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Immunosuppression by fractionated total lymphoid irradiation in collagen arthritis.

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532
IMMUNOSUPPRESSION BY FRACTIONATED TOTAL
LYMPHOID IRRADIATION IN COLLAGEN ARTHRITIS
W. JOSEPH McCUNE, JUDITH A. BUCKLEY, JAMES A. BELLI, and DAVID E. TRENTHAM
Treatments with fractionated total lymphoid irradiation (TLI) and cyclophosphamide were evaluated
for rats injected with type I1 collagen. Preadministration of TLI and repeated injections of cyclophosphamide
suppressed the severity of arthritis and lowered antibody titers to collagen significantly. TLI initiated at the
onset of collagen arthritis decreased humoral and cellular responses to collagen but did not affect the severity of
arthritis. These data demonstrate that both TLI and
cyclophospharnide are immunosuppressivein an experimentally inducible autoimmune disease.
The immunosuppression produced in mice by
fractionated total lymphoid irradiation (TLI) can proA preliminary account of this work was presented at the
annual meeting of the American Rheumatism Association at Boston,
MA, June 5 , 1981, and was published in abstract form in Arthritis
and Rheumatism, 242359, 1981.
From the Departments of Medicine and Radiation Therapy,
Harvard Medical School, the Division of Rheumatology and Immunology, Brigham and Women’s Hospital, and the Joint Center for
Radiation Therapy.
Supported in part by Research Grants AM-21490, AI-07685,
AI-07167, AM-05588, and AM-20580 from the US Public Health
Service and by a grant from the New England Peabody Home
Foundation. Dr. Trentham is the recipient of an Arthritis Senior
Investigator Award from the Arthritis Foundation.
W. Joseph McCune, MD: Research Fellow in Medicine;
Judith A. Buckley, MD: Chief Resident, Radiation Therapy; James
A. Belli, MD: Professor of Radiation Therapy; David E. Trentham,
MD: Assistant Professor of Medicine. Dr. McCune’s current address is The Division of Rheumatology, University of Michigan
Hospital, Ann Arbor, MI 48109. Dr. Buckley’s current address is
The Department of Radiation The,rapy, Columbia University, 630
West 168th Street, New York, NY 10032.
Address reprint requests to David E. Trentham, MD, The
Seeley G. Mudd Building, 250 Longwood Avenue, Boston, MA
02115.
Submitted for publication September 4, 1981; accepted in
revised form November 4, 1981.
Arthritis and Rheumatism, Vol. 25, No. 5 (May 1982)
long allogeneic skin (1,2) and bone marrow (2-5)
engraftment ,expedite the development of tolerance to
foreign protein antigens (6), decrease the antibody
response to a foreign antigen (7), and ameliorate
autoimmune disease in the NZB/NZW (8,9) and
MRL/1 (10) strains. In rats, TLI has been shown to
facilitate the induction of allograft tolerance (1 1,12), to
decrease, preferentially, lymphocyte concentrations in
the blood, and to partially suppress adjuvant arthritis
(13). In view of the prospect of using this technique
[which is a recognized therapy for Hodgkin’s disease
(14,15)] as an alternative to cytotoxic drug therapy
(16,17) in the treatment of patients with severe rheumatoid arthritis (18,19), we investigated whether TLI
could modify in rats the clinical, radiographic, and
immunologic manifestations of an inflammatory polyarthritis induced by immunization with type I1 collagen (20,21). We also compared the efficacy of TLI with
that of cyclophosphamide in this model.
MATERIALS AND METHODS
Rats. We used female Sprague-Dawley rats (Charles
River Breeding Laboratories, Wilmington, MA) that
weighed 100-130 gm.
Collagen and immunization. Rats were immunized
during ether anesthesia by intradermal injection of the dorsal
skin with approximately 0.4 mg of previously prepared (22)
native pepsin-modified chick type I1 collagen dissolved in
0.1M acetic acid and emulsified in incomplete Freund’s
adjuvant (20). In one experiment, immunized rats were
boosted with approximately 0.4 mg of dissolved collagen
that was injected intraperitoneally (20).
