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The role of NZBNZW F1 thymus in experimental tolerance and auto-immunity.

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The Role of NZB/NZW F1 Thymus in Experimental
Tolerance and Auto-Immunity
Alfred D. Stehberg, Lloyd
D. Law and Norman Tala1
The role of the NZBlNZW F, (B/W) thymus was studied with respect to tolerance
to ultracentrifuged bovine globulin (BGG) and poly I poly C, and spontaneous
anti-DNA antibody formation. Thymectomy alone had little effect on the induction or escape from tolerance. An adult B / W thymus could not prevent toleranceinduction in young B/W mice. However, a young B/W thymus could facilitate the
induction of partial tolerance in older B / W mice under appropriate conditions.
These results suggest that the adult B/W thymus may be functionally deficient
relative to the young thymus. Neonatal thymectomy accelerated the autoimmune
disease, suggesting that the young B/W thymus has some normal regulatory
function. Thymectomy at 6 weeks of age did not accelerate autoimmunity. A
young B/W thymus, but not an older B/W thymus reversed the accelerated
disease of neonatally thymectomized B/W mice. This again suggests that the
older B/W thymus is functionally deficient.
Ultracentrifuged BGG is capable of inNZB/NZW F, (B/W) mice spontalleously
develop a disorder resembling human sys- ducing immunologic tolerance in normal
temic lupus erythematosus, (1,2) and show mice (3, 7,9) although biofiltered or salt
augmented antibody responses to certain fractionated BGG is a better tolerogen,
antigens (3-6). Our laboratory studied the particularly in BALB/c mice (10). Adult
immunogenicity of two antigens, one a New Zealand mice are relatively resistant
protein, bovine globulin (BGG) , and the to tolerance induced by ultracentrifuged
BGG as shown by immune elimination and
other a synthetic nucleic acid, polyinosinic
hemagglutination
assays (3) . This resistpolycytidylic acid (poly I*poly C) in these
ance
can
be
overcome
b y preparing a highanimals 1 3 6 - 8 ) .
ly
tolerogenic
BGG
(1
1) or by using New
From the National Institutes of Health, Bethesda,
Md .
Zealand mice under 3 weeks of age (7).
ALFREDD. STEINBERG,
MD: Clinical Associate, However, it cannot be overcome by biofilRoom 9N218, Building 10, National Institute of
Arthritis and Metabolic Diseases, National Institutes tration (12).
of Health, Bethesda, Md 20014. LLOYD D. LAW,
There is a difference in the response of
PHD: Head, Carcinogenesis Section, Laboratory of
young
(less than 3 weeks old) and older (6
Biology, National Cancer Institute, National Institutes of Health, Bethesda, Md. NORMAN
TALAL,weeks old) B/W mice to ultracentrifuged
MD: Senior Investigator, National Institute of Ar- BGG (7). Tolerance to BGG can be inthritis and Metabolic Diseases, National Institutes
duced in young B/W mice, although this
of Health, Bethesda, Md.
Reprint requests should be addressed to Dr. tolerance is lost rapidly. Older B/W mice,
Steinberg.
on the other hand, are relatively resistant
Submitted for publication Dec 15, 1969; accepted
to tolerance-induction to as much as 24 mg
April 4, 1970.
Arthritis and Rheumatism, Vol. 13, No. 4 (July-August 1970)
369
STEINBERG ET A 1
of ultracentrifuged BGG (3). This agedependent difference to tolerogenic BGG
allowed us to study the effect of reciprocal
thymic transplants o n tolerance-induction
in a syngeneic system. T h e thymus has
been implicated in tolerance-transfer and
maintenance i n normal mice (13-16)- We
therefore grafted young B/W thymuses
into 6-week-old B / W mice and studied the
induction and maintenance of tolerance to
BGG. T h e reciprocal experiment was also
performed.
Tolerance to poly I*poly C can be induced in B / W mice using cyclophosphamide (8). We studied the effect of
neonatal thymectomy on this tolerance.
Additional experiments with reciprocal
thymic transplants investigated the influence of the B/W thymus on the spontaneous production of anti-DNA and anti-RNA
antibodies during the course of disease in
B/W mice.
MATERIALS AND METHODS
Thymectomy. Newborn B / W mice
were thymectomized under a dissecting microscope within 18 h r after birth using a
suction catheter and light ether anesthesia.
Adult B/W mice were thymectomized at
6 weeks of age. There was greater than
80% survival in both groups of B/W mice.
