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Treatment of collagen-induced arthritis in rats with a monoclonal antibody against the ╨Ю┬▒ T cell antigen receptor.

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1039
TREATMENT OF COLLAGEN-INDUCED ARTHRITIS IN
RATS WITH A MONOCLONAL ANTIBODY AGAINST
THE
T CELL ANTIGEN RECEPTOR
SHIN YOSHINO, LESLIE G. CLELAND, and GRAHAM MAYRHOFER
A monoclonal antibody (MAb) to the d/3T cell
receptor (TCRdP), R73 MAb, completely blocked the
induction of collagen-induced arthritis (CIA) in rats
when the MAb was administered at the time of immunization with type I1 collagen. When administered after
CIA had begun, the progression of the arthritis was
suppressed significantly by R73 MAb treatment. The
preventive and suppressive effects of R73 MAb on CIA
were associated with the depletion of peripheral blood
d&positive T cells. These results indicate that d p positive T cells play a role in the progression of existing
CIA as well as in its induction.
Collagen-induced arthritis (CIA) can be induced
in mice (l), rats (2), and primates (3) by intradermal
injection of type I1 native articular cartilage collagen
(CII). Many features of CIA resemble those of rheumatoid arthritis in humans (43). It has been shown
that both cellular and humoral immune responses to
CII are involved in the pathogenesis of CIA. The
disease can be transferred by antibodies specific for
CII (6,7). Adoptive transfer of lymphoid cells from rats
From the Rheumatology Unit, Royal Adelaide Hospital,
and the Department of Microbiology and Immunology, University
of Adelaide, Adelaide, South Australia, Australia.
Supported by the Royal Adelaide Hospital Research Fund.
Shin Yoshino, BS, MS, PhD: Senior Research Officer,
Rheumatology Unit; Leslie G . Cleland, MD, FRACP: Director,
Rheumatology Unit; Graham Mayrhofer, BA(Hons), DPhil, BM,
BCh, MA: Senior Lecturer, Department of Microbiology and Immunology.
Address reprint requests to Shin Yoshino, BS, MS, PhD,
Rheumatology Unit, Royal Adelaide Hospital, Adelaide, SA 5000,
Australia.
Submitted for publication October 22, 1990; accepted in
revised form February 21, 1991.
Arthritis and Rheumatism, Vol. 34, No. 8 (August 1991)
immunized with CII (8) and of CII-specific T cell lines
and clones (9) also transmits the disease.
It was previously demonstrated that heterologous anti-T cell sera delayed the onset and reduced
the severity of CIA in rats (10). In the mouse model of
CIA, monoclonal antibodies (MAb) to CD4 (1l),
interleukin-2 receptor (IL-2R) (12), and Ia antigens
(1 3,14) were also effective in preventing or delaying
the induction of arthritis when animals were treated
before or at the time of immunization with CII. However, treatment with the antibodies after an immune
response to CII had become established failed to show
any beneficial effect on the disease. The effects of
these antibodies suggest that T cells play a role in the
induction of CIA, but not in the subsequent evolution
of the disease.
We report here that administration of a MAb
against T cell receptor alp (TCRdp) after the onset of
CIA in rats was able to suppress the progress of the
disease without altering the production of anti-CII
antibody. Treatment with R73 MAb from the time of
immunization completely blocked the induction of the
arthritis. Thus, T cells may be involved in the continuation of CIA as well as in its induction.
MATERIALS AND METHODS
Animals. Inbred female Dark Agouti rats weighing
70-80 gm were obtained from Gilles Plains Animal Resource
Center (Gilles Plains, South Australia). They were housed 5
per cage and fed a standard rodent chow (Milling Industries,
Dulwich, South Australia) and water ad libitum.