Irradiation. Rats were irradiated with a 250-kV Westinghouse x-ray machine operated at 15 mamp at a rate of 40
rads per minute and a source-axis distance of 60 cm. The
beam was corrected with 0.5-mm copper and 1.O-mm alumi-
IRRADIATION IN COLLAGEN ARTHRITIS
num filters (13). Shielding and irradiation ports (Figure 1)
were identical to those described by Schurman et al (13),
except for these modifications: the anatomic confines of the
thymus and spleen were identified by autopsies, and the
ports over these organs were slightly enlarged to ensure total
inclusion of these tissues. Because of the lateral scatter that
occurs when irradiation is delivered in this energy spectrum
(23,24), vertical lead shields, 2 mm in thickness, were
positioned to further protect the hindpaws from scatter
through the irradiation ports. The skull, ears, lungs, and tail
were shielded, and in experiment 2, because the irradiated
rats were arthritic, the forepaws were also shielded. To
prevent movement during irradiation, rats were anesthetized
by subcutaneous injection of 0.15-0.25 ml of ketamine
hydrochloride solution (Ketalar, Parke-Davis and Co, Detroit, MI), at a concentration of 100 mg/ml, and were held in
wooden cages with soft restraints. TLI consisted of 17 daily
doses of 200 rads (1,13) delivered at the midplane of the rat
to the ports specified. TLI was completed in each experiment in approximately 4 weeks. Sham TLI, which we
considered important in these experiments because stress
can affect clinical aspects of this model (25,26), was performed by transporting the rats to the room used for irradiation and anesthetizing them in the irradiation jigs with
A
533
restraints for a time identical to that required for actual
irradiation.
Cyclophosphamide. Cyclophosphamide (Cytoxan,
Mead Johnson and Co, Evansville, IN) was dissolved in
sterile 0.9% saline, at a concentration of 20 mg/ml, and was
injected intraperitoneally.
Clinical evaluation. For each rat, arthritis was graded
by 1 investigator, who scored the severity of inflammation in
each paw: 0, 1, 2, 3, or 4. The sum of scores of all 4 paws is
designated by the arthritic index (20,22). Histologic evaluations were not performed in these experiments because of
the correlation between macroscopic and microscopic judgements of the severity of arthritis found in previous studies
(25,27).
Radiographic evaluation. After killing the rats by
ether anesthesia, we disarticulated all hindpaws above the
knee; then the hindpaws were coded, mounted with adhesive
tape on cardboard, and frozen at -20°C until radiographs on
plain x-ray film were performed. Radiographs of clinically
arthritic forepaws, disarticulated proximal to the wrist, were
also obtained. The severity of arthritis in each paw, based on
the amount of narrowing or loss of joint spaces, bony
destruction, periosteal new bone formation, and soft tissue
swelling (20,22,28), was graded in numeric increments from
B
Figure 1. A, The configuration of the lead shield jig used in experiment 1, which included the forepaws in the irradiation field, and B, the
configuration used in experiment 2, which shielded the forepaws. In both figures, the rats are supine in these overhead views, and the enlarged
splenic portal appears over the left side of each rat.
McCUNE ET AL
534
0-3 by the same observer, who did not know to which
experimental group the radiograph’s subject belonged. The
radiographic joint index represents the sum of the paw
scores for each rat (22).
Hemagglutination assay. Rats were bled during ether
anesthesia by distal tail amputation, and sera were stored at
-20°C until antibodies to native type I1 collagen were
measured by passive microhemagglutination (29). Titers,
determined in a blinded fashion, were expressed as -log*
dilutions, and titers 2 2 were considered to represent a
significant response to collagen (29).
