| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Department of Pathology, University of Cambridge, Cambridge, United Kingdom; and
Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, IL-2) responses. A type 2
cytokine response is characterized by increased (Th2) cell development
(production of IL-4 and IL-5) resulting in IgE production and
eosinophilia. Type 2 cytokine responses are causally associated with
allergies, asthma, and helminth infections (1). During the
last decade, IL-4 has been proposed as the key regulatory molecule for
Th2 cell differentiation and type 2 cytokine responses
(2). More recently, IL-13 has been implicated as a central
mediator in certain Th2-cytokine pathologies (3, 4, 5, 6, 7). IL-13
shares 30% homology with IL-4 and appears to have certain overlapping
biological activities (8). This overlap in biological
activity is due to IL-4 and IL-13 using the IL-4 receptor 
-chain
(IL-4R) as a component of their receptor complexes (9)
and signal through a shared STAT6-dependent pathway (10).
Both cytokines have been demonstrated to modulate IgE expression
(11, 12), the development of type 2 cytokine responses
(13, 14), and the suppression of inflammatory cytokine
production from monocytes (15, 16). Indeed, recent
experiments have shown that IL-4 and IL-13 may perform additive roles
in type 2 cytokine responses (14). However, it is clear
that these cytokines also have distinct biological roles. IL-4 directly
induces T cell proliferation and differentiation (2, 17, 18), whilst IL-13 probably mediates its effects on T cells
indirectly (13). In contrast, studies using
gastrointestinal helminth parasite infections have identified that
IL-13 plays a more dominant role in the expulsion of certain worm
infections (5, 6, 7, 19).
A number of recent studies have used the synchronous schistosome egg
pulmonary granuloma model to elucidate the relative roles of IL-4 and
IL-13 in the formation of the schistosome granuloma. In this model,
schistosome eggs elicit pulmonary granulomas after i.v. injection of
eggs into naive or egg-sensitized mice (20). Using
cytokine-deficient mice, we have shown that the pulmonary granulomatous
inflammation is partially impaired in IL-4- or IL-13-deficient mice;
with a reduction in pulmonary eosinophil infiltration and IgE and Th2
(IL-5, IL-10) production relative to wild-type animals
(14). In contrast, these responses were abolished in
combined IL-4/IL-13-deficient mice, with a type 1 (IFN-) dominated
response (14). Similar findings were observed following
blocking IL-13 activity in IL-4-deficient mice with a soluble IL-13R
2-Fc fusion protein (21).
Studies to date employing IL-4-, STAT6-, or IL-4R-deficient mice
have suggested IL-13 may have a role in IL-4-independent responses
during helminth infections (7, 19, 22, 23). It has been
observed that a caveat in these models is that the biological phenotype
observed can only be surmised to be solely due to IL-13, with other,
possible unknown, factors having a potential role (24).
With respect to murine schistosomiasis, a potential role for IL-13 in
granuloma formation and fibrosis was implied by early studies in
IL-4R-deficient mice (23), and, more recently, a direct
role for IL-13 was shown by blocking IL-13 activity (25).
In this study, the availability of IL-4-alone, IL-13-alone, and both
IL-4 and IL-13 cytokine gene-targeted mouse lines has permitted the
intimate dissection of the direct role of IL-13 in a type 2
cytokine-mediated infection. This study demonstrates that removal of
IL-13 from the Th2 cytokine response to Schistosoma mansoni
infection is beneficial to host survival. This enhanced prognosis
correlates with a reduction in collagen deposition and indicates a
novel role for IL-13 in the development of hepatic fibrosis. By
contrast, we also show that removal of IL-4 results in very high
mortality characterized by a breakdown in intestinal integrity and the
development of endotoxemia; implicating IL-4 as a protective cytokine
in schistosome infection. The combined removal of both IL-4 and IL-13
demonstrated that the positive effects resulting from the ablation of
IL-13 were over-ridden by the detrimental pathology resulting from IL-4
removal. Moreover, combined cytokine deletion resulted in a phenotype
that was considerably more severe and deleterious than that observed in
the IL-4-deficient line. These data identify the potential benefits of
targeting IL-13 removal, but also highlight the dangers of blocking
both IL-13 and IL-4 concurrently.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The preparation of IL-4 (26), IL-13 (13) and IL-4/13 (14) gene-targeted mice has been described. All animals had been back-crossed on a BALB/c background at least four times. Animals were housed under standard conditions in a specific pathogen free facility. A Puerto Rican strain of S. mansoni was used for all experiments. Six- to 8 wk-old female mice were percutaneously infected with S. mansoni (27). In three separate experiments, mice were acutely infected (exposure to 100 cercariae) for 8 wk. In all acute infections, 6–12 mice were used per group. In separate studies, IL-13-/-, IL-4/13-/-, and homozygous (+/+) litter-mates on a 129 x C57BL/6 (F2) background were chronically infected (exposure to 25 cercariae) for 16 wk. For chronic infections, 14–15 mice were infected per group. Portal perfusion for worm counts, digestion of tissue for egg counts, and fecal egg counts were as described (27, 28).
During the infection, the body weights of all mice were monitored. In compliance with U.K. Home Office Licence legislation, animals that developed severe overt morbidity during infection were humanely killed.
