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*
U.S. Department of Agriculture, Beltsville, MD, 20705;
Division of Immunology, University of Cincinnati College of Medicine, Cincinnati, OH 45267 and Cincinnati Veterans Administration Medical Center, Cincinnati, OH 45220;
Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
§
University of Manchester, Manchester, United Kingdom; and
¶
Genetics Institute, Cambridge, MA 02140
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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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-chain; and 3) the activation of the
transcription molecule, Stat6 (1, 2). The Stat6
requirement for N. brasiliensis expulsion is not related to
Stat6 effects on B cells, T cells, or mast cells because none of these
cell types is required for IL-4-induced worm expulsion (1, 3, 4). Furthermore, N. brasiliensis-induced type 2
cytokine production, IgG1 secretion, and eosinophil responses are all
normal or increased, and mast cell responses are greatly increased, in
Stat6-deficient mice (1). These observations, along with
demonstration of roles for IL-4 and/or IL-13 in protective immunity
against other gastrointestinal parasites, such as Trichuris
muris (5, 6) and Heligmosomoides polygyrus
(7), raised the possibility that Stat6 signaling by one or
both of these cytokines is a universal requirement for host protection
against gastrointestinal nematode parasites. Against this hypothesis was strong evidence that mast cells play a decisive role in host protection against at least three gastrointestinal nematode parasites: Trichinella spiralis, Strongyloides ratti, and Strongyloides venezuelensis (8, 9, 10, 11, 12, 13). Evidence that 1) expulsion of each of these parasites is severely impaired in mast cell-deficient mice; 2) expulsion of Strongyloides is impaired in mice deficient in the mast cell-stimulating cytokine, IL-3 (8); and 3) exogenous IL-3 stimulates expulsion of S. ratti and T. spiralis (10, 14) raised the possibility that IL-4 and IL-13 might have little role in protective immunity against these parasites, unless these cytokines were needed to promote the production of Abs that stimulate mast cell activation and degranulation. In fact, evidence that Stat6 signaling suppresses mast cell responses in mice infected with N. brasiliensis (1) raised the possibility that Stat6 deficiency might enhance protective immunity against T. spiralis and Strongyloides species.
To examine these possibilities, we studied the roles of IL-4, IL-13,
IL-4R -chain, and Stat6 in worm expulsion during a primary infection
of mice with one of these parasites, T. spiralis.
Surprisingly, the results of these studies demonstrated that IL-4,
IL-13, IL-4R, and Stat6 are all important for protective immunity
against this parasite. However, in contrast to results observed in mice
infected with N. brasiliensis, Stat6 signaling was found to
be important for the induction of type 2 cytokine production and
intestinal mastocytosis in T. spiralis-infected
mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female BALB/c mice and athymic nude male mice were purchased
from the Small Animals Division of the National Cancer Institute
(Frederick, MD). Mice heterozygous for a defective IFN-
gene
(15) and bred onto a BALB/c background were originally
obtained from Dr. Richard Locksley (San Francisco, CA). Mice homozygous
for the defective or wild-type IFN- gene were bred from these
heterozygotes at the Cincinnati Veterans Administration Medical Center
Animal Facility. Homozygous IL-4R-deficient (16) mice
on a BALB/c background were obtained from Dr. Nancy Noben-Trauth
(Rockville, MD). Homozygous IL-4-deficient mice on a C57BL/6 background
(17) were obtained from Manfred Kopf (Freiburg, Germany).
Stat6-deficient mice on a mixed 129/C57BL/6 background
(18) were obtained from Dr. James Ihle (Memphis, TN).
RAG2-deficient mice (19) on a C57BL/10 background were
obtained from Dr. Ronald Schwartz (Bethesda, MD). Genetic background
controls were bred or purchased for all mouse strains. Mice were age-,
sex-, and background strain-matched with controls in all
experiments.
