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*
Immunobiology Section, Laboratory of Parasitic Diseases, and
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Animal Science Branch, National Cancer Institute, National Institutes of Health, Frederick, MD 21702; and
§
Biomedical Research Institute, Rockville, MD 20852
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-deficient mice, which are nonresponsive to both IL-4 and
IL-13. In striking contrast to IL-4 KO animals, infected IL-4R KO
mice developed only minimal hepatic granulomas and fibrosis despite the
presence of CD3+ T cells in the residual egg lesions.
Moreover, liver lymphokine mRNA levels in these animals and IL-4 KO
mice were equivalent. In addition, infected IL-4R-deficient,
IL-4-deficient, and wt animals developed similar egg Ag-specific IgG Ab
titers, arguing that CD4-dependent Th activity is intact in KO mice. As
expected, IFN-
secretion was strongly up-regulated in mesenteric
lymph node cultures from both groups of deficient animals, a change
reflected in increased serum IgG2a and IgG2b Ab levels. Surprisingly,
Th2 cytokine production in infected IL-4R KO mice was not abolished
but was only reduced and resembled that previously documented in IL-4
KO animals. This residual Th2 response is likely to explain the ability
of IL-4 KO mice to generate egg granulomas, which cannot be formed in
IL-4R-deficient animals because of their lack of responsiveness to
the same cytokine ligands. Taken together, these findings argue that
tissue pathology in schistosomiasis requires, in addition to
egg-specific CD4+ lymphocytes, a previously unrecognized
IL-4R+ non-T cell effector
population. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A pertinent example of this paradox is the granulomatous inflammation in murine schistosomiasis. Humans and experimental animals infected with the helminth parasite Schistosoma mansoni react to eggs produced by the female worms by forming granulomas in the liver and other organs. This host inflammatory response leads to tissue fibrosis and circulatory impairment. Both granuloma formation and fibrosis have been shown to be CD4+ lymphocyte dependent (7). Since Th2 cytokines dominate during the peak of the granulomatous response, it has been proposed that schistosome egg pathology depends primarily on the activity of Ag-specific Th2 cells (8). However, it has been difficult to formally demonstrate a requirement for Th2 cells in this process, since anti-IL-4-treated mice show only a minor reduction in granuloma volume (9), and IL-4 KO4 mice infected with S. mansoni display either no (10) or only a small reduction (11) in granuloma size. Nevertheless, mice deficient in the Th2-specific signaling molecule STAT-6 recently have been shown to develop markedly reduced granulomas (12). The latter observation suggests that although IL-4 itself may not be essential for egg pathology, the IL-4R signaling pathway is nevertheless involved.
In the present study we directly addressed the role of the IL-4R in egg
pathology in S. mansoni-infected mice by comparing granuloma
formation and fibrosis in wild-type (wt), IL-4 KO, and
IL-4R-deficient animals. The latter mice lack the subunit of the
IL-4R and as a result are unresponsive to both IL-4 and IL-13 (13) and
thus in contrast to IL-4 KO animals permit an analysis of the function
of signaling by both cytokines. Our results demonstrate that S.
mansoni-infected IL-4R-deficient mice are distinct from both
IL-4 KO and wt animals in showing near complete ablation of egg
pathology while retaining the same lymphokine profile as IL-4 KO
mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c IL-4 KO and BALB/c IL-4R KO mice were generated by
homologous recombination in BALB/c I embryonic stem cells as previously
described (13, 14). Double IL-4/IL-4R KO animals, obtained by an
intercross between the KO mice, were also analyzed. The mice were bred
and maintained at the American Association for Accreditation of
Laboratory Animal Care facility of the National Institute of Allergy
and Infectious Diseases. Control BALB/cJ and BALB/c RAG-2 KO mice were
purchased from The Jackson Laboratory (Bar Harbor, ME) and Taconic
Farms (Germantown, NY), respectively. Age-matched (8–12 wk) and
sex-matched mice were used in each experiment. Mice were percutaneously
infected with 35 S. mansoni cercariae (NMRI strain) as
previously described (15). A soluble extract of schistosome eggs (SEA)
was prepared according to published procedures (16).
Assessment of egg pathology
Liver granuloma diameters were measured in histological sections (17), and the presence of eosinophils (percentage) and mast cells (arbitrary units from 0–7, where a score of 7 indicates approximately 10 mast cells/lesion) in the same granulomas were estimated by microscopic examination. Tissue egg counts were performed on liver digested in 4% KOH, and liver collagen levels were determined by measurement of hydroxyproline (18). The statistical significance of differences in granuloma volumes and cell composition between groups was evaluated by Student’s two-tailed t test, and differences in fibrosis were evaluated by analysis of covariance.