Induction of arthritis. To induce CIA, 8 mg of type I1
collagen extracted from native calf articular cartilage (Elastin Products, Owensville, MO) was dissolved in 1 ml of
0.01M acetic acid and emulsified with an equal volume of
1040
Freund’s incomplete adjuvant. Rats were injected intradermally, into the base of the tail, with 0.1 ml of the emulsion
containing 400 pg of CII. The seventy of arthritis was
evaluated in all 4 paws, each of which was graded 0-4
according to the extent of erythema and edema of the
periarticular tissues, as described by Wood et a1 (15) (maximum possible score 16).
Treatment with R73 MAb. Mouse monoclonal antibody R73 against the rat T C R d p was a gift from Dr. T.
Hiinig (Institute for Virology and Immunobiology, University of Wiirzburg, FRG). The preparation and characterization of R73 MAb have been reported (16). One hundred
micrograms of R73 MAb was dissolved in 1 ml of phosphate
buffered saline (PBS), and the solution was injected intraperitoneally at the time of immunization with CII (day 0) and
then every 3 days up to day 27 in one group or on days 17,
20, 23, and 26 after CII immunization in the other group.
Two groups of arthritic controls were given 1 ml of PBS
alone, on the same days as the 2 MAb-treatment groups.
Detection of R73-positive T cells. A small volume of
blood was withdrawn from the tail vein for preparation of
smears prior to each injection of R73 MAb. R73-positive
cells were detected by the alkaline phosphatase/anti-alkaline
phosphatase (APAAP) method described by Cordell et a1
(17). Briefly, blood smears were air dried for 2 hours, fixed in
acetone for 10 minutes, and kept at 4°C until used. The blood
smears were washed 3 times with Tris buffered saline (TBS),
preincubated with 20% normal sheep serum for 20 minutes,
and then incubated with R73 MAb for 60 minutes. The
smears were then washed with TBS and incubated for 30
minutes with F(ab’), fragments of sheep anti-mouse IgG
(Sigma, St. Louis, MO). After washing, the preparations
were incubated for 30 minutes with APAAP complex
(Boehringer Mannheim, North Ryde, New South Wales,
Australia), washed again, and further incubated for 30 minutes with an alkaline phosphatase substrate solution. The
substrate solution was prepared by dissolving 100 mg of
naphthol AS-MX phosphate in 5 ml of dimethyl formamide
and then adding 95 ml of TBS. For use, 1 ml of this solution
plus 1 mg of Fast Red TR and 10 pl of 0.1M levamisole were
mixed and filtered. The smears were counterstained with
hematoxylin, and the percentage of leukocytes that bound to
R73 MAb was determined.
Morphologic studies. Photographs were taken on day
26 after CII immunization to record gross swelling of the
paws. For histologic examination, animals were killed on
day 27, and the hind paws were removed, fixed in 4%
formalin, and decalcified in a solution of 3.1% HCI, 5%
formic acid, and 7% aluminum chloride. The tissues were
embedded in paraffin, sectioned at 4-7 pm, and stained with
hematoxylin and eosin.
Delayed-type hypersensitivity (DTH). On day 25 after
CII immunization, 20 pg of CII was dissolved in 50 pl of
O.OO5M acetic acid and then injected subcutaneously into the
left ear, and 50 p1 of O.OO5M acetic acid alone was injected
into the right ear, of rats treated with R73 MAb and PBS.
The thickness of the right and left ears was measured using
dial-gauge calipers (calibrated with 0.01-mm graduations;
Mitutoyo, Japan) immediately before and 48 hours after a
YOSHINO ET AL
challenge injection of CII. There was minimal ear swelling
after 48 hours in response to 50 pl of O.OO5M acetic acid
alone. Because of the specific response to antigen, the
increase in left ear thickness was subtracted from the increase in right ear thickness to determine the actual values.
