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-Deficient Mice in Chronic Leishmaniasis Reveal a Protective Role for IL-13 Receptor Signaling1
*
Max-Planck-Institute for Immunobiology, Freiburg, Germany;
Novartis Pharma Ltd., Basel, Switzerland;
Department of Pathology, University Freiburg, Freiburg, Germany;
§
Institute for Clinical Microbiology and Immunology, University Erlangen, Erlangen, Germany; and
¶
Department of Immunology, University of Cape Town, Cape Town, South Africa
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain-deficient (IL-4R-/-) mice
were generated by homologous and site-specific recombination, using the
Cre/loxP system in BALB/c-derived embryonic stem cells. In vitro
analysis of cells from these mice revealed impaired IL-4- and
IL-13-mediated functions, demonstrating that the IL-4R-chain is an
essential component of both the IL-4 and the IL-13 receptor. Whereas
Leishmania major-infected BALB/c mice developed fatal
progressive disease with type 2 Ab responses within 3 mo, both
IL-4R-/- and IL-4-/- BALB/c mice
contained infection with reduced footpad swelling, parasite load,
moderate histopathology, and type 1 Ab responses during this time
period. Conclusively, these results demonstrate an IL-4-dependent
mechanism of susceptibility in BALB/c mice. Nevertheless, in contrast
to mutant mice, infected C57BL/6 mice healed completely within 3 mo,
indicating that additional factors are necessary for subsequent healing
and elimination of the pathogen. During the further course of
infection, IL-4R-/- mice developed progressive disease
with massive footpad swelling. Lesions became ulcerative and necrotic
with subsequent destruction of connective tissue and bones, as well as
dissemination into organs and consequent mortality within the monitored
6 mo of chronic infection. In striking contrast, IL-4-/-
mice maintained control of infection on a moderate level, but were
unable to clear the pathogen. The distinct phenotypes of the BALB/c
embryonic stem cell-derived IL-4-/- and
IL-4R-/- mouse strains identify previously unsuspected
mechanisms for maintaining host immunity to chronic infection with
L. major, mediated by a functional IL-13
receptor. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain, which has low but IL-13-specific binding activity,
it is now suggested that the IL-4R-chain associates either with the
c chain to form an IL-4 receptor (IL-4R type I), or with the
IL-13-binding chain to form an IL-13 receptor (IL-4R type II) (7).
Experimental murine leishmaniasis is a paradigm example of the
relationship between the genetic factors that control Th cell
differentiation and the outcome of the disease. Healer strains, such as
C57BL/6, develop predominant Th1 responses with high IFN-, low IL-4
production, and protective cellular immune responses, whereas nonhealer
strains, such as BALB/c, develop predominant Th2 responses with high
IL-4 and low IFN- production, resulting in exacerbation of the
disease (8, 9). IL-4 promotes Th2 cell differentiation in vitro, and
depletion of IL-4 in vivo by mAb converts nonhealers to healers (10, 11). However, conflicting results were observed in mice deficient for
IL-4 (12, 13).
To establish an independent BALB/c mouse model in the absence of
IL-4-mediated functions, we introduced a null mutation into the
IL-4R gene in BALB/c-derived embryonic stem
(ES)3 cells and generated
IL-4R BALB/c-deficient mice. Mutant mice were impaired in IL-4- and
IL-13-mediated functions, formally proving that the IL-4R-chain is a
crucial component of both the IL-4 and the IL-13 receptors. To dissect
the role of IL-4 and IL-13 in leishmaniasis, we infected IL-4R
BALB/c-deficient mice with Leishmania major and compared the
outcome with parallel-infected IL-4 BALB/c-deficient mice.
Interestingly, we observed striking differences between the mutant
mouse strains that were evident during late (chronic) phase of
leishmaniasis. The conclusions and implications of these results are
discussed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The gene-targeting vector was constructed from a genomic clone
containing an EcoRI fragment of the IL-4R derived from
BALB/c DNA (14). A selection cassette comprising a resistance gene for
neomycin and the HSV thymidine kinase flanked by loxP sites (15) was
introduced into a MscI site 5' to exon 7. A single loxP site
was cloned into a SphI site 5' to exon 10. The linear
targeting construct was electroporated into BALB/c ES cells (16) using
a Bio-Rad (Richmond, CA) gene pulser set at 500 µF/500 V. After 9
days of selection with 400 µg/ml G418, resistant clones were isolated
into 48-well plates and expanded in culture. Screening for correctly
targeted clones was conducted by PCR and Southern blot analysis using
standard procedures. Clones with a correct integration of the targeting
vector were electroporated with a plasmid expressing the
cre-recombinase (15). After 9 days of selection with 2 µM
gancyclovir, counterselected clones were isolated into 48-well
plates and expanded in culture as recently described (17). Screening
for the different forms of deletions in the targeted locus were
performed by PCR and Southern blot analysis. Clones with a deletion of
exons 7–9 were injected into C57BL/6 blastocysts. Chimeric male
offspring were mated to BALB/c females, and progeny with the mutated
allele were intercrossed to obtain mice homozygous for the gene
disruption. Mice were tested routinely for their genotype by PCR of
tissue biopsies. For functional experiments, littermates of both sexes
from heterozygous breedings were used. All mice were housed in
filter-top cages and maintained in barrier facilities at the
Max-Planck-Institute for Immunobiology (Freiburg, Germany).