Immunohistochemical staining for CD3+ cells
Liver sections were stained with a polyclonal rabbit anti-human CD3 Ab cross-reactive with mouse CD3 (Dako, Carpinteria, CA), and the reaction was developed using an ABC Vectastain Elite kit (Vector Laboratories, Burlingame, CA) (19).
Cell cultures and cytokine assays
Mesenteric lymph nodes were pooled from mice (n
= 6/group) at 8 wk after infection, and single-cell suspensions (3
x 106/ml) were stimulated in vitro with medium
alone or SEA (20 µg/ml) for 72 h (17). When indicated,
anti-CD4 mAb (GK1.5, rat IgG2b) (20) and anti-CD8 mAb (2.43,
rat IgG2b) (21) were added to the cultures 2 h before addition of
SEA. IFN-, IL-5, and IL-10 were measured in culture supernatants by
ELISA as previously described (22, 23), while IL-4 and IL-13 were
detected using commercial kits from Endogen (Woburn, MA) and R&D
Systems (Minneapolis, MN), respectively.
RT-PCR detection of cytokine mRNAs
Liver tissue from infected animals was homogenized in RNA STAT-60 (Tel-Test, Friendswood, TX) using a tissue Polytron (Omni, Waterbury, CT), and total RNA was isolated as recommended by the manufacturer. A RT-PCR (24) was used to determine relative amounts of mRNA for IL-4 (34 cycles), IL-5 (35 cycles), IL-13 (33 cycles), and hypoxanthine phosphoribosyltransferase (HPRT) (23 cycles). The sequences of the primers and probes have been previously published (24, 25).
Measurement of circulating SEA-specific Ab and IgE levels
Blood was collected from individual mice at the time of sacrifice. Levels of egg-specific Ab were determined by ELISA (26) in pools obtained by mixing equal volumes of serum from each animal within a group. The assay employed Immunolon 2 plates (Dynex Laboratories, Chantilly, VA) coated overnight at 4°C with SEA (0.5 µg/well). Peroxidase-conjugated rabbit Ab specific for mouse IgG or specific IgG isotypes (Zymed, San Francisco, CA) were used to develop the reactions. Total serum IgE was measured by a specific ELISA (PharMingen, San Diego, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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KO mice
To formally address the requirement for IL-4 signaling in
egg-induced granuloma formation and fibrosis, we infected groups of
BALB/c IL-4 KO, IL-4R KO, and double IL-4/IL-4R-deficient as well
as wt animals by percutaneous exposure to cercariae. At 8 wk
postinfection no significant differences in worm or tissue egg burdens
were observed among the four groups of mice (data not shown),
confirming the lack of involvement of IL-4 in parasite development (10, 11). In contrast, the same animal groups displayed major differences in
egg-induced pathology. As observed with mice on other genetic
backgrounds (10, 11), BALB/c IL-4 KO animals failed to display
significant alterations in granuloma size, and only a small difference
in hepatic fibrosis measured by tissue hydroxyproline. In striking
contrast, granuloma volumes in both IL-4R and double IL-4/IL-4R
KO mice were markedly diminished to the level seen in T cell-deficient
RAG-2 KO mice (Fig. 1
A).
Hepatic fibrosis was also dramatically reduced in IL-4R-deficient
animals but remained significantly higher than that observed in RAG-2
KO mice (Fig. 1B). Similarly, the percentage of eosinophils
in granulomas from IL-4R-deficient animals was significantly lower
than that in lesions from wt or IL-4 KO animals but, nevertheless, was
higher than that in RAG-2 KO granulomas (Fig. 1C). As
described previously (10, 11) granulomas in IL-4 KO mice were only
marginally reduced in their eosinophil composition with respect to
lesions in wt animals. In contrast, mice deficient in either IL-4 or
IL-4R developed granulomas almost totally devoid of mast cells (Fig. 1D), consistent with the known involvement of IL-4 in
mastocytosis (27). In general, the residual lesions in IL-4R KO
animals were found to be primarily mononuclear in composition and, with
the exception of the reduced numbers of eosinophils and mast cells and
the absence of concentric fibrosis, failed to display detectable
cellular differences when compared with granulomas in wt mice.
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KO mice is not the result of
defective T cell infiltration
Immunohistochemistry was performed on liver sections from 8-wk
infected wt and KO animals to determine whether the decreased pathology
in schistosome-infected IL-4R KO mice is due to defective migration
of effector T cells into egg-induced lesions. The granulomas in
IL-4R KO mice, although reduced in size, nevertheless contained
large numbers of CD3+ lymphocytes, while no
staining was observed in the equivalent lesions in RAG-2 KO mice (Fig. 2). Accurate quantitation of the number
of CD3+ cells present was not feasible, although
they appeared to be in higher density in granulomas from IL-4R KO
livers.