Radiometric ear assay. Delayed-type hypersensitivity
(DTH) to native chick type I1 collagen was quantified in vivo
by a radiometric ear assay (30). To perform this assay, native
type I1 collagen is dissolved at a concentration of 1.O m g h l
in 0.1M acetic acid for 24 hours at 4°C and then dialyzed
against cold 0.05M calcium acetate. Dividing cells that might
accumulate at the site of a delayed reaction are radiolabeled
by injecting a rat subcutaneously with 0.34 pCi/gm body
weight of tritiated thymidine (specific activity 6.7 Wmmol,
New England Nuclear, Boston, MA). Twenty-four hours
later, 20 pl of the collagen solution is injected intradermally
into the right ear. To control for any inflammation attributable to the buffer, an identical volume of calcium acetate
solution alone is injected into the left ear. A delayed reaction
is allowed to develop for 24 hours (30). The rat is then killed
and punch biopsies are performed on both ears to obtain
specimens that are 6 mm in diameter. After digestion of the
tissue, the radioactivity present in each biopsy is counted,
and the radiometric ear index is then expressed as the ratio
of the counts per minute (cprn) in the antigen-challenged ear
versus the control ear. Radiometric ear indices 21.6 have
been previously calculated to represent significant DTH
reactions to chick type I1 collagen in this assay (25).
Thymidine incorporation assay. Incorporation of tritiated thymidine by purified blood mononuclear cells in response to phytohemagglutinin (PHA) was measured in vitro
by a technique previously described (29). Responses are
expressed as the stimulation index obtained by dividing the
mean cpm for quadruplicate cultures performed in the presence of PHA by the mean cpm for unstimulated quadruplicate cultures (29,30).
Experimental protocols. In experiment 1, TLI and
sham TLI were completed in groups of 16 rats on day -7. On
day -1, 4 rats, randomly selected from each group, underwent cardiac puncture (29) to obtain approximately 3.0 ml of
blood for thymidine incorporation assays. On day 0, the rats
in each group, along with 16 age-matched untreated rats,
were immunized with collagen. Clinical assessments, beginning on day 10 and continuing until day 40, were performed
at least 3 times a week by the same investigator who was
frequently blinded to group assignments. These clinical
assessments were supplemented at least weekly by those of
another observer who was experienced with the model but
unaware of group assignments. Rats were bled to collect sera
for antibody determinations on days 21 and 34. On day 42,
the radiometric ear assays were completed; the rats were
killed, and paws were obtained for radiographic evaluation.
In experiment 2, collagen immunization and boosting
occurred on days 0 and 45, respectively. Beginning on day 11
and continuing until day 14, a total of 40 rats were entered
into the study; each rat was entered on the day that her
arthritic index increased to 22. Rats that were entered on
the same day were bled to obtain sera and were paired
according to the severity of arthritis. To be paired, arthritic
indices could not differ by > 1. One member of each pair was
then randomly assigned to receive TLI, and the other was
assigned to receive sham TLI from the day of entry into the
study. Clinical evaluations of arthritis were conducted at
least 3 times a week by the same observer, who was unaware
of the treatment group to which each rat was assigned. These
assessments were supplemented at least weekly by those of
the other evaluator, who was also unaware of group assignments. Sera were also collected on days 43 and 59. On day
61, the radiometric ear assays were completed; the rats were
killed, and paws were obtained for radiographic evaluation.
In experiment 3, because a single injection of 75 mg
cyclophosphamidelkg body weight produced no deaths,
whereas a dose of 90 mgkg was consistently lethal, 29 rats
received cyclophosphamide, 60 mg/kg, on day - 10 and onethird of this dose at weekly intervals beginning on day 7. As
a control, 18 rats received sterile 0.9% saline at a volume and
schedule identical to that used with cyclophosphamide. Rats
were immunized on day 0 and clinically assessed for arthritis
between days 11 and 39. They were bled on days 27 and 39.
On day 42, radiometric ear assays were completed; the rats
were killed, and paws were obtained.
Statistical analyses. Continuous variables were analyzed by their group means (Student’s t-test) and dichotomous variables by their proportionate group frequencies
(chi-square test).