Pathology studies
The methods used for measurement of pathological parameters have been described (29). In brief, liver or intestinal sections were stained with hematoxylin and eosin for granuloma diameter measurement, Giemsa-stained for eosinophil counts, or stained with Martius Scarlet Blue for examination of tissue fibrosis. All histological samples (histology slides, plasma) were numerically coded before analysis. The same individual measured all pathological parameters blind. The diameters of the granuloma surrounding individual eggs were measured using an ocular micrometer. For each mouse, the diameters of at least 21 individual egg granulomas were measured, with 6–12 mice examined (minimum of 126 individual granulomas measured per group in each of three separate experiments). The volume of the granuloma was calculated assuming a spherical shape. Tissue collagen in the livers of uninfected and infected mice was quantified by differential staining of sections (three per mouse) on slides and was expressed as the increase in hepatic collagen, micrograms of collagen per milligram of protein. To determine hepatocyte damage, plasma aspartate aminotransferase levels were assayed (Sigma, Dorset, U.K.). LPS was measured in plasma using a commercial kit (COATEST Plasma-Endotoxin; Chromogenic AB, Molndal, Sweden); plasma samples were diluted in endotoxin-free water and assayed according to the manufacturers instructions. Intestinal eosinophilia was determined using the eosinophil peroxidase assay, essentially as described (30). The numbers of eosinophils (expressed as 106 per gram of tissue) were interpolated from a standard curve prepared from eosinophils purified from the blood of Nippostrongylus braziliensis- infected mice.
Immunological assays
Animals were sacrificed on day 45 after infection, before
substantial deaths in IL-4- and IL-4/13-deficient mice, for analysis of
their immune responses. Plasma and blood were recovered. The spleen and
mesenteric lymph node cells were aseptically removed. Single-cell
suspensions were prepared as described (31). Cells (5
x 106/ml) were stimulated with parasite egg Ags
(10 µg/ml) or Escherichia coli LPS serotype 0127:B8 (1
µg/ml; Sigma). IL-4, IL-5, IL-10, IL-13, TNF-, and IFN- were
detected in culture supernatants by ELISA as described previously
(14, 29). The Griess reaction (32) was used
to quantify nitrite levels in the supernatants of cell cultures. Lamina
propria cells were isolated from the ileum of infected mice using
standard techniques (33). Cells recovered from the ileums
of two individual mice were pooled and restimulated in vitro with Con A
(25 µg/ml) for 8 h with Brefeldin A (5 µg/ml) added for the
last 3 h of culture. Surface staining of lamina propria
CD4+ T cells, intracellular IL-5, or IFN-
staining and subsequent FACS analysis were as reported previously
(31). Analysis of parasite Ag-specific Ab responses were
as described (29).
Statistical analysis
Data from individual mice are presented as the group mean ± SD or SEM, as indicated. Statistical differences between groups was determined using ANOVA, and post hoc comparisons were done with Dunnett’s test. Differences between survival of mice were analyzed by Kruskal-Wallis test of ranked survival times. Values of p < 0.05 were considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Following acute infection with S. mansoni (exposure to
100 cercariae), significant mortality was observed in the
IL-4-/- and IL-4/13-deficient mice, with >80%
expiration by day 56 (Fig. 1
A). Death was preceded by
progressive weight loss and cachexia (data not shown). In marked
contrast, there were considerably fewer mortalities in wild-type
animals (13%) and no deaths in the IL-13-/-
mice (Fig. 1A). In three separate acute infections,
IL-13-/- mice had significantly lower
mortalities than wild-type animals (p < 0.05).
A similar mortality profile was observed when animals were subjected to
a chronic (exposure to 25 cercariae) infection (Fig. 1B).
All IL-4/13-deficient mice (100% mortality) died by week 10, whereas
by 16 wk of infection significantly fewer wild-type mice (36%
mortality) and still fewer IL-13-/- mice (7%
mortality) had expired (p < 0.05;
n = 14–15 mice per group). Determination of parasite
worm burdens and parasite fecundity demonstrated that the differences
in mortality between groups were not simply due to variation in
infectivity or fecundity of the parasite between the mouse lines (Table I). These data demonstrate that the
absence of IL-13 was beneficial for infected animals, with
IL-13-/- mice surviving longer than wild-type
animals. Conversely, deficiency in IL-4 results in increased mortality,
suggesting that IL-4, or IL-4-dependent responses, have a protective
role in infection.
|
|
During schistosome infection, the liver is the major organ
affected, with eggs trapped in the liver parenchyma evoking type 2
cytokine-dependent granulomatous inflammation. This is characterized by
the presence of numerous infiltrating eosinophils, but also by the
deposition of collagen and a resultant fibrotic lesion. Histological
analysis identified that while wild-type,
IL-4-/-, and IL-13-/-
mice had comparable hepatic granuloma formation, there was a striking
reduction in granuloma development in the IL-4/13-deficient mice (Fig. 2a and Fig. 3A). Additionally, granulomas
from the IL-4/13-deficient animals were virtually devoid of the
characteristic eosinophil infiltration present in the granulomas of the
other mouse lines (Fig. 3B). Instead, the limited granuloma
response from the IL-4/13-deficient animals was comprised of
macrophages (data not shown).
|
|
Because hepatic fibrosis is a major clinical manifestation of
schistosomiasis, we examined collagen deposition in the livers of
infected mice. Histological analysis and collagen quantification
identified that there was negligible hepatic fibrosis in the
IL-13-deficient or IL-4/13-deficient mice when compared with wild-type
or IL-4-deficient mice (Fig. 2
b and Fig. 3C).
