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Axis in the Development of Autoimmune Myocarditis: Induction by IL-12 and Protection by IFN-1
*
Medicine A, University Hospital, and
Basel Institute for Immunology, Basel, Switzerland;
Department of Pathology, University Hospital, Zurich, Switzerland;
Theodor Boveri Institut für Biowissenschaften, Wurzburg, Germany; and
¶ Department of Immunology, University of Cape Town, Cape Town, South Africa
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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positively regulate each other and type 1
inflammatory responses, which are believed to cause tissue damage in
autoimmune diseases. We investigated the role of the IL-12/IFN-
(Th1) axis in the development of autoimmune myocarditis.
IL-12p40-deficient mice on a susceptible background resisted
myocarditis. In the absence of IL-12, autospecific CD4+ T
cells proliferated poorly and showed increased Th2 cytokine responses.
However, IFN--deficient mice developed fatal autoimmune disease, and
blockade of IL-4R signaling did not confer susceptibility to
myocarditis in IL-12p40-deficient mice, demonstrating that IL-12
triggers autoimmunity by a mechanism independent of the effector
cytokines IFN- and IL-4. In conclusion, our results suggest that the
IL-12/IFN- axis is a double-edged sword for the development of
autoimmune myocarditis. Although IL-12 mediates disease by
induction/expansion of Th1-type cells, IFN- production from these
cells limits disease progression. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-myosin H chain-derived peptides (3, 5) and is mainly
dependent on CD4+ T cells (6, 7),
recognizing heart muscle-specific peptides presented by MHC class II
molecules of interstitial APC residing in the heart (8).
Myocarditis can be transferred by injection of autodestructive T cells
into mice pretreated with LPS or TNF- (8).
IL-12 is a covalently linked heterodimer of 
75 kDa composed of two
subunits, p40 and p35, which is mainly produced by macrophages and
dendritic cells upon CD40 ligation, viral infection, and/or stimulation
with certain pathogen components (e.g., LPS and staphylococcus
enterotoxin B) (9, 10). IL-12 plays a key role in
the induction and maintenance of IFN- production by
CD4+ T cells and cell-mediated immunity
(CMI)3 (11, 12). Indeed, defective Th1 differentiation and CMI is a
phenotype observed in both IL-12-/- and
IFN--/- mice infected with various pathogens
(13, 14). In the context of autoimmunity, results from
several experimental models, including 2,4,6-trinitrobenzene sulfonic
acid-induced colitis (15), experimental allergic
encephalitis (EAE) (16), uveitis (17),
collagen-induced arthritis (18), and myocarditis
(19), indicate that IL-12 mediates disease involving
IFN-. However, recent studies suggest that IL-12 induces colitis
independently of IFN- (20). Moreover, IL-12, but not
IFN-, has been shown to protect from acute vaccinia virus infection,
indicating unique effector pathways (21).
In the present report we investigated the role of the IL-12/IFN-
axis in autoimmune myocarditis using the relevant knockout mice. Our
data demonstrate that IL-12 is required for CD4+
T cell-mediated inflammatory heart disease by a mechanism independent
of IFN- and IL-4.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice deficient for IL-12p40 (12), IL-12R
1
(22) (provided by J. Magram, Department of Inflammation,
Autoimmune Diseases, Hofmann-LaRoche, Nutley, NJ), and IFN-
(provided by D. Dalton, University of California, La Jolla, CA) were
backcrossed with BALB/c mice for more than seven generations before
heterozygous mice were interbred to obtain homozygous knockouts.
IL-4R-deficient mice (23) on a genetically pure BALB/c
background and all other mutant mouse strains were maintained in a
facility free of specific pathogens at the Basel Insitute for
Immunology until transfer to conventional housing at the start of the
experiment. Wild-type (WT) BALB/c mice were purchased from Biological
Research Laboratories (Fullinsdorf, Switzerland).
