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Suppression of type II collageninduced arthritis by monoclonal antibodies.

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48
SUPPRESSION OF TYPE I1 COLLAGEN-INDUCED
ARTHRITIS BY MONOCLONAL ANTIBODIES
SEIICHI KOBAYASHI, KUNIAKI TERATO, YOSHITADA HARADA,
HIDESHIGE MORIYA, and MASARU TANIGUCHI
Some mouse monoclonal antibodies raised
against chicken type I1 collagen suppressed or delayed
the onset of chicken type I1 collagen-induced arthritis in
DBA/l mice. This was correlated with the suppression of
anti-mouse type I1 collagen antibody responses following immunization with chicken type I1 collagen. The
epitopes recognized by the suppressive antibodies were
found to be present on cyanogen bromide (CB)Aigested
collagen peptides CB-11 and CB-12. This was also
confirmed by the finding that administration of the
CB-11 or CB-12 peptide suppressed the induction of
arthritis.
Immunization with native chicken type I1 collagen (CII) is known to cause arthritis in animals (1-3).
Collagen-induced arthritis can also be adoptively
transferred by sensitized spleen cells, and can be
induced by passive transfer with anti-type I1 collagen
antibodies (4). Moreover, for the development of
arthritis, a specific epitope of collagen is important:
From the Tsukuba Research Laboratories, Esai Co., Ibaraki, Japan; the Veterans Administration Hospital Medical Center,
Memphis, Tennessee; and the School of Medicine, Chiba University, Chiba, Japan.
Seiichi Kobayashi, PhD: Tsukuba Research Laboratories;
Kuniaki Terato, PhD: VA Hospital Medical Center; Yoshitada
Harada, MD: Department of Orthopedics and Division of Molecular
Immunology, Center for Neurobiology and Molecular Immunology,
School of Medicine, Chiba University; Hideshige Moriya, MD:
Department of Orthopedics, School of Medicine, Chiba University;
Masaru Taniguchi, MD: Division of Molecular Immunology, Center
for Neurobiology and Molecular Immunology, School of Medicine,
Chiba University.
Address reprint requests to Seiichi Kobayashi, PhD,
Tsukuba Research Laboratories, Eisai Co., Ltd., Tokodai 5-1-3,
Tsukuba, Ibaraki 300-26, Japan.
Submitted for publication February 16, 1990; accepted in
revised form July 27, 1990.
Arthritis and Rheumatism, Vol. 34, No. 1 (January 1991)
Immunization with the cyanogen bromide (CB)digested type I1 collagen peptide 11 (CB-11 peptide),
but not with other peptides, successfully induced
arthritis in DBA/l mice (5). This indicates that the
CB-11 peptide, rather than other portions of collagen,
has an immunogenic epitope important in the induction of arthritis in the mouse.
Conversely, recent studies have demonstrated
that the immune response to collagen, as well as the
induction of arthritis, can be modified by free collagen
or anticollagen antisera (6). Administration of collagen-coupled spleen cells, native CII, a specific CB
peptide, or polyclonal anti-CII before immunization
with type I1 collagen results in the suppression or
delayed onset of collagen-induced arthritis (6-9). Since
the suppression of arthritis can be transferred by
administration of splenic T cells obtained from the
suppressed donor, type I1 collagen is thought to possess epitopes important for the suppression, as well as
the induction, of anti-CII responses or arthritis (10).
In this study, we successfully isolated monoclonal antibodies (MAb) against collagen peptides that
inhibit type I1 collagen-induced arthritis. We also
demonstrated that the epitopes important for the suppression of arthritis are located on the CB-11 and
CB-12 peptides.
MATERIALS AND METHODS
Mice. Male D B N l J mice (H-2q), ages 6-10 weeks,
were obtained from Jackson Laboratories (Bar Harbor, ME)
BALBIc mice, ages 10-20 weeks, were obtained from
Charles River Japan (Atsugi, Kanagawa, Japan). All animals
were housed in a barrier system and fed standard rodent
chow and water ad libitum.