RESULTS
In experiment 1, pretreatment with TLI significantly delayed the onset and reduced the clinical and
radiographic severity of collagen arthritis, in comparison to the sham-irradiated rats or the untreated rats
(Table 1 and Figure 2). Although fewer rats developed
arthritis in the irradiated group, the differences were
not significant statistically. On both day 21 and day 34,
mean hemagglutinating antibody titers to collagen
were significantly lower in the sera from the group
pretreated with TLI than in the sera from the 2 control
groups. Only 10 of 16 rats (62%) who received TLI
pretreatment had antibody responses to collagen on
day 34, compared with all of 16 sham-irradiated and 16
untreated rats (P < 0.05 for both comparisons). There
was no difference in DTH to collagen by radiometric
ear assays, performed on day 42, among the 3 groups.
Thymidine incorporation in response to PHA, measured immediately before immunization, was markedly impaired in cells from irradiated rats compared with
cells from the sham-irradiated rats (mean stimulation
index 5 SEM 1.2 0.1 in the TLI group versus 16.6 5
5.9 in the sham-irradiated group, P < 0.05). Mean
background cpm, used to derive the stimulation indi-
*
IRRADIATION IN COLLAGEN ARTHRITIS
535
Table 1. Effects of preadministration of total lymphoid irradiation (TLI) on collagen arthritis
Incidence of arthritis
Day of onset
Maximum arthritic index§
Radiographic joint index
Antibody response to collagen
Day 21
Prevalence
Titer
Day 34
Prevalence
Titer
Delayed-type hypersensitivity
to collagen on day 42
Prevalence
Radiometric ear index$$
TLI
Sham TLI
Untreated
6/16 (38%)
25.0 t 2.7*
3.5 2 1.0
1.0 2 0.4
11/16 (69%)
14.0 t 1.4t
7.0 2 1.17
3.6 ? 0.9#
13/16 (81%)
16.0 ? 2.0$
6.2 2 2.0
3.6 ? 0.7**
9/16 (56%)
4.0 2 0.9
15/15 (100%)Ttt
8.3 ? 0.3t
16/16 (lOO%)ll
8.1 2 0.3t
10/16 (62%)
5.4 f 1.0
16/16 (100%)7
9.9 2 0.2t
16/16 (loo%)(
9.8 2 0.2t
12/15 (80%)
2.5 2 0.4
11/14 (78%)
2.8 2 0.4
15/16 (94%)
3.7 ? 0.5
* Arithmetic mean ? the standard error of the mean (SEM).
t P < 0.001 versus the TLI group.
$ P < 0.02 versus the TLI group.
§ Expressed as the mean of maximum arthritic indices ? SEM for arthritic rats.
ll P < 0.05 versus the TLI group.
< 0.01 versus the TLI group.
** P < 0.002 versus the TLI group.
#P
tt Occasional differences in the number of rats tested are due to the inability to obtain adequate
quantities of sera or to technical problems that prevented completion of the ear assay.
$$ Mean counts per minute of tritiated thymidine in the control ears challenged with buffer alone, used
to derive these ear indices, were 8,880 2 800,9,800 f 990, and 6,540 2 500 for the TLI-treated, sham
TLI-treated, and untreated rats, respectively ( P not significant).
ces, were lower in cell cultures from the TLI rats, but
this difference was not significant (245 & 29 cpm in the
TLI group versus 1,062 ? 513 in the sham group, P not
significant).
Of the 40 arthritic rats that were entered into
experiment 2, 15 and 16 rats in the TLI and sham-TLI
groups, respectively, were alive at the end of the
study. All deaths, except for 3 rats that had received
TLI, occurred during anesthesia. Initiation of TLI at
the onset of arthritis had no effect on the clinical
course of arthritis, as assessed by clinical or radiographic joint indices, in the irradiated versus the shamirradiated rats (Table 2). None of the clinical evaluations during or subsequent to the irradiation period
showed a significant difference in the severity of
arthritis. Antibody titers to collagen were similar in the
2 groups before irradiation. After irradiation, antibody
titers continued to rise significantly in the shamirradiated group but did not increase in the rats that
had received TLI. DTH responses to collagen were
significantly lower in irradiated rats at the end of the
experiment.
