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*
Biozentrum, Physiologische Chemie II, Universität Würzburg, Würzburg, Germany;
Klinik und Poliklinik für Haut- und Geschlechtskrankheiten der Universität Würzburg, Würzburg, Germany; and
Max-Planck-Institut für Immunbiologie, Freiburg, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and
is an antagonist for IL-4 and IL-13 in vitro. Treatment of BALB/c mice
with QY during immunization with OVA completely inhibited synthesis of
OVA-specific IgE and IgG1. BALB/c-derived knockout mice lacking either
IL-4 or IL-4R also did not develop specific IgE or IgG1, but mounted
a much stronger IgG2a and IgG2b response than wild-type mice. In
contrast, QY treatment of normal BALB/c mice suppressed specific IgG2a,
IgG2b, and IgG3 synthesis, which may indicate the development of
tolerance toward the allergen. Associated with the lack of IgE
synthesis in QY-treated wild-type mice and in
IL-4-/- mice used as a control was the failure to
develop immediate cutaneous hypersensitivity or anaphylactic shock upon
rechallenge. Interestingly, QY treatment also inhibited humoral immune
responses and allergic reactivity in SJL/J mice, a strain that did not
produce IgE, but displayed IgE-independent mast cell degranulation
mediated by specific IgG1. We conclude that QY inhibits Ag-specific
humoral immune responses and allergic symptoms mediated either by IgE
or IgG1. It needs to be clarified how QY abrogates synthesis of IgG2a,
IgG2b, and IgG3, but the induction of tolerance toward nonhazardous
protein Ags should be advantageous for therapy of atopic disorders and
other Th2-dominated diseases. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, which organizes intracellular
signals in response to both cytokines (5, 6). Signal transduction is
induced by heterodimerization of the IL-4R with a second subunit,
which may vary in different cell types.
Specific inhibition of IL-4 can be achieved with antagonistic IL-4
mutants. Variants of human IL-4 that bind to the first receptor subunit
(IL-4R) but not to the second (either 
c or IL-13R1) are
competitive antagonists for IL-4 (7, 8). IL-13 is inhibited by the same
variants, which form unproductive complexes with IL-4R (5, 9). The
single site human IL-4 mutant Y124D has been used as IL-4/IL-13
inhibitor in various studies (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17), but this variant retains some
residual agonistic activity, which could be relevant for in vivo
applications (7, 8). The double mutant R121D/Y124D lacks detectable
activity and appears to be a perfect antagonist for human IL-4 and
IL-13 (5, 18). A major obstacle for testing the effects of antagonistic
IL-4 mutants in vivo is the species specificity of IL-4. Human IL-4
does not bind to the mouse receptor and vice versa, so human IL-4
antagonists cannot be tested in mice.
We have recently developed a highly efficient murine IL-4 antagonist
(QY), where the amino acids glutamine 116 and tyrosine 119 were mutated
to aspartic acid (19). This murine mutant is analogous to the
R121D/Y124D double mutant of human IL-4. QY binds with high affinity to
the murine IL-4R without inducing signal transduction, has no
detectable activity upon proliferation or differentiation of murine
cells, and an excess of QY completely inhibits responses toward
wild-type IL-4 (19). Like its human analogue, the QY mutant is an
antagonist for IL-13 (B. Schnarr et al., unpublished observations).
Recent experiments with monocytic cells from mice lacking a functional
c gene showed, that QY is a complete inhibitor for IL-4 in the
absence of c as well (20).
In this study we have examined the effects of QY in vivo, using a mouse
model of allergy against the protein antigen OVA. The effects of the
inhibition of IL-4 and IL-13 by QY on the humoral immune response were
compared with knockout mice lacking either IL-4 (21) or IL-4R (M.
Mohrs et al., manuscript in preparation). We show here that QY
treatment prevented humoral immune responses toward the Ag, as well as
clinical manifestations of type I allergic symptoms.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female BALB/c and SJL/J mice between 8 and 12 wk of age were
purchased from Charles River (Sulzfeld, Germany). The animals were kept
under specific pathogen-free conditions and maintained on OVA-free
diets. BALB/c IL-4-/- mice and BALB/c
IL-4R-/- mice were obtained from the
Max-Planck-Institut für Immunbiologie (Freiburg, Germany).
Allergic sensitization procedure
Mice were immunized by i.p. injection with 10 µg OVA (Sigma, Deisenhofen, Germany; Grade V) in a solution containing 200 µl PBS and 70 µl Imject Alum (Pierce/KMF, St. Augustin, Germany) as an adjuvant.