Wasting disease did not develop. Completeness of thymectomy was confirmed by
autopsy at intervals throughout the study
and at its conclusion.
Thymic grafts. Donor animals were
anesthetized by hypothermia. T h e mediastinum was opened surgically and the thymus dissected and removed intact after
which the donor was discarded. T h e thymus was placed in tissue culture medium
199+ and divided into 2 lobes. Each recipient received 1 lobe implanted subcutane*Microbiological Associates, Inc, Bethesda, Md.
370
ously near the right axilla through a sterile
13-gauge trocar. Care was taken to avoid
inclusion of visible mediastinal lymph
nodes with the thymic grafts.
Neonatally thymectomized animals received thymic grafts a t 1 week of age.
Animals thymectomized at 6 weeks of age
received thymic grafts 2 weeks later.
Antigens.
Pretreatment antigens were
bovine y globulin (BGG) Cohn Fraction
1I-f and egg albumin (Ea) crystallized x 2.1
Soluble proteins were prepared in a Spinco
40 rotor at 105,000 g for 30 min as previously described (3). Antibody assays were
performed using chromatographically pure
7s-BGG.? This latter material gave only a
single precipitin line at a concentration of
10 mg/ml after immunoelectrophoresis with
rabbit anti-whole bovine serum.
Tolerance to BOG. T e n days after receiving thymic grafts, the mice were injected intraperitoneally (IP) with either soluble BGG (10-15 mg) or Ea (5 mg). Two
weeks later all animals were challenged
with 1.0 mg 7s-BGG in complete Freunds
adjuvants equally distributed over 4 footpads in a total volume of 0.2 ml.
I n a single experiment, female donor
mice were pretreated with 10-15 mg soluble
BGG IP at either 1 or 6 weeks of age. One
week later they were sacrificed and their
thymuses used as donor grafts for recipient
%week, female B/W mice who had been
tliymectomized a t 6 weeks of age.
Anti-BOG antibody assay. A t 2 to 4
week intervals after challenge, mice were
bled by orbital sinus puncture. Antibody
titers to BGG were determined in micro
titer agglutination plates11 by a standard
hemagglutination method using tanned
tMann Research Laboratories, New York, NY.
:Worthington Biochemical Corporation, Freehold,
NJ .
SDifco Laboratories, Detroit, Mich.
IlCooke Engineering Co, Alexandria, Va.
Arthritis and Rheumatism, Vol. 13, No. 4 (July-August 1970)
NZB/NZW Fi THYMUS
formalinized sheep cells (17, 18) . All sera
from a single bleeding were studied on the
same day. Known positive and negative
sera were included with each assay.
Tolerance t o poly I.poly C. Polyinosinic*polycytidylic acid* (poly 1 - p l y C)
was kept frozen in aliquots at -20°C at a
concentration of 1 mg/ml. One-month-old
neonatally thymectomized and control
B/W mice of both sexes were injected I P
with 100pg poly I*poly C.
Twenty-four hours later they were injected IP with cyclophosphamide 75 pg/g. One
week later they received 100 p g poly I *poly
C IP followed 24 hr later by IP cyclophosphamide 50 pg/g. Control mice received
cyclophosphamide but not poly I*poly C.
Eleven days after the second injection of
cyclophosphamide, all mice were challenged
IP with 0.3 ml poly Ppoly C (1 mg/ml)
emulsified with an equal volume of complete Freund's adjuvant. T w o and 7 weeks
after challenge they were bled for assay of
anti-RNA antibodies.
Anti-DNA and anti-RNA antibody a s say. Anti-DNA and anti-RNA anti,bodies
were measured by a modification of the
Farr assay (19) using C14-labeled KB cell
DNA or C14-labeled poly I-poly Ct. Individual sera diluted 1:4 with borate buffer
(pH 8.0) were incubated with 60 mpg of C14
native DNA (20,000 dpm/pg) or 80 mpg C14
poly Iopoly C (4,000 dpm/pg) at 37" C for
30 min and then at 4" C for 18 hr. An
equal volume (0.1 ml) of ammonium sulfate was added to give a final concentration
of 50% for the anti-DNA assay and 35%
for the anti-RNA assay. After 1 hr at
0" C, the precipitate and supernatant fractions were separated by centrifugation, suspended in Bray's solution, and assayed for
radioactivity in a liquid scintillation counter as previously described (19). T h e re*P-L Biochemicals, Inc, Milwaukee, Wis.
+Miles Laboratories, Elkhart, Ind.
sults are expressed as the percent of added
antigen bound by serum.