Induction of experimental autoimmune myocarditis
A murine heart muscle specific peptide derived from -myosin H
chain (myhc614–634
(Ac-SLKLMATLFSTYASADTGDSGKGKGKGGKKG-OH), designated
MA30) was used as Ag (5). The
peptide (purity, >85%; Chiron, Clayton, Australia) was dissolved in
PBS (1 mg/ml) and emulsified 1/1 with CFA (1 mg/ml, H37Ra; Difco,
Detroit, MI). Mice were immunized s.c. with 100 µg/0.2 ml on days 0
and 7. Sham-immunized controls were injected with CFA emulsified with
PBS alone. On day 0 before immunization all mice were injected i.p.
with 400 ng pertussis toxin diluted in 400 µl distilled water, 0.015
M Tris, 0.5 M NaCl, and 0.017% (v/v) Triton X-100 (pH
7.5).
Histopathology
Fourteen, 22, and 44 days after the immunization mice were anesthetized, and their hearts were perfused with normal saline. Hearts were removed, fixed in 4% buffered formaldehyde, and processed for H&E staining. The glass slides were coded and evaluated by a pathologist. For diagnosis of myocarditis, an inflammatory infiltrate forming foci between muscle fibers or surrounding individual myocytes, with or without associated myocyte necrosis or apoptosis, was considered essential. A vague increase in interstitial cellularity was not considered sufficient for diagnosis. Myocarditis was scored on a semiquantitative scale using grades from 0 to 4 (0, no inflammatory infiltrates; 1, small foci of inflammatory cells between myocytes or inflammatory cells surrounding individual myocytes; 2, larger foci of >100 inflammatory cells or involving >30 myocytes; 3, >10% of a myocardial cross-section involved; and 4, >30% of a myocardial cross-section involved).
Measurement of Abs
Specific IgG1 and IgG2a responses were evaluated by ELISA using microtiter plates coated with streptavidin and biotinylated MA30 (2 µg/ml; purity, >95%; Chiron). Two-fold serial dilutions of serum were incubated for 1 h at room temperature, followed by extensive washing and the addition of HRP-conjugated F(ab')2 sheep anti-mouse IgG (A 7282; Sigma, St. Louis, MO). Plates were washed and incubated with ABTS (Sigma) substrate solution (0.5 mg/ml in 0.1% phosphate/0.08 M citrate buffer, pH 4.0) for 30 min before measurement of OD at 405 nm on a Titer-Tek Multiscan MC plate (Miles, Elkhart, IN). A dilution was defined as positive when the reading exceeded 3 SD above mean values of negative controls.
Cytokine production
Cells from inguinal lymph nodes were harvested 22 days after
immunization. Cells were cultured in 96-well round-bottom plates (Nunc,
Roskilde, Denmark) in RPMI 1640 with 25 mM HEPES (Life Technologies,
Basel, Switzerland), 10% heat-inactivated FCS, 50 µM 2-ME,
gentamicin (20 µg/ml; Life Technologies) 2 mM
L-glutamine, and one of the following stimuli: 50 µg/ml
MA30 or 100 µg/ml OVA as nonspecific control
(Sigma,). Cytokines were measured in supernatants of pooled triplicate
wells after 40 h of incubation by commercial ELISA kits according
to the manufacturers’ instructions (Biotrak mouse ELISA systems from
Amersham International (Little Chalfont, U.K.) for IFN-
(sensitivity, 10 pg/ml) and BioSource Europe (Fleurus, Belgium) for
IL-2 (sensitivity, 13 pg/ml), IL-10 (ultrasensitive; sensitivity, 2
pg/ml), and IL-4 (sensitivity, 5 pg/ml)).
CD4+ T cell proliferation
Spleen cells were harvested on day 22 after immunization, and CD4+ T cells were enriched by negatively sorting out B220+, Mac-1+, CD11b+, DX5+, and CD8+ cells with specific Abs coupled to magnetic beads according to the manufacturer’s instructions (MACS; Miltenyi Biotech, Bergisch Gladbach, Germany). FACS analysis of the resulting CD4+ T cell population revealed 90–95% purity. CD4+ T cells (1 x 105/well) were cultured with irradiated syngenic splenocytes (5 x 105/well) pulsed with MA30 in 96-well plates (Nunc) with or without 100 U/ml recombinant mouse IL-12p75 and/or 50 U/ml recombinant mouse IL-2 in serum-free X-VIVO 20 medium (BioWhittaker, Walkersville, MD) supplemented as described above. Cells were cultured for 72 h until the addition of [methyl-3H]thymidine (1 µCi; Amersham International) and were harvested 12 h later. [3H]Thymidine incorporation was measured in a flat-bed beta scintillation counter (Wallac, Gaithersburg, MD).