IL-4 antagonist (QY)
The QY mutant was synthesized and purified as described (19). Briefly, the protein was expressed in Sf9 insect cells after infection with recombinant baculoviruses. QY was secreted as active protein into the cell culture supernatant and purified by ion exchange chromatography and reversed phase HPLC to a final purity between 80 and 90%. Protein was lyophilized and stored at -20°C until use. For in vivo therapy, QY was first dissolved in water. Mice were injected i.p. twice a day with QY diluted in 200 µl PBS. At day 0, QY was applied 2 h pre- and post-Ova immunization as a 50-µg dose each. QY treatment was continued from day 1 to 8 with 30 µg QY per injection twice a day.
Serum Ab titers
Anti-OVA IgE and IgG subclasses were measured by ELISA. Plates were coated for 6 h at 37°C with 100 µl 0.1 M NaHCO3 containing 100 µg OVA per milliliter. The plates were blocked 2 h at 37°C with 200 µl 3% BSA in PBS. Plates were washed, and 100 µl of 1:40 serum dilutions with PBS containing 1% BSA were applied overnight at 4°C. The amount of bound Ab was analyzed using horseradish peroxidase-conjugated Abs against mouse heavy chain classes. Rat mAbs against mouse IgE and IgG1 were from PharMingen (Hamburg, Germany), goat antisera against mouse IgG2a, IgG2b, and IgG3 were from SBA (Biozol, Eching, Germany). Plates were read in a microplate autoreader (Dynatech MR5000, Denkendorf, Germany) at 405 nm. Serum titers for all Abs were expressed as relative ELISA units (RU),4 referring to a laboratory standard sera pool, which was collected 20 days after sensitization with OVA (22). Standard sera were applied on each plate in a 1:10 dilution. To obtain optimal signal/noise ratios for each subtype, plates were read when the standard samples reached a previously defined optical density (OD 0.130 or 130 units for IgE and OD 2–2.5 or 2000–2500 units for the IgG subtypes). All samples from one experiment were developed simultaneously on a single plate.
Immediate cutaneous hypersensitivity
Active cutaneous anaphylaxis was tested by skin test after i.v. injection of 200 µl of 0.5% Evans Blue dye in PBS. The skin of the belly was shaved with an electric clipper and four injection sites were marked with a felt tip pen on the skin. Two of the marked sites were injected intradermally with 50 µl PBS containing 1 mg/ml OVA, and the other two sites with protein-free PBS. After 15 min, the mice were killed by cervical dislocation and the skin was stripped off for inspection of the injected sites. The intensity of blue patch formation on the dorsal side of the skin, resulting from fluid extravasation into the injection site upon mast cell degranulation, was scored by two independent observers.
Anaphylactic shock
Mice were injected i.v. with 200 µl 0.5% Evans Blue solution containing 500 µg OVA. After 15 min, symptoms of an anaphylactic shock were assessed by two independent observers who were unaware of the sensitization status of each animal.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Groups of wild-type BALB/c, BALB/c IL-4-/-,
BALB/c IL-4R-/-, and SJL/J mice were immunized i.p.
with 10 µg OVA plus Alum as adjuvant. Negative control animals were
injected only with the adjuvant. In one group of mice, QY was applied
2 h pre- and post-OVA immunization as a 50-µg dose each and was
continued twice a day from day 1 to 8 after sensitization with 30 µg
QY per injection. A second group was injected with PBS instead of QY.
Mice were bled at day 0 before immunization with OVA, and 10 days
later. OVA-specific serum Abs were measured by ELISA. Data for BALB/c
and IL-4-/- mice were collected in three independent in
vivo tests. SJL/J and IL-4R-/- animals were tested in
one in vivo test. Figure 1
shows data
from one representative in vivo test for each mouse strain.
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A, there was a massive induction of IgE
in OVA-sensitized, PBS-treated animals (10 µg OVA BALB/c
IL-4+/+). In contrast, QY therapy (QY + 10 µg OVA
BALB/c IL-4+/+) completely inhibited induction of
OVA-specific IgE in wild-type BALB/c mice. A total of 19 mice were
treated with QY during sensitization in three separate experiments.
None of these mice showed an Ab titer above the baseline level found in
nonsensitized animals (0 µg OVA BALB/c IL-4+/+).
Furthermore, there was no detectable induction of OVA-specific IgE in
OVA-sensitized IL-4 knockout mice (10 µg OVA BALB/c
IL-4-/-), IL-4R knockout mice (10 µg OVA BALB/c
IL-4-/-), or immunized SJL/J mice (10 µg OVA SJL/J) in
comparison with untreated mice (0 µg OVA SJL/J).