Although schistosome-infected mice do not develop portal fibrosis to
the same extent as schistosome-infected humans (34), it is
noteworthy that IL-4/13-deficient mice also displayed reduced
periportal fibrosis compared with the collagen deposition in wild-type
animals (Fig. 2b).
IL-4 protects against liver damage
To determine whether the alterations in the liver pathology
generated in the different mouse strains affected hepatocyte integrity,
we measured plasma aspartate aminotransferase levels as an indicator of
cell damage. IL-13-deficient mice had similar transaminase levels to
wild-type mice (Fig. 3D). In contrast, although
IL-4-deficient mice demonstrated normal granulomatous responses, these
animals had 
5-fold greater levels of circulating transaminase than
wild-type mice. Hepatocyte damage was even more markedly exacerbated in
IL-4/13-deficient mice, with transaminase levels 10-fold higher than
wild-type mice (Fig. 3D). Elevated plasma transaminase
levels and impaired hepatic granuloma responses in schistosome-infected
mice have been associated with steatohepatitis and extensive
microvesicular steatosis (29, 35). However, there was no
microvesicular damage in IL-4/13-deficient mice, although there were
sporadic polymorphonuclear leukocyte infiltrations (primarily
neutrophils) and foci of necrosis throughout the hepatic parenchyma
(data not shown).
IL-4 but not IL-13 has a distinct role in intestinal function during schistosome infection
Intestinal pathology is a feature of schistosome infections of
humans and mice. During S. mansoni infection, the intestine
is subject to the insult of eggs laid by the adult worms in the
mesenteric venules. These eggs must then translocate across the
intestinal wall to the gut lumen for excretion in the feces.
Examination of the gastrointestinal tracts from the infected mice
revealed marked distension and inflammation of the ileum, but not the
colon, in the IL-4/13-deficient and IL-4-deficient mice (data not
shown). In contrast, the intestines of IL-13-/-
mice were comparable to wild-type animals. The intestinal inflammation
observed in the IL-4/13-deficient and IL-4-deficient mice correlated
with dramatically impaired parasite egg excretion from the intestine
(Fig. 4A), leading to an
accumulation of eggs in the intestinal wall (Table I). The limited
granulomatous response surrounding eggs in the ileums of
IL-4-/- and IL-4/13-/-
mice was characterized by limited eosinophil inflitration, <1 x
106 eosinophils per gram of intestine; whereas in
both wild-type and IL-13-/- mice there was
marked intestinal eosinophilia, >10 x 106
eosinophils per gram.
|
20-fold greater levels of LPS in the circulation of
IL-4-deficient and IL-4/13-deficient mice compared with levels in
wild-type and IL-13-/- mice (Fig. 4B). The levels of systemic LPS in the
IL-4-/- or IL-4/13-deficient mice are
comparable to circulating endotoxin levels in mice suffering from acute
endotoxemia (36). In support of this conclusion,
proliferation responses to cecal bacteria, by splenocytes or mesenteric
lymph node cells derived from these mice, were substantially elevated
(data not shown). Furthermore, splenocytes from IL-4-deficient and,
even more markedly from IL-4/13-deficient mice, produced highly
elevated levels of TNF- and NO in response to LPS (Fig. 4C). Thus, as reported previously, IL-4 represents an
important factor in the response to S. mansoni infection
(37). However, the additional absence of IL-13 exacerbated
the intestinal pathology, the associated elevation in systemic LPS
leakage, and the increase in TNF- and NO production (Fig. 4, B and C), indicating that IL-13 can also modify
this immune response.
In many models of gastrointestinal inflammation, there is an alteration
in the normal cytokine repertoire of the intestine (38).
To examine the cytokine profile elicited in the intestines of the
cytokine-deficient animals, ileum-derived CD4+
lamina propria T cells from infected mice were examined using
intracellular cytokine staining. Schistosome-infected wild-type and
IL-13-/- mice had 10–15% IL-5-positive
CD4+ lamina propria T cells, with <5% of cells
producing IFN-, indicative of a Th2-like phenotype in the intestines
of infected mice (Fig. 4D). In contrast,
CD4+ T cells from the lamina propria of both the
IL-4-/- and IL-4/13-deficient mice had 3-fold
higher frequencies of IFN--producing cells, with no IL-5-positive
CD4+ T cells detected (Fig. 4D),
typical of a Th1-like response. The absence of Th2 cells in the lamina
propria of IL-4- and IL-4/13-deficient mice was reflected by the
virtual absence of eosinophils in the ileums of these mice (see
above).
Systemic responses
To determine how the absence of IL-4, IL-13, or IL-4 and IL-13
together influenced the development of cytokine responses to infection,
we isolated splenocytes from infected mice 45 days postinfection
(before high mortality in the IL-4/13-deficient population) and
assessed cytokine production following restimulation in vitro with
soluble schistosome egg Ags. Wild-type animals exhibited a type 2
cytokine response with elevated IL-4, IL-5, IL-10, and IL-13 production
and limited expression of IFN- (Fig. 5). A similar profile was observed in the
analysis of IL-13-deficient mice, with the exception that IL-13 was not
detected (Fig. 4). IL-4-deficient mice developed a diminished type 2
cytokine response, with limited IL-5, IL-10, and IL-13 being produced
and a marginal (2-fold) increase in IFN- production compared with
wild-type animals (Fig. 5). In contrast to the single
cytokine-deficient animals, IL-4/13-deficient mice developed a type 1
cytokine dominated response, with a 10-fold increase in the secretion
of IFN- and negligible production of type 2 cytokines (Fig. 5).
|
. |
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
IL-4-deficient animals had normal levels of hepatic collagen
deposition, whereas the doubly deficient mice exhibited a more profound
reduction in collagen levels than the IL-13-deficient animals,
indicating an additive effect of IL-13 and IL-4. The lower levels of
hepatic collagen in IL-4/13-/- mice relative to
IL-13-/- animals may reflect the elevated
IFN- in double-deficient mice; IFN- has been shown to reduce
hepatic fibrosis in murine schistosome infection (40).