I n the poly I*poly C tolerance experiment, individual sera were titered against
the Cl4-poly I * p l y C. The 50% binding
point was considered the antigen-binding
capacity of the serum.
Animals with various thymic manipulations studied for spontaneous formation of
anti-DNA and anti-RNA antibodies were
additional animals not used in the earlier
experiments. They were not injected with
any antigen and received no adjuvant.
Thymectomized and grafted animals were
housed with sham operated control litter
mates.
RESULTS
B/ W mice thymectomized at 6 weeks
of age. Six-week-old B/W mice are relatively resistant to tolerance induction by
ultracentrifuged BGG (9). When B/W
mice were thymectomized at 6 weeks of age
and grafted 2 weeks later with a 1-week-old
B/W thymus, partial tolerance to BGG
(reduced antibody titer) was induced
(Table 1). Thymectomy alone did not
result in tolerance.
Table 2 shows a similar result when
1-week-old B/W donors were pretreated
with BGG and the recipient was also
treated with BGG. Pretreatment alone of
the young donor was not sufficient to induce tolerance in the untreated recipient.
Similarly, 6-week-old B/W grafts were
ineffective even when both donor and recipient were given ultracentrifuged BGG
(Table 2 ) .
N e o n a t a l l y t h y m ec t o m i z e d mice.
Young B/W mice treated with soluble
BGG at 18 days of age developed transient
tolerance to BGG (Table 3). Neonatally
thymectomized B/W mice became tolerant
to BGG and also escaped from tolerance by
8 weeks postchallenge as did the sham
Arthritis and Rheumatism, Vol. 13, No. 4 (July-August 1970)
371
STEINBERG E l A 1
Table 1. Reduced Anti-BGG Antibodies in B/W Mice Thymectomized at 6 Weeks,
Grafted with a 1-Week-Old B/W Thymus 2 Weeks Later, and Treated with Soluble EGG
Age
Donor thymus
Treatment
Thymectom ized groups
6 weeks
Thymectomy
None
6 weeks
Thymectomy
1week B/W
6 weeks
Thymectomy
6 week B/W
Controls
6 weeks
Sham
None
1week
None
None
Mean anti-EGG titer
and SEM
Injection
EGG
Ea
EGG
Ea
EGG
Ea
4.8 f 0.4
6.6 f 0.2
2.5 f 0.6
6.4 f 0.3
4.0 f 0.2
7.2f0.4
(13)t
(11)
(15)i
( 5)
EGG
Ea
EGG
Ea
5.3 f 0.6
7.6 f 0.4
1 . 5 f 0.4
5.8 f 0.2
(11)
(12)
( 5)
( 5)
( 8)*
( 6)
* Number of animals appears in parentheses; 4 weeks after challenge with EGG in complete Freund's
adjuvant.
t Significant difference (P = 0.03) compared t o thyrnectomy alone (4 way t test).
$ Not significant (4 way t test).
-
-
operated controls (Table 3) . Implantation sexes became tolerant to subsequent chalof a 6 week B/W graft did not prevent lenge with poly I-poly C in complete
tolerance-induction in either neonatally Freund's adjuvant when pretreated with
thymectomized or sham operated B/W poly I*poly C plus cyclophosphamide (Tamice (Table 3 ) . Thus, tolerance occurred ble 4 ) . Mice treated with cyclophosin young mice that received a thymus from phamide alone made large quantities of
an adult donor that would not itself be
tolerant.
Table 3. Transient Tolerance to BGG in
Tolerance to poly I.poly C.
Intact Neonatally Thymectomized B/W Mice Receiving
1Week or 6 Week B/W Thymic Grafts and
and thymectomized B/W mice of both
Treated with Soluble BGG at 18 Days of Age
Number of Animals
with Anti-EGG Titer
less than 2/total
number of animals*
Table 2. Anti-BGG Antibody in Female B/W Mice
Thymectomized at 6 Weeks of Age, Given a
Pretreated Female Thymic Graft 2 Weeks Later
Donor
thymus
6 week
6week
1week
6 week
1week
B/W
B/W
B/W
B/W
B/W
Pretreat- Treatment of ment of
donor* recipient
Ea
EGG
EGG
EGG
EGG
Ea
Ea
Ea
EGG
BGG
Anti-BGG titer
4 weeks after
challenge
f SEM
6.3 f 0.8
6.7 f 0.6
6.7 f 0.6
6.0f 0.2
2.5 f 0.4
(5)t
(6)
(6)
(5)
(6)
* Pretreatment was 1 week prior t o transplantation.
t Number of animals appears in parentheses.