Treatment protocols
For IL-4 neutralization, we used a rIL-4 mutant protein that
binds to the IL-4R without inducing a cellular signal
(24). Mice were injected i.p. with 10 µg of the IL-4
antagonist every other day starting on day 0 until day 20. On days 0
and 7, mice received the antagonist twice, 2 h before and 2 h
after immunization. Mice were treated with 1 µg of rIL-12p70 on day 0
and every second day thereafter.
Statistics
Mann-Whitney U test was used for the evaluation of continuous data. Dichotomous data were analyzed by Fisher’s exact test. A p < 0.05 was considered to be significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To investigate the role of IL-12 in a model of murine autoimmune
myocarditis, IL-12p40-/-,
IL-12R-/-, and BALB/c WT control mice were
immunized on days 0 and 7 with a peptide (MA30 =
myhc614–643) derived from -myosin H chain.
Sham-immunized control mice received CFA alone. Hearts were removed on
days 14, 22, and 44 and were evaluated by histology. WT mice developed
severe myocarditis with a high prevalence (Table I
). Diseased hearts revealed patchy
inflammatory lesions consisting primarily of lymphocytes, histiocytes,
and occasional neutrophils (Fig. 1). By
contrast, mice deficient for IL-12p40 or IL-12R1 were protected from
disease, since no specific myocarditic infiltrates were found in their
hearts (Table I). Few IL-12p40-/- mice (2 of
19) showed slightly increased interstitial cellularity that was
considered unspecific because such infiltration was also found in some
WT control mice immunized with CFA alone. Injection of rIL-12p70 into
immunized IL-12p40-/- mice resulted in small
myocarditic lesions together with epicardial inflammation in five of
six mice on day 22 (Table II),
demonstrating that susceptibility to disease can be restored by
supplementing bioactive IL-12p70. Thus, IL-12 is critically involved in
the induction of autoimmune myocarditis.
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CD4+ T cells are the critical effector
population responsible for autoimmune myocarditis. We determined T cell
responses in immunized mice by measurement of cytokines in the
supernatants of lymph node cell cultures stimulated with peptide
MA30. BALB/c WT mice mounted a typical Th1-type
response, indicated by high IFN- and low IL-4 levels (Fig. 2). In contrast,
IL-12p40-/- mice mounted a Th2-type response
indicated by 300-fold reduced levels of IFN- and elevated IL-4 (Fig. 2). On the other hand, IL-10 levels were indistinguishable in
supernatants of the two groups of mice, which may indicate that IL-10
was produced by macrophages in addition to CD4+ T
cells in these lymph node cell cultures. Whereas IFN- levels were
<100 pg/ml, IL-4 and IL-10 were not detectable in supernatants of
lymph node cells stimulated with nonspecific peptide.
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A, levels of
MA30-specific IgG2a were much higher than IgG1
levels in WT mice. In contrast, IL-12p40-/-
mice produced primarily IgG1 Abs, indicative of a Th2-type response.
Furthermore, treatment of IL-12p40-/- mice with
a rIL-4 antagonist that inhibits Th2 responses significantly reduced
IgG1 levels, although IgG2a levels remained unaffected (Fig. 3B). In conclusion, our results demonstrate that protection
from autoimmune myocarditis in IL-12p40-/-
correlated with reduced Th1 and augmented Th2 responses.
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We next assessed the proliferation of purified splenic
CD4+ T cells after stimulation with
MA30 peptide in vitro. As demonstrated in Fig. 4, CD4+ T cells
from immunized IL-12p40-/- mice showed a
dramatically reduced proliferation compared with WT
CD4+ T cells. The addition of IL-12p70 partially
rescued the proliferative response of
IL-12p40-/- CD4+ T cells,
but differences between Ag-restimulated WT and
IL-12p40-/- CD4+ T cells
were still significant (Fig. 4). In contrast,
CD4+ T cells from immunized IL-12R1 mice do
not show any proliferation in the presence of IL-12p70. These findings
confirm the presence of Ag-specific CD4 T cells in immunized
IL-12p40-/- mice and suggest that the
proliferation of these cells depends, at least partly, on IL-12p70.