However, it is evident that IL-13 is the primary cytokine responsible
for fibrosis. These data clarify the results reported for schistosome
infections of STAT6- and IL-4R-deficient animals in which
collagen deposition was found to be reduced (22, 23) and
IL-4-deficient animals in which collagen responses were normal
(41). Because periportal fibrosis is a major cause of
hepatic pathology in human schistosomiasis (42),
regulation of IL-13 activity to limit collagen formation and deposition
may have therapeutic implications. Furthermore, the evidence described
here for IL-13 acting as a fibrogenic agent highlights the importance
of assessing its role in other fibrotic pathologies associated with
type 2 cytokine responses, in particular asthma.
Obvious demarcation of cytokine function is demonstrated by the high mortality rates observed in the IL-4-deficient population. These animals display prominent intestinal damage resulting from an inability to regulate the translocation of the parasite egg across the intestinal wall to the gut lumen. Our data extends earlier observations implicating IL-4 having a potential protective role in schistosome infection (37). It is known that IL-4 can directly regulate various physiological activities of the intestine (43), and alterations in these processes in IL-4-deficient mice may account for the inability of parasite eggs to transverse the intestine in these mice. In the absence of IL-4 (IL-4-deficient or IL-4-/13-deficient mice), parasite eggs are not excreted efficiently and are trapped in the intestine, causing intestinal inflammation leading to systemic LPS leakage. In contrast, the IL-13-deficient mice do not develop intestinal inflammation in response to infection. As the livers of schistosome-infected mice are more susceptible to endotoxins (44), leakage of LPS will exacerbate liver damage and ultimately result in the death of the mouse. Because IL-4 and IL-13 have both been shown to suppress proinflammatory responses, the combined absence of both cytokines may result in unregulated expression of inflammatory mediators (45). Thus, the combined liver-intestine insult in a proinflammatory environment may account for the hepatocyte damage observed in IL-4-deficient and IL-4/13-deficient animals.
In the absence of IL-4, the cytokine response during schistosome infection is changed from a type 2 phenotype to a more type 1-dominated response. However, as reported previously, IL-4-/- mice do produce type 2 cytokines during infection (23, 37, 41, 46). However, while IL-13-deficient mice retain a Th2 phenotype in response to infection, the doubly deficient animals verify that IL-13 does play an additive role with IL-4 in suppressing the emergence of a type 1 response. Thus, the IL-4/13-deficient animals display a highly polarized Th1-like phenotype. However, it is clear that IL-4 is the dominant factor in this process.
Despite the formation of the schistosome granuloma being type 2
cytokine dependent, it has recently been highlighted that type 2
cytokine responses have a protective role in schistosome infection
(34). Thus, in a number of different mouse models
(IL-4-deficient mice; schistosome egg-tolerised mice;
CD4+ T cell-depleted mice) there are marked
mortalities during schistosome infection that are associated with
diminished type 2 cytokine responses (29, 35, 37). In this
study, we further demonstrate that the protective role of type 2
responses is particularly apparent in the intestines of infected mice.
During infections of normal mice, the process of egg translocation
through the intestinal wall is associated with local granulomatous
inflammation, eosinophilia, and a Th2 response (Fig. 4D,
above). In contrast, in mice that fail to excrete parasite eggs (Refs.
29 and 35 , this study), there is intestinal
inflammation. The intestinal pathology in these mice is associated with
a Th1-dominated response in the ileum and impaired recruitment of
eosinophils to intestine. This implicates that type 2 cytokine
responses, in particular intestinal eosinophilia, reduce intestinal
damage elicited during schistosome infection.
In this study, cytokine-deficient animals have enabled us to decipher
the individual effects of IL-4 and IL-13 and to assess the result of
combined IL-4/13 disruption on the pathology of infection. These
results are summarized in Table II, and
demonstrate a clear demarcation of function for IL-4 and IL-13 in the
development of pathology. It is clear that inhibiting IL-13 results in
an improved prognosis that is characterized by the generation of a
normal Th2 response, but an attendant decrease in hepatic fibrosis and
an associated reduction in mortality. In contrast, IL-4-deficient mice
display depressed Th2 responses, continue to deposit hepatic collagen,
and succumb to severe intestinal inflammation resulting in endotoxemia
and death. Analysis of the doubly deficient animals shows that combined
blocking of both IL-4 and IL-13 is extremely detrimental, resulting in
an even more severe phenotype than that displayed by the IL-4-deficient
mice. IL-4/13-deficient animals demonstrate that the beneficial effects
of removing IL-13 in isolation are overcome by the pathological
consequences of removing IL-4 and highlight the additive roles that
both of these cytokines play in suppressing the development of Th1
responses. These results indicate that IL-13 is a key target for
therapeutic intervention.