In experiment 3, the severity of arthritis, as
assessed by clinical and radiographic joint indices, was
significantly suppressed by cyclophosphamide compared with the group receiving injections of saline
(Table 3 and Figure 3 ) . However, the incidence and
mean day of onset of arthritis were not altered by this
cyclophosphamide protocol. The prevalence and titers
of antibodies to collagen were significantly lower in
the cyclophosphamide group on days 27 and 39, but
DTH responses at the end of the experiment were not
significantly lower.
When the treated rats were compared to the
rats in the control group, none of the protocols produced significant changes in weight or overt evidence
of illness (e.g., loss of hair or diarrhea). Ketamine
injections occasionally produced subcutaneous ulcers
on the back, which were approximately 0.3-1.5 cm in
diameter and which gradually healed over a period of
1-2 weeks. The ulcers occurred with equal frequency
in the irradiated and sham-irradiated rats.
DISCUSSION
TLI completed 7 days before immunization was
associated with a delay in the onset and a suppression
of the severity of arthritis in the collagen model. In
contrast, TLI administered during the initial stage of
macroscopically evident arthritis did not affect the
degree of joint inflammation or destruction in this
disease. The rapidity of onset and fulminant nature of
McCUNE ET AL
536
1
T
1
~~
,~
~-~
25
20
30
34
DAY AFTER IMMUNIZATION
A
B
Figure 2. A, The prevalence of collagen arthritis in 16 rats administered total lymphoid irradiation (TLI) before immunization (open circles), 16
rats receiving sham TLI (closed circles), and 16 untreated rats (triangles). B, The severity of arthritis, expressed as a mean arthritic index t
standard error of mean, in arthritic rats in the 3 groups. Variability between the 2 evaluators was determined in this experiment. This analysis
showed that the mean percentage of spread in the mean arthritic indices was 14.
with hindpaw irradiation is more effective than TLI
alone in suppressing established adjuvant arthritis is
consistent with both of these possibilities.
TLl administered either before immunization or
during the early course of collagen arthritis suppressed
antibody responses to collagen. Cellular immunocompetence, as measured by the incorporation of thymidine in response to in vitro stimulation with PHA, was
abrogated in rats 6 days after the end of TLI. In
collagen arthritis (20,22) may have masked mild or
slowly evolving antiinflammatory properties of TLI in
established disease. In addition, inflammatory cells
that reside in the hypertrophied synovium of peripheral joints in arthritic rats (20,31) would have been
shielded from irradiation. The persistence of these
cells could be the reason that TLI that is started after
the onset of collagen arthritis is not clinically effective.
The finding of Schurman et a1 (13) that TLI combined
Table 2. Effects of TLI* initiated at the onset of collagen arthritis
Maximum arthritic index
Before treatment?
After treatments
Radiographic joint index
Antibody titer to collagen
Before treatment
Day 43
Day 59
Radiometric ear index to collagen7
TLI
Sham TLI
P value
4.0 t 0.4
3.4 t 0.3
2.1 t 1.2
4.2 t 0.4
3.3 0.3
1.9 t 0.2
*
NSS
NS
NS
7.0 t 0.2
7.7 t 0.3
7.5 t 0.6
2.8 0.4
7 . 4 t 0.2
9.7 2 0.2
10.7 t 0.3
4.0 t 0.4
< 0.0001
< 0.001
< 0.05
*
NS
* All of the rats in both groups had significant antibody and delayed-type hypersensitivity responses to
collagen at each testing. TLI = total lymphoid irradiation.
t Days 11-14.
$ NS = not significant.
§ Days 43-59.
ll Day 61. Mean counts per minute in the control ears were 2,360 t 300 and 2,340 t 200 for the TLIand sham TLI-treated rats, respectively ( P not significant).