FACS analysis and cell separation
Cells (1–5 x 105) were labeled and washed in
PBS, 3% FCS, and 0.1% NaN3. Between each step of
staining, cells were washed two times extensively. Unlabeled rat
anti-IL-4R (R&D Systems, Minneapolis, MN) was used in
combination with PE- or FITC-coupled goat-anti-rat
F(ab')2 (Southern Biotechnology Associates, Birmingham,
AL). Nonviable cells were excluded by propidium iodide (Sigma, St.
Louis, MO) staining. To avoid nonspecific binding, cells were
preincubated for 20 min with a mixture of mouse and rat sera
diluted 1/40 and unlabeled anti-CD32 (2.4G2) Ab. The latter two
were omitted when anti-rat Abs were used for staining. Cells
were analyzed on a FACScan (Becton Dickinson, Heidelberg, Germany).
Proliferation assays
Lymph node cells were placed in round-bottom microwell culture plates (5 x 104/well) with serial dilutions of IL-2 (PharMingen, San Diego, CA), IL-4 (PharMingen), and IL-13 (R&D Systems) in IMDM (Life Technologies, Paisley, Scotland) supplemented with 10% (v/v) heat-inactivated FCS, 100 U/ml penicillin, 100 mg/ml streptomycin, 1 mM sodium pyruvate, nonessential amino acids, 2 mM L-glutamine, 10 mM HEPES, and 10-5 M 2-ME (complete IMDM). Following culture for 48 h at 37°C, 5% CO2, cells were pulsed with 1 mCi [3H]thymidine for 18 h. Values represent the mean ± SEM cpm from triplicate cultures.
ELISA
A sandwich ELISA using two different mAbs was used for
quantitative determination of soluble IL-4R (sIL-4R) in the sera
of mice. Recombinant murine sIL-4R at known concentrations was used
as a standard as described (18). The detection limit for soluble murine
IL-4R was 30 pg/ml. Experiments revealed that mean recovery rates
for sIL-4R were >95%, and excessive amounts of murine IL-4 did not
influence the sIL-4R detection.
Levels of L. major-specific serum Ab isotypes were measured by coating plates with freeze and thaw preparations of L. major promastigotes and detected by anti-mouse isotype-specific polyclonal Abs (Southern Biotechnology Associates). Serum samples and appropriate Ig standards (Southern Biotechnology Associates) were used in 3-fold serial dilutions. Detection limits were 5 ng/ml for IgG1 and IgG2b and 0.1ng/ml for IgG2a and IgG3. Total IgE was determined with mAbs 84.1C for coating and alkaline phosphatase labeled EM95.3 for detection. The detection limit for IgE was 10 ng/ml.
Macrophage NO production and killing of L. major
Induction of NO production was performed as described (19).
Briefly, mice were injected i.p. with 0.5 ml 10% proteose peptone, and
elicited peritoneal macrophages were harvested after 72 h by
peritoneal lavage with complete IMDM. Peritoneal exudate cells were
allowed to adhere to 24-well tissue culture plates (1 x
106/ml/well) for 2 h at 37°C and washed twice to
remove nonadherent cells. Adherent cells were incubated with medium
alone, IL-4 (500 U/ml; PharMingen), or IL-13 (100 ng/ml; R&D Systems)
for 16 h. Cells were subsequently stimulated with LPS (10 ng/ml;
Sigma) and IFN- (100 U/ml; PharMingen). After 48 h, levels of
NO in supernatants were measured by Griess reaction (20). The detection
limit for NO in supernatants was 1 µM. Values represent the mean
± SEM from triplicate cultures.
The ability of macrophages to kill L. major was performed as
follows. Before infection with L. major promastigotes
(parasite-cell ratio, 10:1; 4 h), macrophage cultures were either
incubated for 4 h in culture medium with and without IFN-,
IL-4, IL-7, or IL-13. Thereafter, nonphagocytosed parasites were washed
off and the cultures incubated an additional 72–96 h. Live
intracellular amastigotes were assessed after staining with ethidium
bromide (50 µg/ml) and acridine orange (5 µg/ml) in PBS by
fluorescence photography, as described (21).