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-deficient mice develop enhanced autoimmune myocarditis
We recently reported that IFN-R1-deficient mice develop fatal
myocarditis (26). However, resistance to myocarditis in
IL-12-deficient mice was associated with severely reduced IFN- (Th1)
responses. To rule out that IFN- induces myocarditis by signaling
through a receptor other than IFN-R1 (i.e., IFN-R2), we compared
IFN--deficient mice immunized with MA30.
Consistent with the results in IFN-R1-deficient mice,
IFN--deficient mice developed disease with increased prevalence and
severity compared with WT mice. In contrast to WT controls and
IL-4R-/- mice, myocarditis persisted up to
44 days after the first immunization (Table I
). Hearts were enlarged
and appeared necrotic, and inflammatory lesions were observed
macroscopically. Histologic analysis revealed dense infiltrations
forming microabscesses with histiocytes, lymphocytes, and numerous
eosinophils (Fig. 1). These results unequivocally demonstrate that the
absence of IFN- promotes autoimmune heart disease and that
protection from disease in IL-12p40-deficient mice was not a
consequence of defective IFN- production.
Elevated Th2 responses are not responsible for protection in the absence of IL-12
Next, we investigated the role of Th2 responses in autoimmune
myocarditis using IL-4R-deficient mice with defective Th2
development (27). Interestingly, in contrast to WT
controls, disease showed high prevalence in
IL4R-/- mice 2 wk after priming with
MA30. On the other hand,
IL-4R-/- mice also seemed to resolve the
disease earlier. On day 22 after priming, disease prevalence was lower
in IL-4R-/- compared with WT mice, and
hearts appeared less inflamed, with an increased number of fibroblasts
indicating repair of inflammatory lesions (Fig. 1). Moreover,
IL-4R-/- mice recovered entirely from
disease 3 wk after challenge, while some WT mice still showed
myocarditis at this time point (Table I). To obtain a more definitive
answer on the role of increased IL-4/Th2 responses in
IL-12p40-deficient mice, we inhibited IL-4R signaling by treatment with
a recombinant IL-4 antagonist (24). However, none of the
treated IL-12p40-deficient mice developed inflammatory infiltrates in
the heart (Table II). Thus, increased Th2 responses were not
responsible for protection in the absence of IL-12. In agreement with
our finding in IL-4R-/- mice, neutralization
of IL-4 in BALB/c control mice slightly reduced disease prevalence 3 wk
after priming (Table II). Together, these results suggest that the Th2
environment can delay induction as well as cure of autoimmune
mycocarditis. Nevertheless, augmented Th2 responses are not responsible
for protection from disease in the absence of IL-12.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1-/- mice developed disease.
Protection in the absence of IL-12 was unequivocally linked with
defective Th1 and augmented Th2 responses to -cardiac myosin. This
finding apparently supports the view that IL-12 induces autoimmunity by
priming autoreactive IFN--producing Th1 cells and/or the inhibition
of protective Th2 cells (28, 29). Indeed, IFN- has been
implicated as an autodestructive cytokine. In contrast, our results
demonstrate that IFN- has a protective, rather than destructive,
role in myocarditis, because IFN--deficient and IFN-R1-deficient
mice developed fatal disease. In agreement with this, IFN- is
dispensable for the development of experimental colitis (20, 30) and confers resistance to EAE (31). We and
others have recently suggested that IFN- is essential to inhibit the
expansion of autoreactive CD4+ T cells (26, 32) through induction of NO (26).
In both disease models, EAE and 2,4,6-trinitrobenzene sulfonic
acid-induced colitis, IFN-R-deficient mice maintained type 1
inflammatory responses, as indicated by high IFN- and TNF-
production and the absence of type 2 responses (30, 31).