Parasites
T. spiralis (Beltsville strain) was maintained by serial passage in female Sprague Dawley rats. First-stage larvae (L1)3 were recovered from infected muscle by pepsin-HCl (1% each) digestion of eviscerated, ground rat carcasses and were washed by settling through several changes of water. Mice were inoculated orally with 50 L1 suspended in 0.2% Bacto Agar (Difco, Detroit, MI) using an 18-gauge feeding tube. Adult worms were recovered from mice after the intestine was slit lengthwise, rinsed, and placed in HBSS for 4 h at 37°C and were counted with a dissecting microscope. Muscle larvae (L1) were recovered from infected muscle by pepsin-HCl (1% each) digestion of evicerated, ground rat or mouse carcasses and washed by settling through several changes of tap water. Larvae were counted from individual carcasses using a dissecting microscope.
Immunological reagents
Recombinant mouse IL-4 was a gift of the Schering-Plough
Research Institute (Kenilworth, NJ). An IL-13 antagonist, soluble
IL-13R2-Fc
(sIL-13R2-Fc) (1), and a control
human IgG Ab were gifts of Genetics Institute (Cambridge, MA). A
neutralizing rat IgG1 anti-mouse IL-4 mAb, 11B11 (20),
was purchased from Verax (Lebanon, NH). Hybridomas that secrete a
neutralizing rat IgG1 anti-mouse IFN- mAb (XMG-6)
(21) or a control rat IgG1 mAb (GL113) were obtained from
the DNAX Research Institute (Palo Alto, CA). Pairs of mAbs used for
measurement of in vivo production of IL-3, IL-4, or IFN- (see below)
were also obtained from the DNAX Research Institute, with the kind
assistance of Dr. Anne O’Garra and Dr. Robert Coffman. ACK-2, a
blocking anti-c-kit mAb, (12), produced by
Dr. S. I. Nishikawa, was obtained from Dr. Richard Grencis
(Manchester, U.K.). Some mAbs were produced as ascites in
pristane-primed athymic nude mice and purified by salt fractionation
and ion exchange chromatography (21). Some mAbs were
labeled with biotin-N-hydroxysuccinimide
(Calbiochem-Behring, La Jolla, CA). Polyclonal and mAbs used for
titering IgG1 and IgG2a anti-T. spiralis Ab levels in
infected mice have been described (1). T.
spiralis Ag used in the ELISA was prepared as previously described
(22). Excretory-secretory protein was collected by
culturing 5000 T. spiralis L1 per ml of DMEM supplemented
with 2 mM glutamine, 10 mM HEPES buffer, 50 U penicillin/ml, and 50
µg streptomycin/ml for 18–20 h at 37°C in an atmosphere that
contained 10% CO2. Culture supernatants were
harvested by filtration, dialyzed against PBS, and concentrated by
pressure filtration. An ELISA kit, purchased from Moredun Scientific
(Penicuik, Scotland), was used to quantitate serum levels of mouse mast
cell protease 1 (MMCP1).
Production and use of IL-4/anti-IL-4 mAb complexes (IL-4C)
Soluble complexes made by mixing IL-4 with the neutralizing anti-IL-4 mAb, 11B11, at a 2:1 molar ratio (1:6 weight ratio) have an in vivo half-life that is much longer than that of uncomplexed IL-4. These complexes slowly and spontaneously dissociate when administered to mice, releasing free, biologically active IL-4. This allows a single injection of IL-4C to sustain an IL-4 effect for 3–5 days (23). In experiments aimed at testing whether IL-4 can promote worm expulsion, mice were injected i.v. every 3 days with IL-4C that contained 5 µg of IL-4 and 25 µg of 11B11 (a dose previously shown to promote N. brasiliensis expulsion; Ref. 4).