Infection with L. major
L. major LV 39 (MRHO/Sv/59/P-strain) (22) was maintained by continuous passage in mice. Parasites were isolated from skin lesions of infected animals and grown in complete IMDM (Life Technologies) on rabbit blood agar. Anesthetized mice were infected s.c. into one hind footpad with 2 x 106 stationary phase metacyclic L. major promastigotes (23) in a final volume of 50 µl HBSS. Stationary phase cultures were also used to prepare frozen and thawed (F/T) Ag of L. major promastigotes (24). Briefly, the cultures were washed three times with PBS and diluted in PBS to a final concentration of 1 x 107/ml. Parasites were rapidly frozen to -80°C and thawed at 37°C four times. F/T preparations were stored at -80°C until use.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-deficient mice
IL-4R-deficient mice were generated using gene targeting with
an isogenic target vector (gene derived from BALB/c) and Cre-mediated
site-specific recombination in BALB/c ES cells. Using this two-step
strategy enabled us to disrupt the gene by deleting exons 7, 8, and 9
(coding for the transmembrane, the soluble, and the extracellular
membrane proximal regions of the receptor (14, 25), respectively), as
well as deleting the selection cassette (Fig. 1
A) and thus avoiding any
possible interference of the selection cassette with normal gene
expression. Correctly targeted clones were identified by PCR and
Southern blotting (data not shown) and subsequently used to generate
chimeric mice. These mice were bred with BALB/c mice that transmitted
the disrupted allele through the germline to offspring. Interbreeding
of heterozygous mice (IL-4R+/-) produced offspring with
a homozygous disruption of the IL-4R gene
(IL-4R-/-; Fig. 1B) on a pure BALB/c
background. The mice were viable with no overt phenotypic abnormalities
and normal lymphocyte numbers. The B and T cell distribution in
lymphatic organs determined by FACS analysis (data not shown) was
normal. As expected from the disruption of the gene, membrane-bound
(Fig. 1C) or soluble (<30 pg/ml in sera of
IL-4R-/- and 1980 + 120pg/ml in
IL-4R+/+ mice) IL-4R was absent in mutant mice.
|
-deficient mice
IL-4 is known to induce proliferation of B lymphocytes (26). To
determine whether the absence of the IL4R-chain influences this
activity, lymph node cells from IL-4R-/- mice and
control mice were stimulated for 48 h in the presence of
increasing doses of IL-4 and subsequently assayed for DNA synthesis by
[3H]thymidine incorporation. As shown in Fig. 2A, the proliferative response
of lymphocytes from IL-4R-/- mice to IL-4 was
completely abrogated. In contrast, lymphocytes from control mice showed
a dose-dependent proliferative response to IL-4 stimulation. When
stimulated with IL-2, proliferation of IL-4R-/-
lymphoctes were normal. Since the IL-2 receptor uses the same c
chain as the IL-4 receptor (27), this result shows that
IL-4R-/- cells are responsive to proliferation if
stimulated independently of the IL-4R type I. No IL-13-mediated
proliferation could be induced in wild-type or
IL-4R-/- murine lymphocytes (Fig. 2A), in
agreement with evidences that human B cells, but not mouse B cells, are
responsive to IL-13 (3, 28). The production of NO by macrophages in
response to LPS and IFN- can be inhibited by IL-4 (3) or IL-13
(4). Therefore, we investigated whether these cytokines could
inhibit NO production by IL-4R-/- macrophages.
Peritoneal macrophages from control and mutant mice were preincubated
with IL-4 or IL-13 and subsequently stimulated with a combination of
IFN- and LPS for NO production. In the absence of IL-4 or IL-13,
macrophages produced comparable amounts of NO. In contrast to wild-type
macrophages, neither IL-4 nor IL-13 inhibited NO production by
IL-4R-/- macrophages (Fig. 2B). In a second
experiment, we tested the ability of IL-4 and IL-13 to modulate
IFN-- or IL-7-stimulated elimination of L. major (21).
Addition of IL-4 to IFN--stimulated macrophages increases
elimination of L. major-infected macrophages, resulting in a
reduction of infected macrophages, whereas addition of IL-13 to
IL-7-stimulated macrophages reduces elimination, resulting in an
increase of infected wild-type macrophages (Fig. 2C).
Addition of IL-4 or IL-13 with the respective stimulant had no
modifying effect on the elimination of IL-4R-/-
macrophages (Fig. 2C). In summary, these results show that
IL-4R-deficient mice are impaired in IL-4- and IL-13-mediated
functions, demonstrating that the IL-4R is an essential component
for signaling of both the IL-4 and the IL-13 receptor complex.
|
BALB/c, C57BL/6, IL-4R-/-, and
IL-4-/- mice were infected with 2 x
106 L. major LV 39 (MRHO/Sv/59/P-strain)
metacyclic promastigotes into one hind footpad, and the swelling of the
footpad was monitored. The nonhealer BALB/c strain developed massive
footpad swelling accompanied by ulceration and necrosis within the
first 80 days after infection (Fig. 3A). In contrast, infected
IL-4R-/- BALB/c mice developed moderate swelling
during the first month and stabilized footpad swelling at a moderate
level during the first 3 mo (Fig. 3A). In accordance with
the containment of infection, the parasite load of the draining
popliteal lymph node (PLN) of IL-4R-/- BALB/c mice was
significantly reduced compared with BALB/c mice, 49 days after
infection (Fig. 3B). A similar phenotype was observed in
infected IL-4-/- BALB/c mice (16) (Fig. 3), confirming
our previous finding of increased resistance in infected IL-4
BALB/c-deficient mice (13). Footpad swelling in infected C57BL/6 mice
was already declining during the 30 days and disappeared completely
within 3 mo. In accordance, parasite burden at 49 days postinfection
was strikingly reduced in C57BL/6 mice compared with the mutant mouse
strains (Fig. 3, A and B). These results
demonstrate that, in the absence of IL-4-mediated functions,
BALB/c mice have an increased resistance to acute Leishmania
infection but are not able to heal completely.