This demonstrates that IFN- is not critically involved in Th subset
polarization. In contrast, IL-12 appears to be critical for the
induction and expansion of myosin
(MA30)-autoreactive Th1-type cells and the
inhibition of Th2-type cells. Preferential Th2 cell development did not
confer protection in IL-12-deficient mice, because inhibition of IL-4
signaling in IL-12p40-/- mice with a potent
IL-4 antagonist failed to promote disease. Although the treatment
successfully inhibited a Th2-type IgG1 Ab response, it remained
possible that Th2 development was not completely abolished. Results
from IL-4R-deficient mice indicated that IL-4-producing Th2 cells have
an ambiguous role in myocarditis. The Th2 subset appears to delay the
onset and recovery from myocarditis. IL-4/IL-13 produced by Th cells or
other cells shortly after immunization may directly inhibit IL-12
production and, consequently, disease induction. In contrast, in a
later stage IL-4-producing cells promote disease, possibly by
inhibiting the production of protective IFN-. Nevertheless, our
results demonstrate that enhanced Th2-type responses did not confer
resistance to myocarditis in the absence of IL-12.
Anti-myosin Abs are a marker of myocardial injury and have been shown to contribute to pathogenesis upon transfer to susceptible mice (33). Resistant IL-12p40-deficient mice produced mainly IgG1 anti-myosin Abs, in contrast to susceptible WT mice with prevailing IgG2a autoantibodies. Nevertheless, protection from myocarditis in IL-12p40-deficient mice was unlikely to have resulted from an altered ratio of IgG1:IgG2a autoantibodies, as a reduction in IgG1 autoantibody levels by inhibition of IL-4 did not induce pathogenesis. Furthermore, myocarditis develops in the complete absence of B cells and autoantibodies (34).
The intriguing question of how Th1 cells mediated disease if not by
secretion of IFN- cannot be answered definitively at present.
TNF- and/or lymphotoxin production by Th1-type cells may be involved
in the induction of autoimmunity. Interestingly, TNFRp55-deficient mice
are protected from myocarditis, whereas the absence of TNF- and
lymphotoxin does not protect susceptible mice from EAE
(35). In this model TNF- appears to mediate an
anti-inflammatory role, as lack of TNF- predisposes resistant
mice to autoimmune EAE (36). We found that administration
of recombinant TNF- to MA30-immunized,
IL-12-deficient mice did not restore susceptibility to myocarditis
(Table II), suggesting that this was not caused by reduced TNF-
production. The observation that MA30-specific T
cells from IL-12-deficient mice proliferated poorly in vitro indicates
that IL-12 was required for the expansion of autoreactive
CD4+ T cells. Furthermore, in the absence of
IL-12, autoreactive Th1 cells may not migrate to the target organ
(i.e., heart) because of reduced expression of chemokine receptor(s)
and/or adhesion molecule(s), such as CXCR3, CCR5 (37, 38),
and/or fucosylated PSGL-1 (39, 40),
respectively.
In summary, we have demonstrated that IL-12 and IFN- have opposing
roles in the development of myocarditis. IL-12 is responsible for
disease induction by a mechanism independent of IL-4/IFN-
regulation, while IFN- ameliorates disease. Targeting both cytokines
individually with specific drugs that inhibit IL-12 and promote the
IFN- pathway may lead to an improved therapy for autoimmune heart
disease.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Manfred Kopf, Basel Institute for Immunology, Grenzacherstrasse 487, CH-4005 Basel, Switzerland. E-mail address: kopf{at}bii.ch; or Dr. Urs Eriksson, Medicine A, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland. E-mail address: ueriksson{at}uhbs.ch
3 Abbreviations used in this paper: CMI, cell-mediated immunity; EAE, experimental allergic encephalitis; MA30, heart muscle-specific peptide derived from -myosin H chain; WT, wild type.
Received for publication April 24, 2001. Accepted for publication August 30, 2001.
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A. Y. Park, B. Hondowicz, M. Kopf, and P. Scott The Role of IL-12 in Maintaining Resistance to Leishmania major J. Immunol., June 1, 2002; 168(11): 5771 - 5777. [Abstract] [Full Text] [PDF]
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) and WT mice ( •).
B, Production of IgG1 vs IgG2a in
IL-12p40-/- ([squlo) and WT mice (
) treated with an
IL-4 antagonist. Groups of mice were immunized with MA30
and bled 22 days later. IgG1 and IgG2a serum levels of
MA30-specific Abs were determined by ELISA. Values indicate
end-point titers of individual mice.
) or unspecific OVA (