Quantitation of in vivo cytokine production
The Cincinnati cytokine capture assay (CCCA) was used to monitor
in vivo production of IL-3, IL-4, and IFN-. This assay allows
cytokines to accumulate in serum by "capturing" them in vivo with
neutralizing IgG mAbs that inhibit their excretion, utilization, and
catabolism (1, 24). The IL-4 CCCA increases the ability to
detect IL-4 in serum by >1000-fold and is specific (no IL-4 response
is detected in IL-4-deficient mice). To capture secreted IL-4, mice
were injected i.v. with 10 µg of biotin-BVD4-1D11, a neutralizing
anti-IL-4 mAb (25). Mice were bled 2–4 h later, and
serum levels of IL-4-biotin-anti-IL-4 complexes were determined by
ELISA using microtiter plates coated with BVD6-24G2.3
(25). This mAb recognizes an IL-4 epitope that is distinct
from that recognized by BVD4-1D11. A CCCA for IFN- was performed
similarly by injecting mice with 50 µg of biotin-R46-A2
(26) and coating microtiter plate wells with AN18
(27); a CCCA for IL-3 was performed by injecting mice with
20 µg of biotin-MP2-8F8 (25) and coating microtiter
plate wells with MP2-43D11 (28).
Quantitation of mucosal mastocytosis
Tissue samples from an 8- to 10-cm mid-jejunal segment from individual mice were prepared by the Swiss role technique and fixed in Carnoy’s fixative. Sections were stained with Alcian blue and safranin O and examined microscopically at a magnification of x400 (29). Alcian blue-positive, safranin O-negative cells in the lamina propria and epithelium of villi and crypts were classified as mucosal mast cells (MMC). Numbers of MMC in 50 adjacent high-power fields were recorded.
Statistical analysis
Data were analyzed using the general linear method procedure with group means compared with the Duncan’s multiple range test for variables (BMDP Statistical Software, Los Angeles, CA).
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and requires either IL-4 or IL-13 stimulation of
IL-4R
Results of earlier studies differed about whether production of
type 1 or type 2 cytokines is associated with host protection against
T. spiralis (30, 31) and did not directly test
the in vivo effects of these cytokines on parasite expulsion. In
experiments that use recombinant mice to directly examine cytokine
effects on expulsion of T. spiralis, we find a clear
association between type 2 cytokine production and host protection.
IFN--deficient mice frequently expel T. spiralis more
rapidly than wild-type mice (Fig. 1
A) and, as a result, develop
fewer muscle larvae after a primary infection (Fig. 1B). In
contrast, mice that cannot respond to either IL-4 or IL-13, because
they lack a functional gene for IL-4R (a component of receptors for
both cytokines; Refs. 32, 33, 34, 35), fail to clear T.
spiralis adults from the gut (Fig. 1C) and develop
increased numbers of muscle larvae (Fig. 1D). Both
endogenously produced IL-4 and IL-13 stimulate IL-4R sufficiently to
expel T. spiralis adults: T. spiralis expulsion
is normal in IL-4-deficient mice and in wild-type mice treated with an
IL-13 antagonist (sIL-13R2-Fc), while IL-13
antagonist-treated IL-4-deficient mice develop a persistent infection
(Fig. 1E).
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The observations that 1) endogenously produced IL-4 stimulates
T. spiralis expulsion (Fig. 1
E) and 2) IL-4
treatment of mice deficient in B cells, T cells, and mast cells
stimulates expulsion of the gastrointestinal nematode parasite,
N. brasiliensis (3, 4), led us to evaluate the
effects of IL-4 treatment on expulsion of T. spiralis.
Increasing IL-4 levels by injecting wild-type mice with a long-acting
formulation of IL-4, IL-4C (23), frequently accelerated
expulsion of T. spiralis worms and decreased the
accumulation of T. spiralis muscle larvae (Fig. 2A). However, in contrast to
IL-4-induced expulsion of N. brasiliensis, IL-4C stimulation
of T. spiralis expulsion is mast cell-dependent and B cell-
and/or T cell-dependent mice (it has no effect in mast cell-deficient
(anti-c-kit mAb-treated) mice or in B and T
cell-deficient (RAG2 knockout) mice; Fig. 2B).