|
-/- mice
To determine the type of Ab response of the infected mouse
strains, serum was obtained at day 49 postinfection, and the
Leishmania-Ag-specific IgG titers and total IgE titers were
measured by ELISA. As known, L. major-infected BALB/c mice
develop a dominant type 2 Ab response with increased levels of
Ag-specific IgG1 and IgE serum Abs and reduced IgG2a, IgG2b, and IgG3
levels (Fig. 4), due to the increased
secretion of IL-4 by differentiated Th2 cells. As expected from the
impaired IL-4-mediated effector functions, IgG1 and IgE Ab levels were
strikingly reduced in infected IL-4R-/- or
IL-4-/- mice. Conversely, type 1 serum Ag-specific IgG2
and IgG3 Ab levels were strikingly increased with no significant
differences between the mutant mouse strains (Fig. 4). C57BL/6 mice
showed very low Ag-specific Ab levels for all isotypes at this time
point of infection. These results demonstrate that
IL-4R-/- mice have an impaired type 2 Ab response with
a shift to a type 1 Ab response during L. major infection.
|
-/- mice, but not IL-4-/- mice,
develop progressive disease during chronic infection
Since both mutant strains controlled acute L. major
infection on a moderate level, we further followed infection to
determine whether the additional absence of IL-13-mediated functions in
IL-4R-/- may influence chronic infection. The footpad
swelling of infected C57BL/6 mice diminished completely during the
following 3 mo (Fig. 5A), and
parasites in the PLN were below detection limit at day 163
postinfection (Fig. 5B; <25 parasites/lymph node). Also,
all IL-4-/- mice survived the course of infection with
moderate swelling of the footpad but containment of rather high
parasite load in the draining PLN (Fig. 5B). The
degree of swelling was constant in size between days 60 and 163 of the
monitoring period (Fig. 5A), and this "controlling"
phenotype was reflected by histological analysis of the infected foot.
We observed moderate inflammation and rather mild bone
destruction with parasites concealing within macrophages only (Fig. 5C). Further on, dissemination of pathogens into other
organs seemed to be under control since only small inflammatory foci
(see arrow), but no detectable L. major, was found in the
liver (Fig. 5C) of infected IL-4-/- mice. In
striking contrast, IL-4R-/- mice showed a continuous
increase of swelling of the infected footpad, and mortality was
observed during the course of infection (Fig. 5A; see
cross). Surviving IL-4R-/- mice developed typical
necrosis and ulceration (Fig. 5A, see asterisks), similar to
BALB/c mice 3 mo earlier. At day 163 postinfection, the experiment had
to be terminated due to the progressive disease of the remaining
infected IL-4R-/- mice. Histological analysis of these
mice revealed a dramatic pathology with nearly complete destruction of
the bone and connective tissue (Fig. 5C) and inflammatory
infiltrates with cells undergoing lysis and high parasite load with
L. major (Fig. 5C). Moreover, dissemination of
pathogens into other organs was observed in liver sections of Fig. 5C. The organ showed a high degree of tissue destruction and
with central necrosis (N) and a massive inflammation (arrows).
Leishmania were present in the liver, within Kupffer’s cell
as well as extracellularly (see inset). PLN of these
IL-4R-/- mice showed similar high parasite loads, as
seen in IL-4-/- mice at the termination of the experiment
at day 163 postinfection (Fig. 5B). Because of the
dissemination into other organs, the total parasite burden in
IL-4R-/- mice is very likely to be much higher than in
IL-4-/- mice. In summary, the striking difference in
disease progression, histopathology, mortality, and dissemination of
L. major between infected IL-4R and IL-4-deficient mice
identify previously unsuspected mechanisms for maintaining host
immunity to chronic infection with L. major, mediated by an
IL-13 receptor, containing the -chain of the IL-4 receptor.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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gene
introduced by gene targeting techniques. Our analysis of
IL-4R-/- mice revealed impaired IL-4- and
IL-13-mediated functions. This is, to our knowledge, the first direct
demonstration that the IL-4R-chain is a crucial component of both
the IL-4 and the IL-13 receptor complexes.