|
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Padraic Fallon, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, United Kingdom. E-mail address:
Received for publication September 27, 1999. Accepted for publication December 14, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, and Stat6 are required for the expulsion of the gastrointestinal parasite Nippostrongylus brasiliensis. Immunity 8:255.[Medline]
deficient mice reveal a role for IL-13 in the regulation of Th2 responses. Curr. Biol. 8:669.[Medline]
mediated cachexia and death during acute schistosomiasis. J. Immunol. 159:777.[Abstract]
-Interferon treatment inhibits collagen deposition in murine schistosomiasis. Hepatology 10:795.[Medline]
production. J. Exp. Med. 181:537.This article has been cited by other articles:
|
|
 |
|
  B. Dewals, J. C. Hoving, M. Leeto, R. G. Marillier, U. Govender, A. J. Cutler, W. G.C. Horsnell, and F. Brombacher IL-4R{alpha} Responsiveness of Non-CD4 T Cells Contributes to Resistance in Schistosoma mansoni Infection in Pan-T Cell-Specific IL-4R{alpha}-Deficient Mice Am. J. Pathol., August 1, 2009; 175(2): 706 - 716. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Dai, N. J. Megjugorac, G. E. Gallagher, R. Y. L. Yu, and G. Gallagher IFN-{lambda}1 (IL-29) inhibits GATA3 expression and suppresses Th2 responses in human naive and memory T cells Blood, June 4, 2009; 113(23): 5829 - 5838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. R. Ramalingam, J. T. Pesce, M. M. Mentink-Kane, S. Madala, A. W. Cheever, M. R. Comeau, S. F. Ziegler, and T. A. Wynn Regulation of Helminth-Induced Th2 Responses by Thymic Stromal Lymphopoietin J. Immunol., May 15, 2009; 182(10): 6452 - 6459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Magalhaes, C. N. Paiva, H. S. P. Souza, A. S. Pyrrho, D. Mourao-Sa, R. T. Figueiredo, A. Vieira-de-Abreu, H. S. Dutra, M. S. Silveira, M. I. C. Gaspar-Elsas, et al. Macrophage migration inhibitory factor is critical to interleukin-5-driven eosinophilopoiesis and tissue eosinophilia triggered by Schistosoma mansoni infection FASEB J, April 1, 2009; 23(4): 1262 - 1271. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Kane, E. Jung, and E. J. Pearce Schistosoma mansoni Egg Antigen-Mediated Modulation of Toll-Like Receptor (TLR)-Induced Activation Occurs Independently of TLR2, TLR4, and MyD88 Infect. Immun., December 1, 2008; 76(12): 5754 - 5759. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. E. Bazzone, P. M. Smith, L. I. Rutitzky, M. G. Shainheit, J. F. Urban, T. Setiawan, A. M. Blum, J. V. Weinstock, and M. J. Stadecker Coinfection with the Intestinal Nematode Heligmosomoides polygyrus Markedly Reduces Hepatic Egg-Induced Immunopathology and Proinflammatory Cytokines in Mouse Models of Severe Schistosomiasis Infect. Immun., November 1, 2008; 76(11): 5164 - 5172. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Martins-Leite, G. Gazzinelli, L. F. Alves-Oliveira, A. Gazzinelli, L. C. C. Malaquias, R. Correa-Oliveira, A. Teixeira-Carvalho, and A. M. S. Silveira Effect of Chemotherapy with Praziquantel on the Production of Cytokines and Morbidity Associated with Schistosomiasis Mansoni Antimicrob. Agents Chemother., August 1, 2008; 52(8): 2780 - 2786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Cihakova, J. G. Barin, M. Afanasyeva, M. Kimura, D. Fairweather, M. Berg, M. V. Talor, G. C. Baldeviano, S. Frisancho, K. Gabrielson, et al. Interleukin-13 Protects Against Experimental Autoimmune Myocarditis by Regulating Macrophage Differentiation Am. J. Pathol., May 1, 2008; 172(5): 1195 - 1208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Herbert, T. Orekov, C. Perkins, M. E. Rothenberg, and F. D. Finkelman IL-4R{alpha} Expression by Bone Marrow-Derived Cells Is Necessary and Sufficient for Host Protection against Acute Schistosomiasis J. Immunol., April 1, 2008; 180(7): 4948 - 4955. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Amatucci, T. Novobrantseva, K. Gilbride, M. Brickelmaier, P. Hochman, and A. Ibraghimov Recombinant ST2 boosts hepatic Th2 response in vivo J. Leukoc. Biol., July 1, 2007; 82(1): 124 - 132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Shainheit, R. Saraceno, L. E. Bazzone, L. I. Rutitzky, and M. J. Stadecker Disruption of Interleukin-27 Signaling Results in Impaired Gamma Interferon Production but Does Not Significantly Affect Immunopathology in Murine Schistosome Infection Infect. Immun., June 1, 2007; 75(6): 3169 - 3177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Harvie, T. W. Jordan, and A. C. La Flamme Differential Liver Protein Expression during Schistosomiasis Infect. Immun., February 1, 2007; 75(2): 736 - 744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Leeto, D. R. Herbert, R. Marillier, A. Schwegmann, L. Fick, and F. Brombacher TH1-Dominant Granulomatous Pathology Does Not Inhibit Fibrosis or Cause Lethality during Murine Schistosomiasis Am. J. Pathol., November 1, 2006; 169(5): 1701 - 1712. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Taylor, M. Mohrs, and E. J. Pearce Regulatory T Cell Responses Develop in Parallel to Th Responses and Control the Magnitude and Phenotype of the Th Effector Populatio J. Immunol., May 15, 2006; 176(10): 5839 - 5847. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Reiman, R. W. Thompson, C. G. Feng, D. Hari, R. Knight, A. W. Cheever, H. F. Rosenberg, and T. A. Wynn Interleukin-5 (IL-5) Augments the Progression of Liver Fibrosis by Regulating IL-13 Activity Infect. Immun., March 1, 2006; 74(3): 1471 - 1479. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. F. Alves Oliveira, E. C. Moreno, G. Gazzinelli, O. A. Martins-Filho, A. M. S. Silveira, A. Gazzinelli, L. C. C. Malaquias, P. LoVerde, P. M. Leite, and R. Correa-Oliveira Cytokine Production Associated with Periportal Fibrosis during Chronic Schistosomiasis Mansoni in Humans Infect. Immun., February 1, 2006; 74(2): 1215 - 1221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. E. Mangan, N. van Rooijen, A. N. J. McKenzie, and P. G. Fallon Helminth-Modified Pulmonary Immune Response Protects Mice from Allergen-Induced Airway Hyperresponsiveness J. Immunol., January 1, 2006; 176(1): 138 - 147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Edwards, O. Buchatska, M. Ashton, M. Montoya, Q. D. Bickle, and P. Borrow Reciprocal Immunomodulation in a Schistosome and Hepatotropic Virus Coinfection Model J. Immunol., November 15, 2005; 175(10): 6275 - 6285. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Arora, Y. Hernandez, J. R. Erb-Downward, R. A. McDonald, G. B. Toews, and G. B. Huffnagle Role of IFN-{gamma} in Regulating T2 Immunity and the Development of Alternatively Activated Macrophages during Allergic Bronchopulmonary Mycosis J. Immunol., May 15, 2005; 174(10): 6346 - 6356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Kane, L. Cervi, J. Sun, A. S. McKee, K. S. Masek, S. Shapira, C. A. Hunter, and E. J. Pearce Helminth Antigens Modulate TLR-Initiated Dendritic Cell Activation J. Immunol., December 15, 2004; 173(12): 7454 - 7461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Jakubzick, H. Wen, A. Matsukawa, M. Keller, S. L. Kunkel, and C. M. Hogaboam Role of CCR4 Ligands, CCL17 and CCL22, During Schistosoma mansoni Egg-Induced Pulmonary Granuloma Formation in Mice Am. J. Pathol., October 1, 2004; 165(4): 1211 - 1221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kaviratne, M. Hesse, M. Leusink, A. W. Cheever, S. J. Davies, J. H. McKerrow, L. M. Wakefield, J. J. Letterio, and T. A. Wynn IL-13 Activates a Mechanism of Tissue Fibrosis That Is Completely TGF-{beta} Independent J. Immunol., September 15, 2004; 173(6): 4020 - 4029. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Kitching, A. L. Turner, G. R.A. Wilson, K. L. Edgtton, P. G. Tipping, and S. R. Holdsworth Endogenous IL-13 Limits Humoral Responses and Injury in Experimental Glomerulonephritis but Does Not Regulate Th1 Cell-Mediated Crescentic Glomerulonephritis J. Am. Soc. Nephrol., September 1, 2004; 15(9): 2373 - 2382. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. McKee and E. J. Pearce CD25+CD4+ Cells Contribute to Th2 Polarization during Helminth Infection by Suppressing Th1 Response Development J. Immunol., July 15, 2004; 173(2): 1224 - 1231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Lauder, H. E. Jolin, P. Smith, J. G. van den Berg, A. Jones, W. Wisden, K. G. C. Smith, A. Dasvarma, P. G. Fallon, and A. N. J. McKenzie Lymphomagenesis, Hydronephrosis, and Autoantibodies Result from Dysregulation of IL-9 and Are Differentially Dependent on Th2 Cytokines J. Immunol., July 1, 2004; 173(1): 113 - 122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Pina, R. C. Valente-Ferreira, E. E. W. Molinari-Madlum, C. A. C. Vaz, A. C. Keller, and V. L. G. Calich Absence of Interleukin-4 Determines Less Severe Pulmonary Paracoccidioidomycosis Associated with Impaired Th2 Response Infect. Immun., April 1, 2004; 72(4): 2369 - 2378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Kolodsick, G. B. Toews, C. Jakubzick, C. Hogaboam, T. A. Moore, A. McKenzie, C. A. Wilke, C. J. Chrisman, and B. B. Moore Protection from Fluorescein Isothiocyanate-Induced Fibrosis in IL-13-Deficient, but Not IL-4-Deficient, Mice Results from Impaired Collagen Synthesis by Fibroblasts J. Immunol., April 1, 2004; 172(7): 4068 - 4076. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hesse, C. A. Piccirillo, Y. Belkaid, J. Prufer, M. Mentink-Kane, M. Leusink, A. W. Cheever, E. M. Shevach, and T. A. Wynn The Pathogenesis of Schistosomiasis Is Controlled by Cooperating IL-10-Producing Innate Effector and Regulatory T Cells J. Immunol., March 1, 2004; 172(5): 3157 - 3166. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Mentink-Kane, A. W. Cheever, R. W. Thompson, D. M. Hari, N. B. Kabatereine, B. J. Vennervald, J. H. Ouma, J. K. Mwatha, F. M. Jones, D. D. Donaldson, et al. IL-13 receptor {alpha} 2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis PNAS, January 13, 2004; 101(2): 586 - 590. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Saeftel, M. Arndt, S. Specht, L. Volkmann, and A. Hoerauf Synergism of Gamma Interferon and Interleukin-5 in the Control of Murine Filariasis Infect. Immun., December 1, 2003; 71(12): 6978 - 6985. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Chung, M. M. Monick, N. Y. Hamzeh, N. S. Butler, L. S. Powers, and G. W. Hunninghake Role of Repeated Lung Injury and Genetic Background in Bleomycin-Induced Fibrosis Am. J. Respir. Cell Mol. Biol., September 1, 2003; 29(3): 375 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. N.J. McKenzie and P. G. Fallon Decoy Receptors in the Regulation of T Helper Cell Type 2 Responses J. Exp. Med., March 17, 2003; 197(6): 675 - 679. [Full Text] [PDF]
|
|
|
|
|
|
M. G. Chiaramonte, M. Mentink-Kane, B. A. Jacobson, A. W. Cheever, M. J. Whitters, M. E.P. Goad, A. Wong, M. Collins, D. D. Donaldson, M. J. Grusby, et al. Regulation and Function of the Interleukin 13 Receptor {alpha} 2 During a T Helper Cell Type 2-dominant Immune Response J. Exp. Med., March 17, 2003; 197(6): 687 - 701. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. R. Johnson, R. A. Parker, J. E. Johnson, and B. S. Graham IL-13 Is Sufficient for Respiratory Syncytial Virus G Glycoprotein-Induced Eosinophilia After Respiratory Syncytial Virus Challenge J. Immunol., February 15, 2003; 170(4): 2037 - 2045. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Huaux, T. Liu, B. McGarry, M. Ullenbruch, and S. H. Phan Dual Roles of IL-4 in Lung Injury and Fibrosis J. Immunol., February 15, 2003; 170(4): 2083 - 2092. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Straw, A. S. MacDonald, E. Y. Denkers, and E. J. Pearce CD154 Plays a Central Role in Regulating Dendritic Cell Activation During Infections That Induce Th1 or Th2 Responses J. Immunol., January 15, 2003; 170(2): 727 - 734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. H. Hogan, M. Wang, M. Suresh, D. O. Co, J. V. Weinstock, and M. Sandor CD4+ TCR Repertoire Heterogeneity in Schistosoma mansoni-Induced Granulomas J. Immunol., December 1, 2002; 169(11): 6386 - 6393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Chen, Y. Wei, G. C. Sharp, and H. Braley-Mullen Inhibition of TGF{beta}1 by Anti-TGF{beta}1 Antibody or Lisinopril Reduces Thyroid Fibrosis in Granulomatous Experimental Autoimmune Thyroiditis J. Immunol., December 1, 2002; 169(11): 6530 - 6538. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. d. S. Pyrrho, J. A. Ramos, R. M. Neto, C. S. d. Silva, H. L. Lenzi, C. M. Takiya, and C. R. Gattass Dexamethasone, a Drug for Attenuation of Schistosoma mansoni Infection Morbidity Antimicrob. Agents Chemother., November 1, 2002; 46(11): 3490 - 3498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Metwali, A. Blum, D. E. Elliott, and J. V. Weinstock Interleukin-4 Receptor {alpha} Chain and STAT6 Signaling Inhibit Gamma Interferon but Not Th2 Cytokine Expression within Schistosome Granulomas Infect. Immun., October 1, 2002; 70(10): 5651 - 5658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Woerly, P. Lacy, A. B. Younes, N. Roger, S. Loiseau, R. Moqbel, and M. Capron Human eosinophils express and release IL-13 following CD28-dependent activation J. Leukoc. Biol., October 1, 2002; 72(4): 769 - 779. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Jakubzick, S. L. Kunkel, B. H. Joshi, R. K. Puri, and C. M. Hogaboam Interleukin-13 Fusion Cytotoxin Arrests Schistosoma mansoni Egg-Induced Pulmonary Granuloma Formation in Mice Am. J. Pathol., October 1, 2002; 161(4): 1283 - 1297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Homer, T. Zheng, G. Chupp, S. He, Z. Zhu, Q. Chen, B. Ma, R. D. Hite, L. I. Gobran, S. A. Rooney, et al. Pulmonary type II cell hypertrophy and pulmonary lipoproteinosis are features of chronic IL-13 exposure Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L52 - L59. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. F. Skinnider and T. W. Mak The role of cytokines in classical Hodgkin lymphoma Blood, May 29, 2002; 99(12): 4283 - 4297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. MacDonald, E. A. Patton, A. C. La Flamme, M. I. Araujo, C. R. Huxtable, B. Bauman, and E. J. Pearce Impaired Th2 Development and Increased Mortality During Schistosoma mansoni Infection in the Absence of CD40/CD154 Interaction J. Immunol., May 1, 2002; 168(9): 4643 - 4649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
