L. R. Schopf, K. F. Hoffmann, A. W. Cheever, J. F. Urban Jr., and T. A. Wynn IL-10 Is Critical for Host Resistance and Survival During Gastrointestinal Helminth Infection J. Immunol., March 1, 2002; 168(5): 2383 - 2392. [Abstract] [Full Text] [PDF]
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J. F. Urban Jr., N. Noben-Trauth, L. Schopf, K. B. Madden, and F. D. Finkelman Cutting Edge: IL-4 Receptor Expression by Non-Bone Marrow-Derived Cells Is Required to Expel Gastrointestinal Nematode Parasites J. Immunol., December 1, 2001; 167(11): 6078 - 6081. [Abstract] [Full Text] [PDF]
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