Anti-CII antibody assay. Blood was collected as
described above. Sera were removed and were heatinactivated at 56°C for 30 minutes and then stored at -20°C
until used. Anti-CII antibody was measured using an
enzyme-linked immunosorbent assay (ELISA) (18). Briefly,
96-well flat-bottom microtiter plates were incubated with 100
pl/well of CII (20 pg/ml) at 37°C for 1 hour and then washed
3 times with PBS containing 0.05% Tween 20. The wells
were then blocked with 200 pl of PBS containing 1% bovine
serum albumin by incubation at 37°C for 1 hour. After
washing, the plates were incubated with 100 pl/well of 2-fold
dilutions of pooled rat sera at 37°C for 30 minutes. The plates
were washed, and 100 pl/well of a 1:250 dilution of sheep
anti-rat IgG labeled with P-galactosidase (Amersham, North
Ryde, New South Wales, Australia) was added. The plates
were incubated at 37°C for 30 minutes, and washed. After
washing, 100 pl of 3 mM o-nitrophenyl-P-D-galactopyranoside (Amersham) was added to each well, and the plates
were incubated in the dark, at room temperature, for 30
minutes. The absorbance was measured at 410 nm in a
Titertek ELISA reader (Flow Laboratories, North Ryde,
New South Wales, Australia). Antibody titers were expressed as -log,, which is the dilution at which an absorbance value that was twice the control value was obtained.
RESULTS
Induction of CIA. When female Dark Agouti
rats, which were immunized with CII on day 0, were
treated with PBS alone, signs of arthritis were seen on
day 15. Joint scores reached a maximum on day 23
(Figures 1A and B). Thereafter, the edema gradually
subsided; however, the ankylosis of joints gradually
progressed until day 60, when the rats were killed. The
incidence of the disease in this strain was loo%, and all
animals developed severe erosive chronic arthritis.
Effects of R73 MAb on the induction of CIA. To
investigate the effects of R73 MAb on the induction of
CIA, the antibody was administered every 3 days from
the time of CII immunization until day 27. As shown in
Figure lA, the R73 MAb-treated rats failed to develop
CIA. In contrast, severe disease was induced in the
PBS-treated control rats. The difference in clinical
appearance between PBS-treated and R73 MAbtreated animals on day 26 is illustrated in Figures 2A
and B. Arthritis did not develop in the R73 MAbtreated rats, which were observed for a further 33 days
after the cessation of treatment (i.e., up to day 60).
1041
ANTI-TCRa/P THERAPY FOR CIA
Rechallenge with CII on day 60 caused arthritis in 2 of
the 5 animals tested.
Effects of R73 MAb on existing CIA. The effect
of R73 MAb on existing CIA was also investigated.
R73 MAb was given on day 17 after immunization,
when edema was progressing, and thereafter on days
20, 23, and 26. The results are shown in Figures lB,
2A, and 2C. R73 MAb significantly suppressed the
progression of the disease. However, there was an
exacerbation of arthritis after treatment was withdrawn, which became evident on day 30. Thereafter,
no significant difference in clinical scores was observed in the R73 MAb-treated versus the PBS-treated
rats, and joint ankylosis was seen in all rats of both
groups on day 40.
Effects of R73 MAb on the body weight of rats
with CIA. When rats were injected with R73 MAb or
with PBS from the time of immunization (day 0), both
l2I
T
A
0
15
20
25
30
60
Days afler immunization
12/
-7t
0
B
1
I
'
15
I
20
25
30
35
40
Days after immunization
Figure 1. Prevention of induction and suppression of progression of
collagen-induced arthritis by monoclonal antibody (MAb) R73. Rats
were immunized with type I1 collagen on day 0. R73 MAb (100 pg)
(0)
was administered intraperitoneally every 3 days from day 0 to
day 27 (A) or on days 17, 20, 23, and 26 (B).Arthritic control rats
received phosphate buffered saline (0).Bars show the mean 2 SEM
of 5 rats. * = P < 0.01 versus controls, by Student's t-test.
Figure 2. Hind paws of rats with collagen-induced arthritis treated
with A, phosphate buffered saline (arthritic controls), B, 100 pg of
R73 monoclonal antibody (MAb) intraperitoneally every 3 days from
day 0 to day 27, or C, 100 pg of R73 MAb on days 17,20,23, and 26.