372
Treatment
Donor
thymus
4
weekst
8
weekst
Sham
Thymectomy
Thyrnectomy
Thymectomy
Sham
None
None
1week E/W
6 week E/W
6weekB/W
26/26
3/21
017
116
1/21
018
717
717
19/21
818
~
* Egg albumin
treated control animals for all
groups became immunized.
f Weeks after challenge with BGG-Freund's
adjuvant.
Arthritis and Rheumatism, Vol. 13, No. 4 (July-August 1970)
NZBlNZW F, THYMUS
antibody when challenged with poyl 1-poly
C in adjuvant. Thus, as with BGG (Table
3 ) , neonatal thymectomy did not alter the
tolerance response. Furthermore, when
tested 7 weeks after challenge, the poly
I*poly C tolerant neonatally thymectomized
mice had already escaped from tolerance.
Spontaneous anti DN A formation.
Neonatally thymectomized female B/W
mice had accelerated anti-DNA antibody
formation (Table 5). This was prevented
if a 2-week thymus was implanted in the
first week of life. However, implantation of
Table 6. Anti-DNA Antibodies in Female B/W
Mice Thymectomized at 6 Weeks of Age
Mean % DNA Bound
(No. >4O%/total)
5% Months
-
Table 4. Tolerance to Poly I-Poly C in
Neonatally Thymectomized B/W Mice
Poly I-Poly C binding
capacity (pg/ml)
Group*
Sex
Sham
Thymectomy
Sham
Thymectomy
M
M
F
F
Poly I* Poly c
and
Cyclophoscyclophosphamide
phamide
alonet
0.2
0.2
0.9
0.3
* Each group
11.6
16.2
25.4
24.3
Sham
Thymectomy
8% Months
(1:20 serum
dilution)
60.1 ( 8/10)
62.1 (19/22)
56.4 ( 9/11)
55.3 (22/28)
a 10-week-old thymus could not prevent the
increased anti-DNA in neonatally thymectomized mice (Table 5). Acceleration of
anti-DNA antibodies was also found in
neonatally thymectomized B/W males (Table 5). On the other hand, B/W mice
thymectomized at 6 weeks of age showed no
acceleration of anti-DNA antibodies (Table
6) and did not die prematurely. I n fact,
female B/W mice thymectomized at 6 weeks
survived, on the average, 2 months longer
than control mice.
DISCUSSION
The Thymus and Tolerance to BGG
had 10-20 animals; all were challenged with poly I-poly C in complete Freund's
adjuvant.
t These did not differ significantly from animals
receiving no pretreatment or pretreatment with
poly I.poly C alone and challenged with poly
I . poly C in adjuvant.
Table 5.
Group
(1:4 serum
dilution)
It is well established that escape from
a previously established state of tolerance is
enhanced by the presence of the thymus,
and diminished by its absence (13, 14, 20,
21). Tolerance has also been transferred
Increased Anti-DNA Antibodies in Neonatally Thymectomired B/W Mice Not
Reversible with an Older B/W Thymus when Grafted at 1Week of Age
Mean % DNA bound (No. >4m/total No. mice)
Sex
Treatment
~~
F
F
F
F
M
M
M
Thymic graft
4 months of age
None
None
2 week B/W
10 week B/W
None
None
10 week B/W
25.7 (4/14)
42.8 (5/9)
21.4 (1/7)
41.0 (6/11)
12.1 (0/16)
24.4 (2/11)
24.6 (3/21)
5 months of age
~
Sham
Thymectomy
T hymectomy
Thymectomy
Sham
Thyrnectomy
Thymectomy
Arthritis and Rheumatism, Vol. 13, No. 4 (July-August 1970).
48.6
69.4
50.4
67.1
13.8
26.5
29.8
(8/14)
(9/9)
(5/7)
(8/10)
(0/16)
(3/11)
(5/21)
373
with the thymus (15,22,23) . The requirement of the thymus for the induction of
tolerance is less well established (24-26).
Histologic abnormalities of the New
Zealand mouse thymus (27,28) suggested
that this organ might influence these responses.