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C). Thus, even in the presence of IL-4, T cells
and/or B cells are required to induce mast cell degranulation in
T. spiralis-infected mice. Worm expulsion and mast cell, type 2 cytokine, and IgG1 responses are Stat6 dependent in T. spiralis-inoculated mice
Prior observations that T. spiralis expulsion is mast
cell dependent and that Stat6 suppresses intestinal mastocytosis and
mast cell degranulation in N. brasiliensis-infected mice
suggested that T. spiralis expulsion might be enhanced in
Stat6-deficient mice. Contrary to this expectation, Stat6-deficient
mice developed chronic infections with T. spiralis (Fig. 3A) and increased numbers of
muscle larvae following T spiralis inoculation (Fig. 3B). Because the failure of Stat6-deficient mice to expel
T. spiralis was surprising in view of the increased mast
cell responses in Stat6-deficient, N.
brasiliensis-inoculated mice (1) and the mast
cell-dependence of T. spiralis expulsion (11, 12), we compared mast cell responses in wild-type and
Stat6-deficient T. spiralis-infected mice. In contrast to
observations made in N. brasiliensis-infected mice,
intestinal MMC numbers and serum MMCP1 responses were greatly depressed
in T. spiralis-inoculated, Stat6-deficient mice (Fig. 4, A and B).
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production was increased
3-fold in T. spiralis-inoculated, Stat6-deficient, as
compared with wild-type mice (Fig. 4C). Consistent with
deviation toward a type 1 cytokine response in T.
spiralis-inoculated Stat6-deficient mice, serum levels of IgG1
anti-T. spiralis Ab were suppressed and IgG2a
anti-T. spiralis Ab increased in Stat6-deficient mice
(Fig. 4D).
Because IFN- can retard T. spiralis expulsion (Fig. 1A) and Stat6-deficient, T. spiralis-inoculated
mice develop an increased IFN- response, we examined whether
anti-IFN- mAb treatment would restore the ability of
Stat6-deficient mice to limit infection with T. spiralis, as
determined by accumulation of muscle larvae. Anti-IFN- mAb treatment
only slightly corrected the increased accumulation of T.
spiralis larvae in Stat6-deficient mice (Fig. 3B) and
had no effect, in this experiment, on the number of muscle larvae in
wild-type mice. Thus, increased production of IFN- may contribute
to, but is not fully responsible for, defective T. spiralis
expulsion in Stat6-deficient mice.
IL-4C treatment partially restores protective immunity against T. spiralis in Stat6-deficient mice
Treatment of Stat6-deficient mice with IL-4C might be expected to
restore the ability of T. spiralis-inoculated
Stat6-deficient mice to expel this parasite because 1) T.
spiralis expulsion is mast cell-dependent (11, 12);
2) mast cell responses are stimulated by IL-4 and suppressed by IFN-
(23, 27, 36); and 3) IL-4 production is suppressed in
Stat6-deficient mice. Indeed, treatment of Stat6-deficient mice with
IL-4C decreased adult worm number by a factor of 3 and muscle larva
number by a factor of 2, although treated mice still retained larger
numbers of adult worms and had more muscle larvae than wild-type mice
and IL-4C treatment had no effect, in this experiment, on the number of
muscle larvae in wild-type mice (Fig. 5A). The effects of IL-4C
treatment on worm expulsion in Stat6-deficient, T.
spiralis-inoculated mice were consistent with the ability of IL-4C
treatment to partially correct the decreased MMC number and serum MMCP1
responses in these mice (Fig. 5, B and C).
IL-4C-treated, T. spiralis-inoculated Stat6-deficient mice
took longer than similarly treated wild-type mice to develop the same
degree of intestinal mastocytosis (Fig. 5B). More
importantly, peak levels of mast cell degranulation, as monitored by
serum MMCP1, were considerably lower in IL-4C-treated, T.
spiralis-inoculated, Stat6-deficient mice than in similarly
treated wild-type mice (Fig. 5C). These observations are
opposite to those made in mice infected with N. brasiliensis
(1) and suggest that Stat6 signaling is required in
T. spiralis-inoculated mice to stimulate conditions that
induce mast cells to degranulate optimally.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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suppresses
T. spiralis expulsion, while production of IL-4 or IL-13 is
not only essential for spontaneous expulsion, but can probably be a
limiting factor in induction of expulsion, inasmuch as treatment with
exogenous IL-4 frequently accelerates expulsion. Spontaneous T.