IRRADIATION IN COLLAGEN ARTHRITIS
537
Table 3. Effects of cyclophosphamide on collagen arthritis
Incidence of arthritis
Day of onset
Maximum arthritic index
Radiographic joint index
Antibody response to collagen
Day 27
Prevalence
,
Titer
Day 39
Prevalence
Titer
Delayed-type hypersensitivity
to collagen on day 42
Prevalence
Radiometric ear index$
Cyclophosphamide
Saline
21/29 (72%)
19.4 1 1.2
2.9 f 0.4
1.0 5 0.3
16/18 (89%)
15.7 t 1.8
5.0 t 0.7
3.1 t 0.8
NS
NS
< 0.01
< 0.01
15/26 (58%)t
2.8 f 0.6
13/13 (100%)
7.5 t 0.5
< 0.05
< 0.0001
15/26 (58%)
3.2 f 0.7
15/15 (100%)
8.5 ? 0.2
< 0.05
< 0.0001
17/29 (59%)
2.3 f 0.3
15/18 (83%)
3.2 t 0.4
NS
NS
P value*
* NS = not significant.
t Occasional differences
in the number of rats tested are due to the inability to obtain adequate
quantities of sera.
$ Mean counts per minute in the control ears were 2.760 t 260 and 3,000 t 390 for the
cyclophosphamide- and saline-treated rats, respectively (Pnot significant).
experiment 2, which assessed the effect of TLI that
was administered during the early course of collagen
arthritis, DTH responses to collagen were decreased
when measured in vivo 19-22 days after the end of
TLI. However, DTH reactions to collagen in the rats
who received TLI pretreatment in experiment 1 did
not differ significantly, when tested 50 days after the
end of TLI, from those of the 2 unirradiated control
groups. The different time, in relation to TLI, at which
DTH was measured may be the reason that DTH
100
75 -
u
fi
G
&
%
/
/
/
50-
/
d
!i
5
0-C
I
25-
/
/
/
/
dl
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/
responses were suppressed in experiment 2 but not in
experiment 1. Because cells from the irradiated rats in
experiment 1 had failed to respond to PHA 43 days
earlier, these data indicate that recovery of at least
some cellular functions had occurred by 7 weeks after
completion of TLI. Our findings in rats are consistent
with previous demonstrations in mice that TLI can
suppress B cell responses to primary immunization (7)
or abnormal antibody titers present in the syndromes
that resemble systemic lupus erythematosus in the
McCUNE ET AL
538
NZB/NZW (8,9) and MRL/l (10) strains, and can
impair T cell functions in mice (1-6,10,12) and rats
(11,12). In addition, the transient nature of the T cell
suppression produced by TLI is similar to the observation of Slavin et a1 (1,2) that murine lymphocytes had
regained the capacity to react to alloantigens in mixed
lymphocyte cultures by 70 days after TLI. Since
ineffectual PHA responses were more sustained (2), it
is probable that there is a temporal dissociation in the
rate of recovery of various T cell activities in rodents
after TLI (12).
The cyclophosphamide protocol used in this
study also suppressed the severity of arthritis and
decreased antibody responses to collagen in this model. Our results in the Sprague-Dawley strain are similar
to those previously reported when cyclophosphamide
was administered to Royal Hart Wistar (28) and Wistar
(32) rats with collagen arthritis. In these studies, there
was a correlation of humoral immunosuppression to
amelioration of collagen arthritis. Synovitis can be
passively transferred by the intravenous injection of
IgG antibodies to type I1 collagen (33), as well as by
sensitized spleen and lymph node cells (27), and the
onset of collagen arthritis can be delayed by complement depletion (34). We have recently shown that
arthritic and IgG antibody responses to collagen, but
not DTH, can be suppressed by the intravenous injection of type I1 collagen-coupled spleen cells (35). Thus,
there is considerable evidence that humoral mechanisms contribute to the joint inflammation in this
experimentally induced disease. Although cellular sensitivity to collagen is also present in this model
(21,22,25,29,36,37), the role of T cell mediated processes in its pathogenesis remains unclear.
ACKNOWLEDGMENTS
The authors wish to thank Ms Donna Rowland for
technical assistance and Ms Christine Sleiman for manuscript preparation.
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