Photographs were taken on day 26.
1042
YOSHINO ET AL
160
-
were treated with R73 MAb 17 days after immunization, weight loss was mitigated significantly (Figure
3B).
A
-
n
w
E
120
.-w
Q)
3
0
rn
O L
1
I
I
I
0
10
20
30
Days after immunization
n
w
U
Ew
140
-
.-
s
c
0
100 -
m
1
I
0
10
1
1
20
30
Days after immunization
Figure 3. Changes in the body weight of rats with collagen-induced
arthritis treated with R73 monoclonal antibody (MAb). Rats were
immunized with type I1 collagen on day 0. R73 MAb (100 pg) (0)
was administered intraperitoneally every 3 days from day 0 to day 27
(A) or on days 17, 20, 23, and 26 (B). Arthritic control rats received
;
in normal, untreated rats are
phosphate buffered saline ( 0 )findings
also shown (A).Bars show the mean 2 SEM of 5 rats. * = P < 0.01
versus phosphate buffered saline-treated controls, by Student's
t-test.
the R73 MAb-treated and the PBS-treated animals
gained weight normally up to day 10 (Figure 3A). From
day 10 to day 23, the PBS-treated arthritic rats lost
weight, but then gained weight thereafter. in contrast,
the R73 MAb-treated
gained weight continuOUslY, at a rate which was not significantly different
from that of normal, untreated rats. When animals
Figure 4. Hematoxylin and eosin-stained sections of tarsal joints
from rats with collagen-induced arthritis treated with A, phosphate
buffered saline (arthritic controls), B, 100 pg of R73 monoclonal
antibody (MAb) intraperitoneally every 3 days from day 0 to day 27,
or C, 100 pg of R73 MAb on days 17, 20, 23 and 26. Joints were
examined on day 27. (Original magnification x 100.)
ANTI-TCRcUIP THERAPY FOR CIA
1043
Effects of R73 MAb on histologic changes in the
tarsal joints. Histologic study of the tarsal joints of rats
treated with R73 MAb was performed on day 27. In
animals treated with R73 MAb from the time of CII
Table 1. Effects of R73 MAb on the delayed-type hypersensitivity
reaction to CII in rats with collagen-induced arthritis*
Increase in ear thickness (x to-* mm)
Group
-- --. --... .
/-j
6 o l wc-f"
..
-- I
8
W
40
-.^
.
._.........-..-
A
B
'.
~~
'.
a
0
(3
b
20
U
O L L
0
I
I
I
10
20
30
/w
60
Days after immunization
n
8
40.
W
-a
fn
0
+
I?
20.
B
OL
I
I
I
I
I
0
10
20
30
40
Days after immunization
Figure 5. Percentage of alppositive T cells in peripheral blood
leukocytes from rats with collagen-induced arthritis treated with
R73 monoclonal antibody (MAb). Rats were immunized with type I1
collagen on day 0. R73 MAb (100 pg) (0) was administered
intraperitoneally every 3 days from day 0 to day 27 (A) or on days
17, 20, 23, and 26 (B). Arthritic control rats received phosphate
buffered saline ( 0 ) ;findings in normal, untreated rats are also shown
(A). Blood smears were prepared just before each R73 MAb
injection, to determine the percentage of leukocytes that bound to
R73 (after in vitro incubation with the MAb by the alkaline
phosphatase/anti-alkaline phosphatase method). Bars show the
mean
SEM of 5 rats. * = P < 0.01 versus phosphate buffered
saline-treated controls, by Student's ?-test.
*
167 2 7.7
137 t 7.6
56 t 5.W
8.5 t 2.3t
--
with type I1 collagen (CII) on day 0. R73
monoclonal antibody (MAb) (100 pg) was administered intraperitoneally every 3 days from day 0 to day 27 (group A) or on days 17,20,
23, and 26 (group B). Phosphate buffered saline (PBS) treatment was
given to arthritic control rats. On day 25, CII (20 pg) was dissolved
in 0.00SM acetic acid (SO pl) and injected subcutaneously into the
left ear; the right ear was injected with 0.005M acetic acid (SO PI).