E. A. Patton, A. C. La Flamme, J. A. Pedras-Vasoncelos, and E. J. Pearce Central Role for Interleukin-4 in Regulating Nitric Oxide-Mediated Inhibition of T-Cell Proliferation and Gamma Interferon Production in Schistosomiasis Infect. Immun., January 1, 2002; 70(1): 177 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. La Flamme, E. A. Patton, and E. J. Pearce Role of Gamma Interferon in the Pathogenesis of Severe Schistosomiasis in Interleukin-4-Deficient Mice Infect. Immun., December 1, 2001; 69(12): 7445 - 7452. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hesse, M. Modolell, A. C. La Flamme, M. Schito, J. M. Fuentes, A. W. Cheever, E. J. Pearce, and T. A. Wynn Differential Regulation of Nitric Oxide Synthase-2 and Arginase-1 by Type 1/Type 2 Cytokines In Vivo: Granulomatous Pathology Is Shaped by the Pattern of L-Arginine Metabolism J. Immunol., December 1, 2001; 167(11): 6533 - 6544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Pedras-Vasconcelos, L. R. Brunet, and E. J. Pearce Profound effect of the absence of IL-4 on T cell responses during infection with Schistosoma mansoni J. Leukoc. Biol., November 1, 2001; 70(5): 737 - 744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. I. Rutitzky, H. J. Hernandez, and M. J. Stadecker Th1-polarizing immunization with egg antigens correlates with severe exacerbation of immunopathology and death in schistosome infection PNAS, October 16, 2001; (2001) 231258498. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Qadir, A. Metwali, A. M. Blum, J. Li, D. E. Elliott, and J. V. Weinstock TGF-beta and IL-10 regulation of IFN-gamma produced in Th2-type schistosome granulomas requires IL-12 Am J Physiol Gastrointest Liver Physiol, October 1, 2001; 281(4): G940 - G946. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. G. Lee, R. J. Homer, Z. Zhu, S. Lanone, X. Wang, V. Koteliansky, J. M. Shipley, P. Gotwals, P. Noble, Q. Chen, et al. Interleukin-13 Induces Tissue Fibrosis by Selectively Stimulating and Activating Transforming Growth Factor {beta}1 J. Exp. Med., September 17, 2001; 194(6): 809 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Angyalosi, R. Neveu, I. Wolowczuk, A. Delanoye, J. Herno, C. Auriault, and V. Pancre HLA Class II Polymorphism Influences Onset and Severity of Pathology in Schistosoma mansoni-Infected Transgenic Mice Infect. Immun., September 1, 2001; 69(9): 5874 - 5882. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Flaherty, M. M. Monick, A. B. Carter, M. W. Peterson, and G. W. Hunninghake GM-CSF Increases AP-1 DNA Binding and Ref-1 Amounts in Human Alveolar Macrophages Am. J. Respir. Cell Mol. Biol., August 1, 2001; 25(2): 254 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Inoue, B. T. Konieczny, M. E. Wagener, A. N. J. McKenzie, and F. G. Lakkis Failure to Induce Neonatal Tolerance in Mice That Lack Both IL-4 and IL-13 but Not in Those That Lack IL-4 Alone J. Immunol., July 15, 2001; 167(2): 1125 - 1128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Blease, C. Jakubzick, J. Westwick, N. Lukacs, S. L. Kunkel, and C. M. Hogaboam Therapeutic Effect of IL-13 Immunoneutralization During Chronic Experimental Fungal Asthma J. Immunol., April 15, 2001; 166(8): 5219 - 5224. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Trollmo, A. L. Meyer, A. C. Steere, D. A. Hafler, and B. T. Huber Molecular Mimicry in Lyme Arthritis Demonstrated at the Single Cell Level: LFA-1{{alpha}}L Is a Partial Agonist for Outer Surface Protein A-Reactive T Cells J. Immunol., April 15, 2001; 166(8): 5286 - 5291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. I. Araujo, S. K. Bliss, Y. Suzuki, A. Alcaraz, E. Y. Denkers, and E. J. Pearce Interleukin-12 Promotes Pathologic Liver Changes and Death in Mice Coinfected with Schistosoma mansoni and Toxoplasma gondii Infect. Immun., March 1, 2001; 69(3): 1454 - 1462. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Fallon, C. L. Emson, P. Smith, and A. N. J. McKenzie IL-13 Overexpression Predisposes to Anaphylaxis Following Antigen Sensitization J. Immunol., February 15, 2001; 166(4): 2712 - 2716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. La Flamme, E. A. Patton, B. Bauman, and E. J. Pearce IL-4 Plays a Crucial Role in Regulating Oxidative Damage in the Liver During Schistosomiasis J. Immunol., February 1, 2001; 166(3): 1903 - 1911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Patton, L. R. Brunet, A. C. La Flamme, J. Pedras-Vasconcelos, M. Kopf, and E. J. Pearce Severe Schistosomiasis in the Absence of Interleukin-4 (IL-4) Is IL-12 Independent Infect. Immun., January 1, 2001; 69(1): 589 - 592. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Kacha, F. Fallarino, M. A. Markiewicz, and T. F. Gajewski Spontaneous Rejection of Poorly Immunogenic P1.HTR Tumors by Stat6-Deficient Mice J. Immunol., December 1, 2000; 165(11): 6024 - 6028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Fallon, P. Smith, E. J. Richardson, F. J. Jones, H. C. Faulkner, J. Van Snick, J.-C. Renauld, R. K. Grencis, and D. W. Dunne Expression of Interleukin-9 Leads to Th2 Cytokine-Dominated Responses and Fatal Enteropathy in Mice with Chronic Schistosoma mansoni Infections Infect. Immun., October 1, 2000; 68(10): 6005 - 6011. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. I. Rutitzky, H. J. Hernandez, and M. J. Stadecker Th1-polarizing immunization with egg antigens correlates with severe exacerbation of immunopathology and death in schistosome infection PNAS, November 6, 2001; 98(23): 13243 - 13248. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