49
MAb SUPPRESSION OF COLLAGEN-INDUCED ARTHRITIS
Preparation of collagen and peptides. Native type I1
collagen from chicken (CII) was prepared according to the
method described by Stuart et a1 (1 1). Type I1 collagen from
mice (MsII) was prepared from articular cartilage as reported previously (5). The purity of CII and MsII was
determined by electrophoresis using 6% polyacrylamide
gels. CII was digested with CB, and CB peptides were
isolated by carboxymethylcellulose column chromatography
as described by Miller (12). Isolated peptides were renatured
to a triple-helical conformation by stepwise cooling. The
physicochemical properties of the CB peptides have been
reported in detail elsewhere (5,13).
Production of MAb. DBA/lJ mice were immunized
with 100 pg of CII. For the immunization, 2 mg/ml of CII
was dissolved in 0.01N acetic acid, emulsified in an equal
volume of Freund’s incomplete adjuvant containing 2 mg/ml
of Mycobacterium tuberculosis (H37.RA; Difco, Detroit,
MI), and injected subcutaneously at the base of the tail as
described previously (5). After 10 days, the mice were given
an intravenous booster injection of 60 pg of antigen dissolved in phosphate buffered saline. Three days later, spleen
cells were collected and fused with Sp2/0-Ag14 myeloma
cells by the polyethylene glycol method, as described by
Kohler (14). After selection by the hypoxanthine, aminopterin, thymidine method, hybridomas were screened by
enzyme-linked immunosorbent assay (ELISA) for the antichicken type I1 collagen antibody. The MAb obtained were
purified by protein A-Sepharose column chromatography
(MAPS-11; BioRad, Richmond, CA).
Induction of type I1 collagen-induced arthritis in mice.
Chicken type I1 collagen was injected subcutaneously into
the base of the tail of DBA/1 mice (100 pghouse). Arthritis
appeared within 4 5 weeks after immunization. The severity
of arthritis symptoms of the forepaws and the hindpaws of
each mouse was scored on a scale of 0-4,where 0 = no
change, 1 = slight change in the joints of the digits, 2 = slight
edema of the paw or swelling of more than 2 digits, 3 =
moderate swelling of the paw; and 4 = severe swelling of the
paw. The sum of the scores of all 4 paws for each animal was
recorded as the arthritis index.
ELISA. Anticollagen antibody levels were determined by ELISA (5). Either chicken or mouse type I1
collagen was dissolved in 0.05M acetic acid and diluted with
phosphate buffer, pH 7.6, p = 0.4, to give a final concentration of 5 pg/ml. A 100-pl aliquot of collagen solution was
added to a round-bottom vinyl plate (Serocluster, #2797;
Costar, Cambridge, MA) and incubated overnight at room
temperature. After extensive washing with 0.15M NaCl
containing 0.05% Tween 20, samples containing antibodies
diluted with 0.1M Tris HCI, 0.15M NaC1, 0.05% Tween 20,
pH 7.6, were added to the plate, and the plate was incubated
for 2 hours. Subsequently, 100 pl of peroxidase-conjugated
anti-mouse IgG (1 :2,000 dilution, P-260; Dakopatts, Glostrup, Denmark) was added as the second antibody, and the
incubation was continued for an additional 2 hours. After
further washing followed by the addition of 100 p1 of 0.05%
o-phenylenediamine containing 0.017% H,O,, enzymatic
activity was measured according to the optical density at 490
nm, using a microplate photometer (type MTP-22; Corona
Electric, Saitama, Japan). Pooled sera from mice with type
I1 collagen-induced arthritis were used as standards, and
antibody levels in tested samples were calculated from a
standard curve.