Increase in ear thickness was determined 48 hours later, as described in Materials and Methods. Values are the mean f SEM of 5
rats.
t P < 0.01 versus PBS-treated rats, by Student's ?-test.
fn
+
R73 MAbtreated
rats
* Rats were immunized
,
-
PBS-treated
rats
immunization, there were no signs of joint inflammation (Figure 4B). In contrast, PBS-treated animals had
active synovitis, characterized by marked hyperplasia
of the synovial tissue, pannus formation, massive
infiltration by mononuclear cells, and severe destruction of cartilage and subchondral bone (Figure 4A). In
the rats treated with R73 MAb after the onset of
disease, there was moderate synovial hyperplasia,
with mild mononuclear cell infiltration, and minimal
cartilage destruction (Figure 4C).
Effects of R73 MAb on Culp T cell numbers in rats
with CIA. To investigate whether the preventive and
suppressive effects of R73 MAb treatment on CIA
were associated with the depletion of alp-positive T
cells, the percentage of peripheral blood leukocytes
binding R73 MAb after in vitro incubation with the
MAb was determined 3 days after each injection. As
shown in Figure 5A, alp-positive T cells were depleted
progressively following sequential injections of R73
MAb and, by day 12, constituted less than 10% of
leukocytes. Subsequent administration of R73 MAb
maintained this level of depletion of alp-positive T
cells. Thirty-three days after R73 treatment was discontinued, the percentage of R73-positive cells had
returned to approximately half the pretreatment value.
R73 MAb treatment after the onset of disease also
markedly depleted dp-positive T cells, and cessation
of therapy was followed by partial restoration of the
proportion of positive cells (Figure 5B).
Effects of R73 MAb on the DTH response to CII.
The effects of the depletion of alp-positive T cells by
R73 MAb on the DTH response to CII were examined
on day 25 by injecting the antigen into 1 ear of rats that
1044
YOSHINO ET AL
12 -
A
8-
4 -
10
20
30
40
60
Days after immunization
12
-
DISCUSSION
B
a-
I
4,
0
10
20
30
23, and 26 showed a 38% inhibition of the DTH
response.
Effects of R73 MAb on anti-CII antibody production. To learn whether the prevention and suppression
of CIA by R73 MAb also affected levels of antibody to
CII, anti-CII antibody titers were measured by an
ELISA (Figure 6). In PBS-treated arthritic rats, antibody to CII was present by day 10 after CII immunization, and reached a maximum on day 26. In rats
treated with R73 MAb from day 0, production of
anti-CII antibodies was somewhat delayed and partly
suppressed. No difference in the anti-CII titers was
observed between groups that had been treated with
R73 MAb and with PBS after the onset of arthritis.
40
Days after immunization
Figure 6. Production of antibody to type I1 collagen (anti-C11) in
rats with collagen-induced arthritis treated with R73 monoclonal
antibody (MAb). Rats were immunized with CII on day 0. R73 MAb
(100 p g ) (0)was administered intraperitoneally every 3 days from
day 0 to day 27 (A) or on days 17,20,23, and 26 (B). Arthritic control
;
untreated rats
rats received phosphate buffered saline ( 0 ) normal,
are also shown. Sera were collected at the times shown to determine
the antibody titer, by enzyme-linked immunosorbent assay. Bars
show the mean 2 SEM of 5 rats. * = P < 0.01 versus phosphate
buffered saline-treated controls, by Student's r-test.
had received R73 MAb every 3 days from day 0 to day
27. Treatment with R73 MAb by this regimen led to a
66% suppression of the DTH response to the antigen,
as measured at 48 hours (Table 1). A similar experiment in animals treated with R73 MAb on days 17,20,
The present studies indicate that T cells are
important in maintaining disease activity in rats with
CIA, since treatment with an anti-TCRdP MAb that
was initiated after the onset of the arthritis significantly suppressed the disease. R73 MAb also completely prevented the induction of CIA when it was
administered from the time of immunization with CII.