Wild-type BALB/c mice developed progressive disease during acute
L. major infection, accompanied by a dominant type 2 Ab
response. In contrast, IL-4R BALB/c-deficient mice were able to
contain infection during the first 80 days, accompanied by a type 1 Ab
response. The different outcome suggests that the impairment of
IL-4R signaling is responsible for the increased resistance during
acute infection in BALB/c mice. IL-4 BALB/c-deficient mice showed a
similar resistant phenotype during acute infection, suggesting that the
absence of IL-4-mediated functions led to the observed increased
resistance in IL-4R BALB/c-deficient mice. Consistent with an
IL-4-dependent mechanism of susceptibility in BALB/c mice, IL-4
neutralization of Leishmania-infected BALB/c mice also
resulted in increased resistance (10, 11, 12, 29). Moreover, our results in
IL-4 and IL-4R-deficient mice support our previous studies in IL-4
BALB/c-deficient mice, demonstrating increased resistance after
infection with a different L. major strain (13). However,
the enhanced swelling and parasite burden in IL-4R and
IL-4-deficient mice compared with resistant C57BL/6 mice during acute
infection further suggests that additional, IL-4-independent mechanisms
may be involved in the susceptible phenotype of BALB/c mice. In a
previous study from others, IL-4-/- BALB/c mice remained
susceptible during acute L. major infection (12), and
authors believed that the susceptibility in BALB/c mice was independent
of IL-4. The contrary studies are not easy to explain since, in the
present study, we used the same IL-4-deficient mouse (16) and parasite
(L. major LV 39 MRHO/Sv/59/P) strain with comparable
infection doses. However, the increased resistance during acute
infection in the independent IL-4R-deficient BALB/c moue model
strongly supports our conclusions of an IL-4-dependent and -independent
mechanism of susceptibility in BALB/c mice. The published discrepancy
in IL-4-deficient mice, however, may indicate that subtle differences
between the laboratory strains may be able to influence these two
mechanisms of acute L. major infection.
Despite the observed increased resistance during the acute phase of
infection, IL-4R-/- mice were not able to contain the
infection and subsequently developed progressive disease with fatal
outcome during the late (chronic) phase of infection. In striking
contrast, IL-4 BALB/c-deficient mice contained infection during the
observed time period of nearly 6 mo. Genetic differences other than the
introduced mutation can be excluded since both gene-deficient mouse
strains were derived from the same BALB/c ES cell line. This late
development of progressive disease in L. major-infected
IL-4R-/-, but not IL-4-/-, mice shows
that nonredundant pathways for maintaining immune control in chronic
infections are mediated by the IL-4R. At the termination of the
infection study, the numbers of parasites in the draining lymph nodes
were similar in both mutant strains, but IL-4R-/- mice
showed a striking dissemination of parasites into other organs. This
difference may indicate that IL-13-mediated functions are involved in
controlling dissemination of the parasite in chronic leishmaniasis.
Recent studies in murine nematode infections have identified a crucial
role for IL-13 signaling through the IL-4R in maintaining worm
immunity (30, 31, 32). It is possible that IL-13 present in
IL-4-/- mice is involved in protection against
progressive inflammation, due to its capacity to abrogate macrophage
activation and resulting immunopathology. On the other hand, it has
been shown that IL-13 is a subtle immune regulator with
antiinflammatory, but also immunostimulatory, properties on in
vitro-stimulated monocytes, depending on the time point of
administration (33). In agreement with an immunostimulatory role of
IL-13, in vivo administration of recombinant IL-13 enhanced
antilisterial resistance accompanied by increased cytokine production
(34). IL-13 may thus play an essentially immunostimulatory role in the
case of an ongoing infection, like in the late phase of a
Leishmania infection. Alternatively, some receptors or
signaling components of the IL-4R may be sequestered into
alternative signal cascades, with ultimately fatal effects. Therefore,
it will be of great importance to identify the mediators of tissue
injury and dissemination in IL-4R-/- mice. Such
mediators might have broader roles in the chronic inflammatory status
that might be amenable to therapeutic manipulation.
|
Acknowledgments |
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gene and
the loxP/cre plasmids. |
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Frank Brombacher, University of Cape Town, Immunology Department, H47 Observatory, 7925 Cape Town, South Africa. E-mail address:
3 Abbreviations used in this paper: ES, embryonic stem; s, soluble; PLN, popliteal lymph node.
Received for publication December 21, 1998. Accepted for publication March 22, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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or interleukin 4 during the resolution or progression of murine leishmaniasis: evidence for expansion of distinct helper T cell subsets. J. Exp. Med. 169:59.-independent mechanism. J. Exp. Med. 171:115. chain: a functional component of the interleukin-4 receptor. Science 262:1880. and IL-4 deficient mice reveal a novel role of IL-13 in the regulation of T helper 2 cells and protection to nematode infection. Curr. Biol. 8:669.[Medline]
, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity 8:255.[Medline]
. Eur. Cytokine Network 8:189.[Medline]
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 A. Schwegmann, R. Guler, A. J. Cutler, B. Arendse, W. G. C. Horsnell, A. Flemming, A. H. Kottmann, G. Ryan, W. Hide, M. Leitges, et al. Protein kinase C {delta} is essential for optimal macrophage-mediated phagosomal containment of Listeria monocytogenes PNAS, October 9, 2007; 104(41): 16251 - 16256. [Abstract] [Full Text] [PDF]
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P. Loke, I. Gallagher, M. G. Nair, X. Zang, F. Brombacher, M. Mohrs, J. P. Allison, and J. E. Allen Alternative Activation Is an Innate Response to Injury That Requires CD4+ T Cells to be Sustained during Chronic Infection J. Immunol., September 15, 2007; 179(6): 3926 - 3936. [Abstract] [Full Text] [PDF]
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 P. Misson, F. Brombacher, M. Delos, D. Lison, and F. Huaux Type 2 immune response associated with silicosis is not instrumental in the development of the disease Am J Physiol Lung Cell Mol Physiol, January 1, 2007; 292(1): L107 - L113. [Abstract] [Full Text] [PDF]
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C. Michels, P. Goyal, N. Nieuwenhuizen, and F. Brombacher Infection with Syphacia obvelata (Pinworm) Induces Protective Th2 Immune Responses and Influences Ovalbumin-Induced Allergic Reactions. Infect. Immun., October 1, 2006; 74(10): 5926 - 5932. [Abstract] [Full Text] [PDF]
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 G. Hassanzadeh Ghassabeh, P. De Baetselier, L. Brys, W. Noel, J. A. Van Ginderachter, S. Meerschaut, A. Beschin, F. Brombacher, and G. Raes Identification of a common gene signature for type II cytokine-associated myeloid cells elicited in vivo in different pathologic conditions Blood, July 15, 2006; 108(2): 575 - 583. [Abstract] [Full Text] [PDF]
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H. W. Murray, C. W. Tsai, J. Liu, and X. Ma Visceral Leishmania donovani Infection in Interleukin-13-/- Mice Infect. Immun., April 1, 2006; 74(4): 2487 - 2490. [Abstract] [Full Text] [PDF]
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 J R McDermott, F C Leslie, M D'Amato, D G Thompson, R K Grencis, and J T McLaughlin Immune control of food intake: enteroendocrine cells are regulated by CD4+ T lymphocytes during small intestinal inflammation Gut, April 1, 2006; 55(4): 492 - 497. [Abstract] [Full Text] [PDF]
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L. Pace, S. Rizzo, C. Palombi, F. Brombacher, and G. Doria Cutting Edge: IL-4-Induced Protection of CD4+CD25- Th Cells from CD4+CD25+ Regulatory T Cell-Mediated Suppression J. Immunol., April 1, 2006; 176(7): 3900 - 3904. [Abstract] [Full Text] [PDF]
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C. Holscher, B. Arendse, A. Schwegmann, E. Myburgh, and F. Brombacher Impairment of Alternative Macrophage Activation Delays Cutaneous Leishmaniasis in Nonhealing BALB/c Mice J. Immunol., January 15, 2006; 176(2): 1115 - 1121. [Abstract] [Full Text] [PDF]
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D. A. Kuperman, X. Huang, L. Nguyenvu, C. Holscher, F. Brombacher, and D. J. Erle IL-4 Receptor Signaling in Clara Cells Is Required for Allergen-Induced Mucus Production J. Immunol., September 15, 2005; 175(6): 3746 - 3752. [Abstract] [Full Text] [PDF]
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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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H. W. Murray, K. C. Flanders, D. D. Donaldson, J. P. Sypek, P. J. Gotwals, J. Liu, and X. Ma Antagonizing Deactivating Cytokines To Enhance Host Defense and Chemotherapy in Experimental Visceral Leishmaniasis Infect. Immun., July 1, 2005; 73(7): 3903 - 3911. [Abstract] [Full Text] [PDF]
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G. Raes, R. Van den Bergh, P. De Baetselier, G. H. Ghassabeh, C. Scotton, M. Locati, A. Mantovani, and S. Sozzani Arginase-1 and Ym1 Are Markers for Murine, but Not Human, Alternatively Activated Myeloid Cells J. Immunol., June 1, 2005; 174(11): 6561 - 6562. [Full Text] [PDF]
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L. Brys, A. Beschin, G. Raes, G. H. Ghassabeh, W. Noel, J. Brandt, F. Brombacher, and P. D. Baetselier Reactive Oxygen Species and 12/15-Lipoxygenase Contribute to the Antiproliferative Capacity of Alternatively Activated Myeloid Cells Elicited during Helminth Infection J. Immunol., May 15, 2005; 174(10): 6095 - 6104. [Abstract] [Full Text] [PDF]