Determination of epitopes recognized by anti-type I1
collagen antibody. To determine the epitopes recognized by
anti-type I1 collagen antibodies, a 96-well microtiter plate
was coated with renatured CB peptides (CB-8, CB-9, CB-10,
CB-11, and CB-12) and incubated overnight with 0.1 ml of
hybridoma supernates. Peroxidase-conjugated anti-mouse
IgG was used as the second antibody. All procedures were
performed at 4°C to avoid denaturation of renatured CB
peptides. For the competitive binding studies with ELISA, a
96-well microtiter plate was coated with 50 pl of antigen per
well and incubated with 50 pl of unlabeled antibody for 30
minutes, followed by incubation with 50 pl of biotinylated
MAb for 2 hours at room temperature.
Statistical analysis. Results are expressed as the mean
SEM of 5-10 samples. Statistical significance was determined using Student’s t-test.
*
6
c
T
Weeks after
1
Immunization
Figure 1. Effect of native chicken type I1 collagen (CII) and its
cyanogen bromide (CB)aigested peptides on type I1 collageninduced arthritis in DBAUJ mice. Mice were injected intravenously
with phosphate buffered saline ( 0 ) (control), 100 pg of CII (0).or
500 pg of CB-8 (A), CB-I0 (A),CB-11 (O),or CB-12 (0).
One week
later, the mice were immunized subcutaneously with CII into the
base of the tail, and the appearance of arthritis was measured as
described in Materials and Methods. Values are the mean maximum
arthritis scores in 5 animals. Bars show the SEM of the control group.
KOBAYASHI ET AL
50
Table 1. Reactivities of monoclonal antibodies (MAb) with cyanogen bromide (CB)-digested
peptides of chicken and mouse type I1 collagen*
Relative reactivity of MAb against CB peptide
Clone
no.
Epitope
CB-8
CB-10
CB-11
CB-11
CB-I 1
CB-11
CB-I 1
CB-I1
CB-I 1
CB-12
Other
CB-11/12
8
5
6
18
45
35
3
4
21
12
21
10
CB-8
CB-I0
CB-I 1
CB-12
MsIIt
100
0
0
0
10
0
0
0
0
0
0
0
6
100
23
0
12
100
100
100
100
100
0
0
0
2
16
8
0
0
0
100
0
85
58
77
3
52
5
16
5
0
0
0
19
0
3
100
100
0
0
100
6
62
57
3
70
3
88
55
* Antibody reactivity was determined by enzyme-linked immunosorbent assay, as described in
Materials and Methods. Each value represents relative reactivity (%) against the fragment, with the
greatest reactivity expressed as 100%.
t Reactivity against mouse type I1 collagen (MsII) was also examined and expressed as a percentage
of reactivity against chicken type I1 collagen.
RESULTS
Suppression of collagen-inducedarthritis by CBdigested collagen peptides. In order to investigate the
immunodominant epitopes on type I1 collagen, we
10
3.0
intravenously injected 100 pg of native CII or 500 pg
of CB-digested CII into DBN1 mice. Seven days later,
the mice were immunized with CII emulsified with
Freund's complete adjuvant. As shown in Figure 1,
the onset of arthritis was significantly delayed when
I
4.0
5.0
6.0
Weeks after Immunization
7.0
Weeks after Immunization
Figure 2. Inhibitory effect of anti-chicken type I1 collagen (anti-CII) antibodies on type I1 collagen-induced arthritis. a, Mice were pretreated
with 1.O mg of pooled anti-CII MAb that recognize cyanogen bromide (CB) peptides of CII, such as CB-8 (A------A), CB-10 (A- --A), CB-I 1
( 0 ) . and CB-12 (B).
One week later, mice were immunized with CII and the appearance of arthritis was measured. Results for the phosphate
buffered saline (PBS)-treated control group (0)and the polyclonal anti-CII antibody-treated group (0)are also shown. b, Effect of MAb
reactive with the CB-11 peptide on type I1 collagen-induced arthritis. One milligram of MAb 6 (A------A), 10 (a), 18 (A- - -A), or 45 (m) was
injected into mice, followed by immunization with CII. Results with mixtures of antibodies, G1 (0)and G2 (O), and with PBS (0)are also
shown. Values are the mean maximum arthritis scores in 5 animals. Bars show the SEM of the control groups.