The present study evaluates the role of
the B/W thymus in the induction of, transfer of, and escape from tolerance to soluble
BGG. The major conclusions of the BGG
studies can be summarized as follows: (1)
thymectomy of B/W mice had little effect
on the development of tolerance to BGGie, young animals (under 3 weeks of age)
became tolerant while older ones (over 6
weeks of age) did not; (2) thymectomy of
newborn B/W mice failed to prevent rapid
escape from tolerance: (3) thymus grafts
from 6-week-old B/W mice did not prevent
the induction of tolerance to BGG in
young B/W mice; (4) thymus grafts from
young B/W mice introduced into older
B/W mice 2 weeks after thymectomy induced a state of partial tolerance; and (5)
thymectomized mice made as much antibody as sham-operated controls.
Partial tolerance was induced in 6 week
B/W mice when a 1 week B/W thymus was
transplanted 2 weeks after thymectomy.
This suggests that the resistance to
tolerance may be reversible if the abnormal
thymus is removed and replaced by a younger one. Thymectomy alone, without restoration of more normal thymic function, did
not lead to tolerance-induction in adult
mice.
It is notable that the young thymus (under appropriate conditions) can facilitate
the induction of tolerance in an older
animal; however, the older thymus cannot
prevent tolerance-induction in a young animal. These studies suggest that the young
thymus can exert an immunologic function, whereas the older thymus may be
374
deficient in this regard. Similarly, id A/Jax
mice, young thymus cells reduced naturally-occurring and experimentally-induced
antinuclear antibodies (29) Thymectomy
accelerates autoimmunity in certain strains
of mice (30).
.
Tolerance to Poly I.Poly C
We have previously shown that poly
I*poly C is antigenic in B/W mice (6).
This enabled us to induce tolerance with
poly I.poly C followed by cyclophosphamide (8) as in the sheep red blood cell
system (21,31,32). We found that neonatally thymectomized animals became tolerant to poly I*poly C as easily as intact
animals. They also lost this tolerance r a p
idly, as is the case with BGG. Thus, whether tolerance was induced by aggregate-free
protein (BGG) or through elimination of
antigen-stimulated cells ( p l y I*poly C and
cyclophosphamide) , the B/W thymus was
found to be unnecessary.
The Thymus and Auto-immunity
The effect of thymus manipulation on
the Coombs’ test in NZB mice has been
studied by several laboratories without uniform agreement. Thymectomy was found
to both accelerate (33) and retard (34) the
development of Coombs’ positivity. Thymic grafts from NZB mice conferred a positive Coombs’ test on neonatally thymectomized control CBA/T6 mice (35) but not
on NZB/T6 or NZB/C3H F, hybrids unless
they were irradiated (36). Spleen cells
from old Coombs’ positive donors could
transfer the Coombs’ reaction to young
Coombs’ negative recipients (36). Other
workers found a diffusible substance in the
NZB thymus which induced a positive
Coombs’ test in several control strains (37).
Helyer and Howie found that the B/W
thymus could induce a positive Coombs’
test and a positive LE cell test in half of
Arthritis and Rheumrtlsla, Yo1 13, No. 4 (Iuly-August 1970)
NZBlNZW Fi THYMUS
recipient CBA/T6 mice after 5 to 7 months
(35). Thymectomy of B/W mice led to
early onset of serologic abnormalities and
severe lupus nephritis by 5 months of age
(35)*
We were able to confirm the findings of
Helyer and Howie in neonatally thymectomized B/W mice. Anti-DNA antibody
formation was accelerated in neonatally
thymectomized mice of both sexes. This
was reversed by grafting a young thymus at
1 week of age, but not by a 10-week thymus
of either sex. This adds support to the
concept of thymic deficiency in young adult
B/W mice. Consistent with this hypothesis,
removal of the young adult thymus did not
cause acceleration of anti-DNA.
The role of the B/W thymus in experimental tolerance and autoimmunity is
clearly very complex. T h e thymus is not
necessary for the induction of tolerance to
BGG or poly I*poly C. Thymuses from
young mice were able, however, to influence both tolerance to BGG and spontaneous anti-DNA antibody formation. Thymic
grafts from young B/W mice were able to
restore some ability to become tolerant to
BGG in thymectomized older B/W mice.
Young grafts, but not older grafts, were
also able to prevent the accelerated antiDNA formation observed in neonatally
thymectomized B/W mice. These studies
suggest that the adult B/W thymus, relative to a young thymus, may be deficient in
some immunologic functions.
ACKNOWLEDGMENT
.
The authors wish to acknowledge the advice of
Drs. Richard Asofsky and Parker Staples in aspects
of the hemagglutination assay, the excellent technical assistance of Mr. Britton H. Smith, Mr. Gerald
G. Daley. and Mrs. Joyce K. Gordon, and the secretarial help of Mrs. Linda Jenkins.
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