There was no induction of Ag-specific IgG1 in immunized but QY-treated
BALB/c mice, or in either of the knockout strains, while BALB/c mice
treated with PBS had a high titer of specific IgG1 (Fig. 1B). In contrast to the results from IgE, SJL/J mice
showed a pronounced production of OVA-specific IgG1, which could be
inhibited by QY.
There was no induction of specific IgG2a or IgG2b over background
levels in QY-treated BALB/c or SJL/J mice, whereas in IL-4 knockout
mice and in IL-4R knockout mice these subclasses were dramatically
up-regulated compared with immunized wild-type BALB/c mice (Fig. 1, C and D).
QY inhibited OVA-specific IgG3 synthesis in SJL/J and BALB/c mice, but
no significant differences in this Ab subclass were found between the
two knockout strains and BALB/c wild-type mice (Fig. 1E). Taken together, these data demonstrate that QY
inhibits the specific humoral immune response to OVA in vivo in two
different mouse strains.
Prevention of immediate cutaneous hypersensitivity in IL-4-/- mice and QY-treated BALB/c or SJL/J wild-type mice
We have further assessed immediate hypersensitivity in skin
responses upon rechallenge of sensitized mice. The mice had been
analyzed for OVA-specific Ab synthesis, 10 days after i.p. immunization
with 10 µg OVA. Following i.v. injection of 0.5% Evans Blue dye
solution, mice received two intradermal injections with OVA in PBS, and
two injections with PBS alone. Positive reactions upon intradermal
injection of Ag resulted in mast cell degranulation and fluid
extravasation, which led to the formation of a blue patch on the
injection site. The intensity of bluing was scored on the dorsal side
of the skin. Data are summarized in Table I.
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(10 µg OVA
BALB/c IL-4R-/-). Non-sensitized wild-type animals (0
µg OVA BALB/c IL-4+/+) also failed to respond to the OVA
injection. Immunized SJL/J mice (10 µg OVA SJL/J) developed positive
skin reactions, despite the fact that these mice did not have a
detectable level of OVA-specific IgE (Fig. 1A). In
QY-treated SJL/J mice, OVA sensitization did not lead to active
cutaneous anaphylaxis (QY + 10 µg OVA SJL/J). These results
indicate that application of QY during the sensitization phase prevents
development of active cutaneous anaphylaxis in response to IgE-mediated
as well as to IgE-independent mast cell degranulation. Prevention of anaphylactic shock in IL-4 knockout mice and QY-treated mice
We have assessed development of anaphylactic shock in wild-type BALB/c and in IL-4 knockout mice, which had been analyzed previously for OVA-specific Ab synthesis, 10 days after i.p. immunization with 10 µg OVA, mice were injected i.v. with 500 µg OVA in an Evans Blue solution. Reactions were scored according to four criteria: Fluid extravasation, piloerection, spontaneous activity, and responsiveness to external stimuli.
OVA sensitized wild-type mice (10 µg OVA BALB/c
IL-4+/+) developed anaphylactic symptoms, which lead
to a severe shock 15 min after injection. The severity of the symptoms
was scored as shown in Table II.
Nonimmunized animals (0 µg OVA BALB/c IL-4+/+; 0 µg OVA
BALB/c IL-4-/-) did not show any reactions. Shock
symptoms were also absent in sensitized but QY treated mice (QY +
10 µg OVA BALB/c IL-4+/+) and in IL-4-/-
mice (10 µg OVA BALB/c IL-4-/-).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been reported that the antagonistic human IL-4 mutant Y124D
leads to decreased ongoing IgE synthesis, which occurs independently of
cytokine treatment in a humanized SCID mouse model (13, 14). Soluble
versions of IL-4R (sIL-4R) or inhibitory anti-IL-4 Abs inhibit
IgE synthesis in mice in response to helminthic infections, treatment
with anti-IgD (24, 25, 26), and inhaled allergen (27, 28). Both sIL-4R
and inhibitory anti-IL-4 Abs have to be used cautiously in vivo,
because binding to these proteins prolongs the serum lifetime of IL-4
and can actually increase its efficiency (26, 29). Class switching to
murine IgG1 and its human analogue IgG4 is regulated by IL-4 (30), but
the inhibition of IL-4 by sIL-4R or inhibitory Abs in vivo results in
most cases only in a moderate decline of IgG1 levels (25, 27, 28) or
has no effect at all (24). In contrast, specific IgG1 synthesis was
completely inhibited by QY treatment. Mast cell degranulation can be
stimulated independently of IgE, presumably mediated through FcRII
receptors (31). We found that IgE-independent mast cell degranulation
occurred in SJL/J mice, which produce very low levels of IL-4 and are
strongly biased toward Th1 immune reactions (32). In accordance, SJL/J
mice failed to develop specific IgE upon sensitization with OVA.