51
MAb SUPPRESSION OF COLLAGEN-INDUCED ARTHRITIS
100
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Antibodies added (vg/ml)
Figure 3. Competitive inhibition of anti-chicken type I1 collagen (CII) monoclonal antibodies (MAb) 6 (1-3 8D8E) (a), 10
(3-1 2A5A) (b), 18 (3-5 3D7H) (c), and 45 (M44 3B9B) (d). Peroxidase-conjugated antibodies (1 pg) were mixed with various
concentrations (10 ng-100 pg) of unlabeled antibody to the cyanogen bromide (CBWigested CB-11 peptide of CII, and
incubated on a CII-coated plate for 1 hour at room temperature. The plate was washed and the amount of peroxidaseconjugated antibody bound to the plate was measured by enzyme-linked immunosorbent assay. In addition to the 4
antibodies shown (group l), 4 other antibodies were also used in competitive inhibition studies (MAb 3,4,21, and 35; group 2).
CII or CB-11 peptide was injected. Moreover, although the effect was less marked than in the CB-11treated group, suppression of arthritis was also observed in the group injected with the CB-12 peptide.
However, no significant effect was observed after
administration of other peptides, such as CB-8 and
CB-10 (Figure 1). These results suggest that both
CB-11 and CB-12 possess epitopes that are important
in the suppression or delayed onset of arthritis.
Characterization of anti-chicken type I1 collagen
MAb. Spleen cells from mice immunized with CII
were fused with SpyO-Ag14 myeloma cells. We obtained 54 clones of hybridomas producing anti-CII
antibodies. These antibodies were classified into 6
52
groups according to their reactivity with the peptides
of the CII molecule. The specificities of typical MAb
used in this study are shown in Table 1. Generally, 1
MAb reacts specifically with 1 CB peptide of CII.
However, there are some antibodies with reactivity
against 2 CB peptides, such as antibody 10, which
reacts with both CB-11 and CB-12 peptides.
Suppression of collagen-induced arthritis by
MAb. To examine the modulating effects of anti-CII
antibodies on collagen-induced arthritis and anticollagen antibody responses, mice were injected with
monoclonal or polyclonal anti-CII antibodies, followed by immunization with CII. Figure 2a shows the
changes in the arthritis index in mice treated with
polyclonal and a mixture of randomly selected monoclonal anti-C11 antibodies. The mixture of MAb recognizing the CB-11 peptide, as well as polyclonal antiCI1 antibody, effectively suppressed arthritis, while
antibodies reactive with other epitopes, such as CB-8,
CB-10, and CB-12, were less effective or ineffective.
Therefore, we further analyzed anti-CB- 11 antibodies.
We randomly chose 8 different anti-CB-11
MAb recognizing distinct epitopes on the CB-11 peptide on the basis of peptide-binding inhibition assays (4
examples are shown in Figure 3 ) , and we examined the
suppressive effects of these MAb on collagen-induced
arthritis. Initially, the antibodies were randomly divided into 2 groups. As shown in Figure 2b, group 1
(Gl), which is a mixture of 4 CB-11 MAb (clones 6, 18,
45,and 10; see Table I), significantly delayed the onset
of arthritis, whereas group 2 (G2) (clones 3, 4,21, and
35) did not. The suppressive effects of the MAb in
group G1 were nearly the same as or more potent than
those seen with conventional anti-CB-l l antibodies.
These findings were confirmed by the additional experiments shown in Table 2.