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KO mice compared with those in wt animals, they
were not significantly different from the levels in IL-4 KO mice, which
display unimpaired egg pathology (Fig. 3). Since previous studies have
determined that the CD8+ cells in S.
mansoni- infected mice are Tc1 rather than Tc2 in phenotype (28),
the presence of comparable levels of Th2 cytokine mRNAs in livers of
IL-4R KO and IL-4 KO animals argue that the
CD3+ cells within the residual lesions are likely
to be CD4+ rather than CD8+
lymphocytes.
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KO mice display
indistinguishable lymphokine secretion profiles
To further characterize the T cell response in infected IL-4R
KO mice, mesenteric LN cells were stimulated in vitro with SEA, and
lymphokine secretion was assayed by ELISA. As previously shown (29), wt
mice mount marginal IFN- responses to SEA at 8 wk postinfection. In
contrast, simultaneously infected IL-4, IL-4R or IL-4/IL-4R KO
animals display markedly increased and comparable IFN- levels (Fig. 4). Thus, the absence of either IL-4
and/or IL-4R signaling allows the development of Th1 responses normally
suppressed in infected IL-4 intact mice.
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). Infected IL-4R and IL-4/IL-4R KO
mice showed nearly the same levels of IL-5, IL-10, and IL-13 as IL-4 KO
animals, indicating that Th2 development is reduced, but not ablated,
in the absence of either IL-4 or IL-4R signaling. In infected IL-4R
KO mice, in which it was possible to assay the synthesis of IL-4,
production of this Th2 lymphokine was also only partially diminished
relative to that in wt animals (Fig. 4). Nevertheless, the lack of IL-4
consumption in vitro in the absence of IL-4R is likely to account
for part of the cytokine accumulation observed. In vitro treatment with
anti-CD4- or anti-CD8-specific mAb confirmed that the observed
Th2 as well as Th1 cytokine production by mesenteric LN cells from
IL-4R KO mice are primarily dependent on CD4+
cells (data not shown).
Infected IL-4 and IL-4R KO mice develop comparable total IgG as
well as isotype-specific anti-SEA Ab levels in sera
Isotype-specific anti-SEA Ab were also measured as a parameter
of Th activity. Infected wt, IL-4 KO, and IL-4R KO mice displayed
indistinguishable levels of total serum anti-SEA IgG (Fig. 5). However, titers of IgG2a and IgG2b Ab
in IL-4 KO and IL-4R KO animals were significantly increased with
respect to those in wt mice, consistent with the augmented Th1 cytokine
production observed in the former animals. Titers of SEA-specific IgG1
Ab were only partially affected by IL-4/IL-4R deficiency (Fig. 5),
and in some experiments no difference in IgG1 levels between wt and KO
mice was detected. Nevertheless, total IgE was reduced to undetectable
levels in both groups of KO animals (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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KO animals show a near complete impairment of both
granulomatous inflammation and fibrosis. Thus, while IL-4 itself is not
essential for pathogenesis, signaling through IL-4R by another cytokine
ligand is clearly required. IL-13, a Th2 cytokine structurally related
to IL-4, is known to signal through the IL-4R/IL-13R complex and
therefore is the likely mediator involved. The latter hypothesis is
strongly supported by recent experiments in the i.v. egg injection
model, in which pulmonary granuloma formation was shown to be partially
inhibited in wt mice and ablated in IL-4 KO mice after in vivo
administration of soluble IL-13R/Fc fusion protein (30). Our findings
also extend previous observations demonstrating impaired hepatic
pathology in schistosome-infected mice deficient in the Th2 signaling
component STAT-6 (12) by implicating both the receptor and the cytokine
involved.
A key question raised by the requirement for IL-4R triggering in egg
pathology concerns the identity of the IL-4R+
effector cell necessary for granulomatous inflammation. The most simple
explanation is that CD4+ lymphocytes or their
helper functions are defective in infected IL-4R, but not in IL-4 KO
mice. Since total IgG SEA-specific Ab levels are equivalent in wt,
IL-4-deficient, and IL-4R-deficient animals, overall CD4-dependent
helper function appears to be intact (Fig. 5). Nevertheless, at a more
specific level it is conceivable that the CD4+
Th2 cells that mediate pathology are somehow dependent on IL-4R, but
not on IL-4, for their generation. For example, one might postulate
that although T cells lack IL-13R (31), IL-13 indirectly influences Th2
development in this model as proposed in another experimental system
(32). However, it is clear that S. mansoni-infected IL-4 and
IL-4R KO animals display indistinguishable in situ (Fig. 3) and in
vitro (Fig. 4) lymphokine as well as qualitatively similar Ab isotype
(Fig. 5) profiles and therefore do not appear to differ in their
Th1/Th2 response patterns. Thus, the critical
IL-4R+ effector cell is unlikely to be a
CD4+ lymphocyte. Since CD8 cells do not appear to
contribute to the observed cytokine production in either wt or
IL-4R-deficient animals, and CD8-deficient mice show unimpaired
acute granuloma formation (33), it is equally improbable that
IL-4R+ CD8 cells are the target of the defect.