However, they developed specific IgG1 and other IgG subtypes and
reacted with mast cell degranulation upon rechallenge. This response
appears to be mediated by IgG1, because IL-4-/- mice,
which produced specific IgGs of all subclasses except IgG1, did not
display mast cell degranulation.
While IL-4 can at least in human cells contribute to the induction of
various IgG subtypes (33), other cytokines are considered to be more
involved, like IFN- for IgG2a (30) or IL-10 for IgG3 (34). Therefore
it was surprising that QY inhibited not only IgE and IgG1 synthesis,
but also the development of allergen-specific IgG2a, IgG2b, and IgG3.
The QY-induced tolerance to protein Ag was not limited to BALB/c mice,
which are prone to develop IL-4 regulated Th2 responses (35), but also
occurred in Th1-prone SJL/J mice (32), suggesting a strain-independent
mechanism. The QY-induced unresponsiveness cannot be due simply to lack
of IL-4 effects, since treatment with inhibitory Abs or sIL-4R does not
prevent induction of IgG2a, but rather up-regulates synthesis of this
subclass, under conditions where IgE and IgG1 are suppressed (24, 28).
In these experiments, the immune response seems to be redirected rather
then abrogated by treatment with these agents. This is particularly
dramatic in IL-4-/- mice, which show strong
superinduction of specific IgG2a, IgG2b, and IgG3 in response to
Nippostrongylus brasiliensis infection or upon immunization
with (4-hydroxy-3-nitrophenyl) acetyl chicken -globulin (21, 36). In
agreement, we found much higher levels of IgG2a and IgG2b upon OVA
sensitization in IL-4R-/-, and even more so in
IL-4-/-, mice, compared with wild-type mice. This
property of IL-4-/- mice can be interpreted as symptom of
a strong Th1 response, which may occur in the absence of
counterregulating Th2 cytokines.
Because Th2 development and IgE class switching are both dependent on
IL-4 in the mouse, QY may exert its effects on T or B cells. Complete
inhibition of Th2 development should prevent the stimulation of B cells
to synthesize IgE, but, since B cells respond already to very low IL-4
concentrations (8), the direct inhibition of B cells may also
contribute to QY effects in vivo. Since nearly all cell types express
IL-4R, inhibitory effects of QY on other cells may also be relevant.
Comparative studies with IL-4-/- and
IL-4R-/- mice should help to understand the specific
effects of QY in the future. It is presently unclear which receptor and
which cells are responsible for the inhibition of IgG subtypes by QY.
The agent may suppress class switching or inhibit Ab production in
general.
The IL-4-/- knockout, sIL-4R, and inhibitory
anti-IL-4 Abs all target IL-4. In contrast, the target of QY is the
receptor IL-4R. Since this receptor is required for responses toward
IL-13 (5, 6), it could be envisioned that inhibition of IL-13 by QY may
be responsible for suppression of the humoral immune response. This is
not the case, since IL-4R-/- mice, which lack a
functional IL-4R gene (M. Mohrs et al., manuscript in preparation)
showed a similar phenotype as IL-4-/-, with significant
induction of specific IgG2a, IgG2b, and IgG3 upon sensitization, while
no specific IgE or IgG1 could be detected. However, the levels of all
three subclasses appeared to be lower than for the
IL-4-/- mice, which may indicate that IL-13 contributes
to the overall Ig response. Therefore, the mechanisms by which QY
inhibits the humoral immune response is not obvious. QY may interact
with another binding partner besides IL-4R, but it is also possible
that lack of an IL-4/IL-13 stimulus throughout development in the two
knockout strains leads to a different response than short term
inhibition by QY.
The induction of tolerance toward an allergen would be advantageous for therapeutic applications. Since allergens are not pathogenic, anergy toward them is the preferred outcome of any treatment.
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Acknowledgments |
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Footnotes |
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2 Present address: University of Cape Town Groote Schuur Hospital, Department of Immunology, Cape Town, South Africa.
3 Address correspondence and reprint requests to Dr. Albert Duschl, Biozentrum, Physiologische Chemie II,Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany. E-mail address:
4 Abbreviations used in this paper: RU, relative ELISA units.
Received for publication September 9, 1997. Accepted for publication December 11, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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chain. Blood 87:4286.c chain are inhibited by an overlapping set of antagonistic interleukin-4 mutant proteins. Int. Immunol. 9:861. chain: defining receptor complexes responsible for IL-4 and IL-13 signaling. Eur. J. Immunol. 27:1762.[Medline]
subclass-specific isotope switch: switching to 1, 3, and 4, but not 2. J. Immunol. 155:2318.[Abstract]
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