To clarify which antibody in group 1 was most
responsible for the suppression of arthritis, we administered each MAb individually and examined its effects
on type I1 collagen-induced arthritis. Among these
suppressive antibodies, MAb 10 appeared to have the
most striking effect. However, the suppressive activity
of MAb 10 was less than that of the mixture of 4 MAb
(Gl) (Figure 2). This suggests that more than 1 epitope
is involved in the suppression of arthritis induction.
Localization of peptide epitopes that are essential
for suppression of arthritis. As demonstrated in Figure
3 , MAb 6, 18, 45, and 10 in group 1 were found to
recognize different epitopes on the CB-11 peptide. We
thus used mixtures of 3 antibodies and compared their
effectiveness in suppressing arthritis. The results pre-
KOBAYASHI ET AL
sented in Table 2 show that mixture G1 - 10, in which
antibody 10 was excluded from group 1, failed to
suppress arthritis (4 of 5 mice developed arthritis).
The other 3 antibody mixtures, G1 - 6, G1 - 18, and
G1 - 45,all of which contained antibody 10, were able
to suppress arthritis (arthritis developed in 2 of 5 mice,
2 of 5 mice, and 1 of 5 mice, respectively). In the
control group that was not given any antibody and in
the group given the G2 mixture, 8 of 10 mice and 5 of
5 mice, respectively, had developed arthritis 6 weeks
after immunization with CII. These results suggest
that antibody 10 is essential for suppression of arthritis, but other anti-CB-11 antibodies may enhance this
suppression.
Of particular importance was the finding that
groups of mice in which the arthritis was suppressed
showed low levels of anti-MsII autoantibodies, while
no significant change in anti-CII antibody production
was observed in any of groups, irrespective of suppression of arthritis. Therefore, the incidence of arthritis and the anti-MsII antibody level appear to be
correlated with each other, and antibody 10 appears to
be largely responsible for suppression of anti-MsII
autoantibody production.
DISCUSSION
Significant amounts of anti-type I1 collagen
have been detected in sera from patients with rheumatoid arthritis (15). Indeed, CII or anti-CII antibodies
induce arthritis in rodents, in which anti-type I1 collagen antibodies and complement have been shown to
play important roles in the onset of arthritis (15,16).
Moreover, induction of autoantibodies that react with
mouse type I1 collagen after immunization with CII
collagen seems to be associated with the development
of arthritis. Conversely, administration of anti-CII
antibodies before immunization with type I1 collagen
results in suppression of the development of arthritis.
Thus, anti-CII antibodies can have 2 opposite functions in the regulation of collagen-induced arthritis. It
is not known, however, whether both functions can be
performed by the same antibody.
Recent studies by several investigators have
demonstrated that there are specific epitopes on an
antigen molecule that are recognized exclusively by
either T helper cells or T suppressor cells (17). For
example, in the hen egg lysozyme system, T suppressor cells are stimulated by a cyanogen bromide fragment, the N-C peptide, which is different from the
portion of the molecule recognized by T helper cells
53
MAb SUPPRESSION OF COLLAGEN-INDUCED ARTHRITIS
Table 2. Suppression of arthritis and of autoantibodies to type 11 collagen from mouse (MsII) and chicken (CII) sources by anti-CII monoclonal
antibodies (MAb)*
6
Experiment 1
Control
GI
G I - 10
GI - 6
GI - 18
G I - 45
G2
Anti-CB-11
Experiment 2
Control
G1
G2
Anti-CB-I I
Anti-CII
10
Antibody level at 6 weeks, pglml
Arthritis at 6 weeks
MAb
18
45
Incidence
Index
Anti-MsII
Anti-CI1
8/10
215
415
215
215
115
515
215
4.7 2 1.0
1.0 ? 0.6t
4.4 5 1.3
1.6 5 1.3t
2.0 ? 0.89
0.8 ? 0.8t
4.6 2 1.0
1.4 -+ 0.9t
203 ? 30 (0)
84 f 25 (58.5)t
173 2 52 (14.9)
42 2 15 (79.1)$
80 2 18 (60.6)t
69 f 21 (65.9)$
109 f 14 (46.2)
37 2 17 (81.9)$
397 f 43 (0)
300 2 57 (25.4)
290 41 (26.9)
331 53 (16.6)
290 L 41 (26.9)
316 2 46 (20.3)
317 ? 36 (20.2)
364 49 (8.2)
8/10
015
315
1I5
015
3.1
0.0
2.4
0.2
0.0
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
2
2
2
2
*
0.9
O.Ot
1.5
0.2t
o.ot
*
*
*
* Values for the arthritis index (see Materials and Methods for details) and antibody levels are the mean 2 SEM; values in parentheses are
percent inhibition. Antibody levels were determined by enzyme-linked immunosorbent assay. Anti-CB-l l = antibody to cyanogen bromide
peptide eleven of CII; ND = not done. See Results for explanation of MAb groups 1 and 2 (G1 and G2).