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C. Holscher, A. Holscher, D. Ruckerl, T. Yoshimoto, H. Yoshida, T. Mak, C. Saris, and S. Ehlers The IL-27 Receptor Chain WSX-1 Differentially Regulates Antibacterial Immunity and Survival during Experimental Tuberculosis J. Immunol., March 15, 2005; 174(6): 3534 - 3544. [Abstract] [Full Text] [PDF]
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 G. Raes, L. Brys, B. K. Dahal, J. Brandt, J. Grooten, F. Brombacher, G. Vanham, W. Noel, P. Bogaert, T. Boonefaes, et al. Macrophage galactose-type C-type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation J. Leukoc. Biol., March 1, 2005; 77(3): 321 - 327. [Abstract] [Full Text] [PDF]
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B. Arendse, J. Van Snick, and F. Brombacher IL-9 Is a Susceptibility Factor in Leishmania major Infection by Promoting Detrimental Th2/Type 2 Responses J. Immunol., February 15, 2005; 174(4): 2205 - 2211. [Abstract] [Full Text] [PDF]
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A. Gessner, K. Mohrs, and M. Mohrs Mast Cells, Basophils, and Eosinophils Acquire Constitutive IL-4 and IL-13 Transcripts during Lineage Differentiation That Are Sufficient for Rapid Cytokine Production J. Immunol., January 15, 2005; 174(2): 1063 - 1072. [Abstract] [Full Text] [PDF]
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B. E. C. Babay, H. Louzir, C. Kebaier, S. Boubaker, K. Dellagi, and P.-A. Cazenave Inbred Strains Derived from Feral Mice Reveal New Pathogenic Mechanisms of Experimental Leishmaniasis Due to Leishmania major Infect. Immun., August 1, 2004; 72(8): 4603 - 4611. [Abstract] [Full Text] [PDF]
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N. Seki, M. Miyazaki, W. Suzuki, K. Hayashi, K. Arima, E. Myburgh, K. Izuhara, F. Brombacher, and M. Kubo IL-4-Induced GATA-3 Expression Is a Time-Restricted Instruction Switch for Th2 Cell Differentiation J. Immunol., May 15, 2004; 172(10): 6158 - 6166. [Abstract] [Full Text] [PDF]
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M. Saeftel, A. Krueger, S. Arriens, V. Heussler, P. Racz, B. Fleischer, F. Brombacher, and A. Hoerauf Mice Deficient in Interleukin-4 (IL-4) or IL-4 Receptor {alpha} Have Higher Resistance to Sporozoite Infection with Plasmodium berghei (ANKA) than Do Naive Wild-Type Mice Infect. Immun., January 1, 2004; 72(1): 322 - 331. [Abstract] [Full Text] [PDF]
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A. Debus, J. Glasner, M. Rollinghoff, and A. Gessner High Levels of Susceptibility and T Helper 2 Response in MyD88-Deficient Mice Infected with Leishmania major Are Interleukin-4 Dependent Infect. Immun., December 1, 2003; 71(12): 7215 - 7218. [Abstract] [Full Text] [PDF]
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S. Stager, J. Alexander, K. C. Carter, F. Brombacher, and P. M. Kaye Both Interleukin-4 (IL-4) and IL-4 Receptor {alpha} Signaling Contribute to the Development of Hepatic Granulomas with Optimal Antileishmanial Activity Infect. Immun., August 1, 2003; 71(8): 4804 - 4807. [Abstract] [Full Text] [PDF]
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H. Hackstein, T. Taner, A. F. Zahorchak, A. E. Morelli, A. J. Logar, A. Gessner, and A. W. Thomson Rapamycin inhibits IL-4--induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo Blood, June 1, 2003; 101(11): 4457 - 4463. [Abstract] [Full Text] [PDF]
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K. G. J. Pollock, K. S. McNeil, J. C. Mottram, R. E. Lyons, J. M. Brewer, P. Scott, G. H. Coombs, and J. Alexander The Leishmania mexicana Cysteine Protease, CPB2.8, Induces Potent Th2 Responses J. Immunol., February 15, 2003; 170(4): 1746 - 1753. [Abstract] [Full Text] [PDF]
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M. Mohrs, D. A. Lacy, and R. M. Locksley Stat Signals Release Activated Naive Th Cells from an Anergic Checkpoint J. Immunol., February 15, 2003; 170(4): 1870 - 1876. [Abstract] [Full Text] [PDF]
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A. A. Akhiani, J. Pappo, Z. Kabok, K. Schon, W. Gao, L. E. Franzen, and N. Lycke Protection Against Helicobacter pylori Infection Following Immunization Is IL-12-Dependent and Mediated by Th1 Cells J. Immunol., December 15, 2002; 169(12): 6977 - 6984. [Abstract] [Full Text] [PDF]
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W. Noel, G. Hassanzadeh, G. Raes, B. Namangala, I. Daems, L. Brys, F. Brombacher, P. D. Baetselier, and A. Beschin Infection Stage-Dependent Modulation of Macrophage Activation in Trypanosoma congolense-Resistant and -Susceptible Mice Infect. Immun., November 1, 2002; 70(11): 6180 - 6187. [Abstract] [Full Text] [PDF]
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C. F. Anderson and D. M. Mosser A novel phenotype for an activated macrophage: the type 2 activated macrophage J. Leukoc. Biol., July 1, 2002; 72(1): 101 - 106. [Abstract] [Full Text] [PDF]