spiralis expulsion also requires expression of IL-4R, a
constituent of receptors for both IL-4 and IL-13, and the
IL-4R-associated signaling molecule Stat6. All of these observations
are consistent with observations made in N.
brasiliensis-infected mice, with the single exception that IL-13
is more critical than IL-4 for expulsion of N. brasiliensis
(1, 2), while either cytokine is sufficient to induce
optimal expulsion of T. spiralis. An additional similarity
between protective immunity against N. brasiliensis and
T. spiralis is that both are B cell and Ig independent.
In contrast to these similarities, T. spiralis and N.
brasiliensis infections differ in that 1) IL-4-accelerated
expulsion of T. spiralis, but not expulsion of N.
brasiliensis, requires the participation of T cells and mast cells
(1, 4); 2) Stat6-deficient mice make normal cytokine
responses to primary infection with N. brasiliensis
(1), but decreased IL-4, decreased IL-3 and increased
IFN- responses to infection with T. spiralis; 3)
intestinal MMC responses and mast cell degranulation are considerably
increased in Stat6-deficient mice infected with N.
brasiliensis (1), but considerably decreased in
Stat6-deficient mice infected with T. spiralis; and 4)
treatment of Stat6-deficient mice with exogenous IL-4 enhances the
expulsion of T. spiralis, but not the expulsion of N.
brasiliensis (1).
These observations are compatible with the view that characteristics
that may be common to T. spiralis and N.
brasiliensis induce T cell production of cytokines that bind to
receptors that contain IL-4R and activate Stat6. This common step is
required for protective immunity against both parasites but promotes
host protection against T. spiralis and N.
brasiliensis through completely different mechanisms. Direct
effects of activated Stat6 on the gut, although still poorly
characterized, appear to be necessary and sufficient to expel N.
brasiliensis but are not sufficient to expel T.
spiralis. Instead, Stat6 signaling appears to promote T.
spiralis expulsion primarily through a less direct effect,
enhancement of IL-3 and IL-4 production and suppression of IFN-
production, which, in turn, enhance the intestinal mast cell response
required for T. spiralis expulsion. Thus, although Stat6
signaling has a direct inhibitory effect on IL-4-induction of
intestinal mastocytosis (1), this negative effect on
mastocytosis is outweighed in T. spiralis-infected mice by
Stat6 promotion of type 2 cytokine production and inhibition of type 1
cytokine production. In contrast, in mice infected with N.
brasiliensis, in which the type 2 cytokine response is Stat6
independent, the inhibitory effect of Stat6 signaling on
intestinal mastocytosis and mast cell degranulation predominates
(1).
This explanation raises the issue of why type 2 cytokine responses are
Stat6 dependent in T. spiralis-infected mice but Stat6
independent in N. brasiliensis-infected mice. It is
noteworthy that N. brasiliensis stimulates an almost pure
type 2 cytokine response while T. spiralis induces
production of considerable IFN-, in addition to IL-4. Stat6
signaling may be required more during a primary response to allow type
2 cytokine responses to progress in the presence of cytokines, such as
IL-12, IFN-ß, or IFN-, that can inhibit type 2 responses
(37, 38, 39) than to promote the initial production of type 2
cytokines by naive T cells. If so, the mixed nature of the cytokine
response to T. spiralis might make its type 2 cytokine
component Stat6 dependent. Although plausible, this explanation raises
the additional question of why T. spiralis induces a mixed
cytokine response while N. brasiliensis induces an almost
pure type 2 response.
In this regard, it has been observed that gastrointestinal nematodes
such as T. spiralis and Trichuris muris, which
live within cells, induce considerably more IFN- production than
gastrointestinal nematodes that have an entirely extracellular
existence, such as N. brasiliensis, H. polygyrus,
and S. venezuelensis (3). Perhaps the presence
of parasites within host cells evolved as a trigger of IFN-
production because IFN- is required for host defense against many
intracellular parasites (40, 41, 42, 43, 44, 45, 46, 47, 48, 49). Alternately, stimuli
associated with N. brasiliensis, but not T.
spiralis, may inhibit production of IFN-, perhaps by
suppressing the production of IL-12 or IFN-ß by dendritic cells
and macrophages. Experiments that examine the Stat6 dependence of type
2 cytokine responses, intestinal mastocytosis, and T.