Brahn and Trentham (10) reported previously that
treatment of rats with antithymocyte serum beginning
1 day before CII immunization delayed the onset of
CIA and reduced its severity. However, when the
anti-T cell serum was given 5 days after immunization,
there was no effect on CIA. Thus, their data suggested
that T cells might play a role only in the early phase of
the induction of CIA in rats. Those authors also
achieved a similar level of depletion of T cell numbers
as that achieved in our study. It is possible that the
specificity of R73 MAb for T C R d P may account for its
greater activity in suppressing disease. More recently,
a MAb against CD4 was found to completely prevent
the induction of CIA in rats (19). However, the effects
of anti-CD4 antibody on the ongoing disease were not
examined in that study. Those authors also described
a preventive effect of anti-CD4 in animals with transient mild disease, whereas the present study shows
that an anti-TCRdp MAb can completely prevent
severe erosive chronic arthritis. In a study of thymusdeficient nude rats, arthritis failed to develop after
inoculation with CII (20). That model, however, only
indicates that T cells are necessary at some point in the
pathogenesis of CIA and does not distinguish between
a role in either humoral or cell-mediated articular
damage.
The preventive effects of MAb to T cell surface
ANTI-TCRdP THERAPY FOR CIA
molecules on collagen-induced arthritis in mice have
also been studied. Treatment of mice with MAb
against CD4 ( I I ) , IL-2R (12), and Ia antigens (13,14),
either before or at the time of immunization with CII,
delayed the onset of the disease. However, there was
no effect on CIA when the MAb were administered to
animals after immunization with CII.
Taken together, the findings from these studies
of rats and mice suggest that T cells contribute to the
induction of CIA, but do not demonstrate that T cells
play a role in the continuation of existing disease.
Support for T cell involvement in maintaining CIA
comes from recent observations that treatment with
anti-mouse lymphocyte sera or with a combination of
MAb against Thy-1.2 and CD4 suppressed the progression of disease in mice (21). However, anti-Thy-1.2
MAb did not, by itself, modify the existing disease.
An anti-TCRalP MAb, such as R73, may have
certain advantages over other MAb against T cell
surface antigens, such as CD4 and IL-2R, in in vivo
investigations of the pathogenic role of T cells.
TCRaIp is expressed on most T cells in the peripheral
blood and in secondary lymphoid organs (1 6), while
CD4 and IL-2R are expressed only by restricted
subsets of T cells. When R73 MAb was injected
intraperitoneally, alp-positive T cell numbers decreased to < 10% of peripheral blood leukocytes within
7 hours (data not shown) but, by day 3, recovered to
half the pretreatment level. More than 4 injections of
R73 at intervals of 3 days were required to achieve a
more sustained depletion of a/&positive T cells to
< 10% of the leukocytes in peripheral blood. This latter
depletion was associated with the complete prevention
of CIA, even though DTH and antibody responses to
CII were detectable (albeit depressed). A regimen of 4
injections of R73 MAb at 3-day intervals as treatment
for existing CIA yielded less depletion of alp-positive
T cells and partial suppression of CIA. A more intensive or sustained regimen may have achieved greater
depletion of alp-positive T cells and suppression of
disease.
The mechanism by which R73 MAb causes
depletion of dp-positive T cells is not clear. R73 MAb
is of the lgGl isotype and therefore should not fix
complement. A relatively weak complement-fixing
IgG2a MAb against Thy-1.2 efficiently eliminated Thy1.2 cells from the blood of mice in vivo and was shown
to opsonize Thy-I .2-bearing cells for phagocytosis in
vitro (22). This suggests that opsonization and clearance by the reticuloendothelial system is a mechanism
for the depletion of T cells, a conclusion supported by
1045
the recent observation that cells bearing CD5 are also
depleted by the MAb (23). Cells from R73 MAbtreated rats did not stain with the secondary antibody
(sheep anti-mouse antibody), which indicates that
TCRalp is not simply masked by the MAb (unpublished observations).