Instead, the cell involved most probably is a non-T lymphocyte that
receives the Th2 signal and responds by performing a critical, but as
yet undefined, function in granuloma formation and fibrosis.
IL-4R is widely distributed on numerous cell types (34), including
eosinophils and mast cells, which are normal constituents of
schistosome egg granulomas. While both of these cell populations are
reduced in the granulomas arising in IL-4R KO mice (Fig. 1), their
loss is unlikely to be the underlying explanation of the ablated tissue
pathology. Thus, previous studies have indicated that
eosinophil-depleted animals develop egg granulomas that are nearly
normal in size (35). Similarly, as illustrated by the data presented
here (Fig. 1), the egg lesions developing in IL-4 KO mice are of
comparable volume to those occurring in wt animals despite the notable
absence of mast cells. Alternative candidates include macrophages,
endothelial cells, and/or fibroblasts, all of which are
IL-4R+ and, in contrast to T lymphocytes, are
responsive to IL-13 as well as to IL-4 (36, 37, 38).
Taken together the results presented in this paper argue that egg
pathology requires both a Th2 response (which occurs residually in IL-4
KO mice) as well as the IL-4R+ non-T cell
population discussed above acting as a primary effector of the
granulomatous response. The latter component of the disease process may
offer a novel target for immunological intervention. On this note, it
is of interest that mice vaccinated with IL-12 plus egg Ags develop
reduced granulomatous pathology and display a Th1/Th2 profile closely
resembling that seen in infected IL-4R KO animals, raising the
possibility that the IL-12 immunization protocol functions by reducing
IL-4R expression. While this mechanism has not been formally
examined, a more likely explanation of the effects of the IL-12
vaccination procedure is the near complete suppression of the synthesis
of the relevant IL-4R ligands, IL-4 and IL-13, observed (39).
Unexpectedly, S. mansoni-infected IL-4R KO mice produced
significant levels of Th2 cytokines despite their inability to receive
IL-4 differentiation signals. Nevertheless, these animals, like
infected IL-4 KO mice, showed markedly enhanced Th1 development,
indicating that, as expected, cross-regulation is impaired. The above
observations argue for the existence of alternative mechanisms for
generating Th2 responses independent of IL-4 signaling. Studies of the
CD4+ T lymphocyte populations arising in
schistosome-infected IL-4R as well as STAT-6-deficient mice are
currently in progress to further investigate this issue.
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Acknowledgments |
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Footnotes |
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2 D.J. and M.C.K. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Dragana Jankovic, Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 4, Room 126, 9000 Rockville Pike, Rockville, MD 20892-0425. E-mail address:
4 Abbreviations used in this paper: KO, knockout; wt, wild type; SEA, soluble egg Ag; RAG, recombinase-activating gene.
Received for publication March 17, 1999. Accepted for publication April 22, 1999.
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References |
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interferon-dependent mechanism. Infect. Immun. 66:5157.-dependent effector mechanisms. J. Immunol. 162:345. interferon deficient mice chronically infected with Schistosoma mansoni. Infect. Immun. 65:2583.[Abstract]
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D. Jankovic, M. C. Kullberg, N. Noben-Trauth, P. Caspar, W. E. Paul, and A. Sher Single Cell Analysis Reveals That IL-4 Receptor/Stat6 Signaling Is Not Required for the In Vivo or In Vitro Development of CD4+ Lymphocytes with a Th2 Cytokine Profile J. Immunol., March 15, 2000; 164(6): 3047 - 3055. [Abstract] [Full Text] [PDF]
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P. G. Fallon, E. J. Richardson, G. J. McKenzie, and A. N. J. McKenzie Schistosome Infection of Transgenic Mice Defines Distinct and Contrasting Pathogenic Roles for IL-4 and IL-13: IL-13 Is a Profibrotic Agent J. Immunol., March 1, 2000; 164(5): 2585 - 2591. [Abstract] [Full Text] [PDF]
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