spiralis expulsion in mice infected simultaneously with T.
spiralis and N. brasiliensis may allow differentiation
of these two possibilities by determining whether the T.
spiralis-associated Stat6 dependence or the N.
brasiliensis-associated Stat6 independence dominates.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Fred D. Finkelman, Department of Internal Medicine, Research Service (151), Cincinnati Veterans Administration Medical Center, 3200 Vine Street, Cincinnati, OH 45220. E-mail address:
3 Abbreviations used in this paper: L1, first-stage larvae; CCCA, Cincinnati cytokine capture assay; MMCP1, mouse mast cell protease 1; MMC, mucosal mast cells; sIL-13R2-Fc, soluble IL-13R2-Fc; IL-4C, IL-4/anti-IL-4 mAb complex.
Received for publication October 14, 1999. Accepted for publication December 6, 1999.
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J. R. McDermott, N. E. Humphreys, S. P. Forman, D. D. Donaldson, and R. K. Grencis Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection J. Immunol., September 1, 2005; 175(5): 3207 - 3213. [Abstract] [Full Text] [PDF]
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 K. Bian, M. Zhong, Y. Harari, M. Lai, N. Weisbrodt, and F. Murad From the Cover: Helminth regulation of host IL-4R{alpha}/Stat6 signaling: Mechanism underlying NOS-2 inhibition by Trichinella spiralis PNAS, March 15, 2005; 102(11): 3936 - 3941. [Abstract] [Full Text] [PDF]
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H. D. Dawson, E. Beshah, S. Nishi, G. Solano-Aguilar, M. Morimoto, A. Zhao, K. B. Madden, T. K. Ledbetter, J. P. Dubey, T. Shea-Donohue, et al. Localized Multigene Expression Patterns Support an Evolving Th1/Th2-Like Paradigm in Response to Infections with Toxoplasma gondii and Ascaris suum Infect. Immun., February 1, 2005; 73(2): 1116 - 1128. [Abstract] [Full Text] [PDF]
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P. A. Knight, A. D. Pemberton, K. A. Robertson, D. J. Roy, S. H. Wright, and H. R. P. Miller Expression Profiling Reveals Novel Innate and Inflammatory Responses in the Jejunal Epithelial Compartment during Infection with Trichinella spiralis Infect. Immun., October 1, 2004; 72(10): 6076 - 6086. [Abstract] [Full Text] [PDF]
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M. Rodriguez-Sosa, R. Saavedra, E. P. Tenorio, L. E. Rosas, A. R. Satoskar, and L. I. Terrazas A STAT4-Dependent Th1 Response Is Required for Resistance to the Helminth Parasite Taenia crassiceps Infect. Immun., August 1, 2004; 72(8): 4552 - 4560. [Abstract] [Full Text] [PDF]
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K. B. Madden, K. A. Yeung, A. Zhao, W. C. Gause, F. D. Finkelman, I. M. Katona, J. F. Urban Jr., and T. Shea-Donohue Enteric Nematodes Induce Stereotypic STAT6-Dependent Alterations in Intestinal Epithelial Cell Function J. Immunol., May 1, 2004; 172(9): 5616 - 5621. [Abstract] [Full Text] [PDF]
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M. F. Gurish, P. J. Bryce, H. Tao, A. B. Kisselgof, E. M. Thornton, H. R. Miller, D. S. Friend, and H. C. Oettgen IgE Enhances Parasite Clearance and Regulates Mast Cell Responses in Mice Infected with Trichinella spiralis J. Immunol., January 15, 2004; 172(2): 1139 - 1145. [Abstract] [Full Text] [PDF]
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H. Helmby and R. K. Grencis IFN-{gamma}-Independent Effects of IL-12 During Intestinal Nematode Infection J. Immunol., October 1, 2003; 171(7): 3691 - 3696. [Abstract] [Full Text] [PDF]