The repeated injection of R73 MAb over a
period of 27 days maintained the marked depletion of
a/p-positive T cells. After stopping treatment, the
proportion of alp-positive T cells recovered, to 50% of
pretreatment levels, within 33 days. However, no
arthritis had developed by day 60 after stopping treatment. When the rats were rechallenged with CII on
day 60, arthritis was induced in only 2 of the 5 animals.
Prevention of disease development beyond the period
of treatment and the low incidence of the disease after
the CII rechallenge might be due to the continued
reduction of alp-positive T cells by R73 MAb. However, it is also possible that tolerance to CIA was
induced in some of the R73 MAb-treated rats. Benjamin and Waldmann (24) showed that treatment of
mice with a MAb to CD4 induced tolerance to certain
protein antigens, including the anti-CD4 antibody itself. Billingham et a1 (19) also recently demonstrated
that pretreatment of rats with anti-CD4 antibody prevented the induction of adjuvant arthritis, and that,
even after the MAb therapy was stopped and the
CD4-positive cell numbers had normalized, rechallenge with mycobacteria failed to induce the disease.
The rats used in the present studies were maintained under clean conventional conditions, without
special precautions to avoid infection. Nevertheless,
as in a previous study (25), none of the alp-positive T
cell-depleted animals showed any evidence of infection, and the animals looked healthy and gained weight
normally. The remaining immunocompetence of the
rats may be due to residual a/p-positive T cells or to
the normal functions of B cells, yl6positive T cells
(26-28), or natural killer cells, which would not be
affected by R73 MAb treatment. The animals retained
some T cell function, as evidenced by the production
of antibodies and the reduction in the DTH reaction to
CII. In addition, acute arthritis induced by the direct
toxic effects of streptococcal cell wall fragments
(29,30) can still develop in alp-positive T cell-depleted
rats (unpublished observations), which attests to the
competence of these animals to mount a nonspecific
inflammatory response.
Although the findings of the present studies
establish an important role for T cells in both the
induction and progression of CIA, the possibility of
1046
YOSHINO ET AL
involvement of anti-CII antibody in the disease has not
been excluded. The suppressive effect of R73 MAb on
progressing CIA seemed weaker than its effect on
established adjuvant arthritis as observed previously
(23,25). Thus, both humoral and cellular responses
might be essential for the maintenance and perpetua-
tion of established CIA, while T cells may play a more
pivotal role in the progression of adjuvant arthritis.
That antibody to CII may not be sufficient (although
perhaps necessary) to cause CIA is evinced by the
presence of substantial levels of antibody to CII in the
rats in which arthritis was completely prevented by
treatment with R73 from the time of CII immunization.
Some features of CIA are similar to those of
rheumatoid arthritis in humans (43).Beneficial effects
of MAbs against CD4 (31) and IL-2R (32) on human
rheumatoid disease have been reported, although to
date, the numbers of patients treated have been small.
The effects of an anti-CD7 MAb in rheumatoid arthritis
were equivocal (33). Since antibodies against TCRaIP
are directed against most T cells in peripheral blood
and because this receptor is likely to have a central
functional role in antigen-driven autoinflammatory diseases, a MAb against the human TCRdp might show
even greater efficacy than the MAb evaluated thus far.
In particular, the demonstration of the beneficial effects of anti-TCRa/P MAb on progressing CIA, at
treatment levels which d o not appear to compromise
all T cell function or resistance to infection, encourages a trial of similar treatment in humans with rheumatoid arthritis.
ACKNOWLEDGMENTS
We thank Dr. T. Hiinig (Institute for Virology and
Immunobiology, Wurzburg, FRG) for generously providing
the MAb to TCRdP, and Junko Yoshino for expert technical
assistance.
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