t P < 0.05 versus controls.
$ P < 0.01 versus controls.
P P < 0.10 versus controls.
(18). These are referred to as suppressor and helper
epitopes, respectively.
In type I1 collagen-induced arthritis, helper
epitopes seem to be present on the CB-11 peptide
since, as we have demonstrated previously, immunization with CB-11 peptide alone can induce arthritis in
DBA/1 mice (5). In contrast, suppressor epitopes are
present on both CB-11 and CB-12, as shown in Figure
1 . Significant suppression of type I1 collagen-induced
arthritis was caused by administration of either CB-11
or CB-12. Myers et a1 have also demonstrated the
existence of a suppressor epitope on the CB-11 peptide
fragment of type I1 collagen (19). They identified the
critical determinant as residing within the region of
CB-11, at residues 137-147 from the N terminus.
Therefore, our data are consistent with their findings,
although we have not yet determined the essential
amino acid sequence.
Moreover, the above findings were supported
by the results shown in Figure 2 and Table 2, which
demonstrate that MAb recognizing the CB-11 and
CB-12 peptides are essential for suppression of arthritis development. For effective suppression, antibodies
recognizing different epitopes on CB-11 and CB-12
peptides are necessary. A similar observation on the
inhibition of arthritis by anti-type I1 collagen antiserum has been reported by Wooley et a1 ( 6 ) .
The mechanisms of suppression of arthritis by
anti-type I1 collagen antibodies are still unknown.
However, it is quite possible that the suppressive MAb
reacts with antiidiotypic T cells bearing the antigen
receptor with the epitope that mimics the suppressor
epitope on the CB-11 and CB-12 peptides (internal
image of the suppressor epitope), and thus stimulates
T suppressor cell pathways. Our group has previously
demonstrated this possibility in the case of suppression of anti-keyhole limpet hemocyanin (anti-KLH)
antibody responses with antibodies (20). In the KLH
system, only 3 of 120 anti-KLH MAb reacted with 1 T
cell hybridoma with KLH-specific suppressor activity
and induced suppression of KLH-specific antibody
responses. In the present study, also, only a few of the
anti-type I1 collagen antibodies (such as antibody 10)
had suppressor activity and could prevent the induction of arthritis.
Another intriguing finding is that anti-type I1
collagen antibodies with suppressive activity do not
affect antibody responses to CII antigen. However, a
suppressive MAb, specifically MAb 10, does inhibit
production of autoantibodies against mouse type I1
collagen. This strongly suggests that the production of
anti-MsII autoantibodies followed by immunization of
mice with chicken type I1 collagen is important for
induction of arthritis, and also indicates that suppression of autoantibodies against mouse type I1 collagen
by a particular MAb, such as antibody 10, leads to
KOBAYASHI ET AL
54
inhibition of the induction of arthritis. Therefore, for
further analysis of the suppression of arthritis development, it is essential to identify the chemical structure of the suppressor epitopes on ~ ~ - and
1 1 CB-12
peptides of CII and MslI recognized by the antibody
10. Such a study is currently in progress.
10.
11.
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