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S. K. Bliss, A. Alcaraz, and J. A. Appleton IL-10 Prevents Liver Necrosis During Murine Infection with Trichinella spiralis J. Immunol., September 15, 2003; 171(6): 3142 - 3147. [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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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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R. T. Strait, S. C. Morris, K. Smiley, J. F. Urban Jr., and F. D. Finkelman IL-4 Exacerbates Anaphylaxis J. Immunol., April 1, 2003; 170(7): 3835 - 3842. [Abstract] [Full Text] [PDF]
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H.-C. Chang, S. Zhang, and M. H. Kaplan Neonatal Tolerance in the Absence of Stat4- and Stat6- Dependent Th Cell Differentiation J. Immunol., October 15, 2002; 169(8): 4124 - 4128. [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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H. Helmby and R. K. Grencis IL-18 Regulates Intestinal Mastocytosis and Th2 Cytokine Production Independently of IFN-{gamma} During Trichinella spiralis Infection J. Immunol., September 1, 2002; 169(5): 2553 - 2560. [Abstract] [Full Text] [PDF]
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K. Suzuki, H. Nakajima, S.-i. Kagami, A. Suto, K. Ikeda, K. Hirose, T. Hiwasa, K. Takeda, Y. Saito, S. Akira, et al. Proteolytic Processing of Stat6 Signaling in Mast Cells as a Negative Regulatory Mechanism J. Exp. Med., July 1, 2002; 196(1): 27 - 38. [Abstract] [Full Text] [PDF]
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M. F. Gurish, A. Humbles, H. Tao, S. Finkelstein, J. A. Boyce, C. Gerard, D. S. Friend, and K. F. Austen CCR3 Is Required for Tissue Eosinophilia and Larval Cytotoxicity After Infection with Trichinella spiralis J. Immunol., June 1, 2002; 168(11): 5730 - 5736. [Abstract] [Full Text] [PDF]
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M. Rodriguez-Sosa, J. R. David, R. Bojalil, A. R. Satoskar, and L. I. Terrazas Cutting Edge: Susceptibility to the Larval Stage of the Helminth Parasite Taenia crassiceps Is Mediated by Th2 Response Induced Via STAT6 Signaling J. Immunol., April 1, 2002; 168(7): 3135 - 3139. [Abstract] [Full Text] [PDF]
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A. S. MacDonald, M. I. Araujo, and E. J. Pearce Immunology of Parasitic Helminth Infections Infect. Immun., February 1, 2002; 70(2): 427 - 433. [Full Text] [PDF]
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L. Spencer, L. Shultz, and T. V. Rajan Interleukin-4 Receptor-Stat6 Signaling in Murine Infections with a Tissue-Dwelling Nematode Parasite Infect. Immun., December 1, 2001; 69(12): 7743 - 7752. [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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M. F. Gurish, H. Tao, J. P. Abonia, A. Arya, D. S. Friend, C. M. Parker, and K. F. Austen Intestinal Mast Cell Progenitors Require CD49d{beta}7 ({alpha}4{beta}7 Integrin) for Tissue-specific Homing J. Exp. Med., October 29, 2001; 194(9): 1243 - 1252. [Abstract] [Full Text] [PDF]
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M. F. Gurish and K. F. Austen The Diverse Roles of Mast Cells J. Exp. Med., July 2, 2001; 194(1): f1 - f6. [Full Text] [PDF]
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W. I. Khan, B. A. Vallance, P. A. Blennerhassett, Y. Deng, E. F. Verdu, K. I. Matthaei, and S. M. Collins Critical Role for Signal Transducer and Activator of Transcription Factor 6 in Mediating Intestinal Muscle Hypercontractility and Worm Expulsion in Trichinella spiralis-Infected Mice Infect. Immun., February 1, 2001; 69(2): 838 - 844. [Abstract] [Full Text] [PDF]
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H. Schjerven, P. Brandtzaeg, and F.-E. Johansen Mechanism of IL-4-Mediated Up-Regulation of the Polymeric Ig Receptor: Role of STAT6 in Cell Type-Specific Delayed Transcriptional Response J. Immunol., October 1, 2000; 165(7): 3898 - 3906. [Abstract] [Full Text] [PDF]
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