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G. Raes, P. De Baetselier, W. Noel, A. Beschin, F. Brombacher, and G. Hassanzadeh Gh. Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages J. Leukoc. Biol., April 1, 2002; 71(4): 597 - 602. [Abstract] [Full Text] [PDF]
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 R. Venkayya, M. Lam, M. Willkom, G. Grunig, D. B. Corry, and D. J. Erle The Th2 Lymphocyte Products IL-4 and IL-13 Rapidly Induce Airway Hyperresponsiveness Through Direct Effects on Resident Airway Cells Am. J. Respir. Cell Mol. Biol., February 1, 2002; 26(2): 202 - 208. [Abstract] [Full Text] [PDF]
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U. Eriksson, M. O. Kurrer, W. Sebald, F. Brombacher, and M. Kopf Dual Role of the IL-12/IFN-{gamma} Axis in the Development of Autoimmune Myocarditis: Induction by IL-12 and Protection by IFN-{gamma} J. Immunol., November 1, 2001; 167(9): 5464 - 5469. [Abstract] [Full Text] [PDF]
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B. Lucas, D. Bumann, A. Walduck, J. Koesling, L. Develioglu, T. F. Meyer, and T. Aebischer Adoptive Transfer of CD4+ T Cells Specific for Subunit A of Helicobacter pylori Urease Reduces H. pylori Stomach Colonization in Mice in the Absence of Interleukin-4 (IL-4)/IL-13 Receptor Signaling Infect. Immun., March 1, 2001; 69(3): 1714 - 1721. [Abstract] [Full Text] [PDF]
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M. M. Fort, R. Lesley, N. J. Davidson, S. Menon, F. Brombacher, M. W. Leach, and D. M. Rennick IL-4 Exacerbates Disease in a Th1 Cell Transfer Model of Colitis J. Immunol., February 15, 2001; 166(4): 2793 - 2800. [Abstract] [Full Text] [PDF]
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A. P. Mountford, K. G. Hogg, P. S. Coulson, and F. Brombacher Signaling via Interleukin-4 Receptor {alpha} Chain Is Required for Successful Vaccination against Schistosomiasis in BALB/c Mice Infect. Immun., January 1, 2001; 69(1): 228 - 236. [Abstract] [Full Text] [PDF]
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T. Aebischer, S. Laforsch, R. Hurwitz, F. Brombacher, and T. F. Meyer Immunity against Helicobacter pylori: Significance of Interleukin-4 Receptor {alpha} Chain Status and Gender of Infected Mice Infect. Immun., January 1, 2001; 69(1): 556 - 558. [Abstract] [Full Text] [PDF]
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K. M. Houston, E. H. Wilson, L. Eyres, F. Brombacher, M. M. Harnett, J. Alexander, and W. Harnett Presence of Phosphorylcholine on a Filarial Nematode Protein Influences Immunoglobulin G Subclass Response to the Molecule by an Interleukin-10-Dependent Mechanism Infect. Immun., September 1, 2000; 68(9): 5466 - 5468. [Abstract] [Full Text] [PDF]
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S. L. Constant, C. Dong, D. D. Yang, M. Wysk, R. J. Davis, and R. A. Flavell JNK1 Is Required for T Cell-Mediated Immunity Against Leishmania major Infection J. Immunol., September 1, 2000; 165(5): 2671 - 2676. [Abstract] [Full Text] [PDF]
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N. Sato, S. K. Ahuja, M. Quinones, V. Kostecki, R. L. Reddick, P. C. Melby, W. A. Kuziel, and S. S. Ahuja CC Chemokine Receptor (CCR)2 Is Required for Langerhans Cell Migration and Localization of T Helper Cell Type 1 (Th1)-inducing Dendritic Cells: Absence of CCR2 Shifts the Leishmania major-resistant Phenotype to a Susceptible State Dominated by Th2 Cytokines, B Cell Outgrowth, and Sustained Neutrophilic Inflammation J. Exp. Med., July 10, 2000; 192(2): 205 - 218. [Abstract] [Full Text] [PDF]
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D. E. Jones, L. U. Buxbaum, and P. Scott IL-4-Independent Inhibition of IL-12 Responsiveness During Leishmania amazonensis Infection J. Immunol., July 1, 2000; 165(1): 364 - 372. [Abstract] [Full Text] [PDF]
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H. Himmelrich, P. Launois, I. Maillard, T. Biedermann, F. Tacchini-Cottier, R. M. Locksley, M. Rocken, and J. A. Louis In BALB/c Mice, IL-4 Production During the Initial Phase of Infection with Leishmania major Is Necessary and Sufficient to Instruct Th2 Cell Development Resulting in Progressive Disease J. Immunol., May 1, 2000; 164(9): 4819 - 4825. [Abstract] [Full Text] [PDF]
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M. Mohrs, C. Holscher, and F. Brombacher Interleukin-4 Receptor Alpha-Deficient BALB/c Mice Show an Unimpaired T Helper 2 Polarization in Response to Leishmania major Infection Infect. Immun., April 1, 2000; 68(4): 1773 - 1780. [Abstract] [Full Text] [PDF]
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D. J. Matthews, C. L. Emson, G. J. McKenzie, H. E. Jolin, J. M. Blackwell, and A. N. J. McKenzie IL-13 Is a Susceptibility Factor for Leishmania major Infection J. Immunol., February 1, 2000; 164(3): 1458 - 1462. [Abstract] [Full Text] [PDF]
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J. M. Brewer, M. Conacher, C. A. Hunter, M. Mohrs, F. Brombacher, and J. Alexander Aluminium Hydroxide Adjuvant Initiates Strong Antigen-Specific Th2 Responses in the Absence of IL-4- or IL-13-Mediated Signaling J. Immunol., December 15, 1999; 163(12): 6448 - 6454. [Abstract] [Full Text] [PDF]
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