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Transfer of experimental antiphospholipid syndrome by bone marrow cell transplantation the importance of the t cell.

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ARTHRITIS & RHEUMATISM Volume 38
Number 1, January 1995, pp 115-122
0 1995, American College of Rheumatology
115
TRANSFER OF EXPERIMENTAL ANTIPHOSPHOLIPID SYNDROME BY
BONE MARROW CELL TRANSPLANTATION
The Importance of the T Cell
M. BLANK, 1. KRAUSE, N. LANIR, P. VARDI, B. GILBURD, A. TINCANI,
Y. TOMER, and Y. SHOENFELD
Objective. To investigate the potential of bone
marrow cells from mice with primary antiphospholipid
syndrome (APS) to transfer the disease to naive mice,
and to determine the importance of the role of T cells in
the APS.
Methods. Experimental primary APS was induced in naive mice following active immunization with
anticardiolipin (aCL) monoclonal antibody (MAb).
Whole-population or T cell-depleted bone marrow cells
from mice with experimental primary APS were infused
into total body-irradiated naive BALBlc recipients.
Results. Bone marrow cells (in the presence of T
cells) had the potential to induce experimental APS in
naive mice, which resulted in high serum titers of aCL,
antiphosphatidylserine, and antiphosphatidylinositol
antibodies; an increased number of antibody-forming
cells specific for each of the above phospholipids; a
positive lymph node cell proliferative response to aCL
MAb; and clinical features of primary APS, including
thrombocytopenia, prolonged activated partial thromboplastin time (indicating the presence of lupus anticoagulant), and a high frequency of fetal resorptions (the
equivalent of human fetal loss). T cell-depleted bone
marrow cells did not transfer the disease.
Supported by a Basic Foundation Grant from the Israeli
Academy of Sciences and the Stanley Burton’s Fund for Research in
Autoimmunity.
M. Blank, PhD, I. Krause, MD, B. Gilburd, MD, Y. Tomer,
MD, Y. Shoenfeld, MD: Sheba Medical Center, Tel-Hashomer, and
The Sackler School of Medicine, Tel-Aviv University, Tel-Aviv,
Israel; N. Lanir, PhD, P. Vardi, MD: Rambam Medical Center,
Haifa, Israel; A. Tincani, MD: Ospedale di Brescia, Brescia, Italy.
Address reprint requests to Y. Shoenfeld, MD, Department
of Medicine “B,” Sheba Medical Center, Tel-Hashomer 52621,
Israel.
Submitted for publication January 10, 1994; accepted in
revised form August 2, 1994.
Conclusion. This study demonstrates the important role of T cells in the development and transfer of
experimental primary APS and raises the possibility of
T cell manipulations in treatments to prevent this condition.
Antiphospholipid syndrome (APS) is characterized by the presence of anticardiolipin antibodies
(aCL) or other antiphospholipid antibodies (aPL)
and/or lupus anticoagulant (LAC), thrombocytopenia,
recurrent thromboembolic phenomena, recurrent fetal
loss, and other diverse manifestations (14). Recently,
we (5-7) and others (8,9) have demonstrated the
pathogenic role of aCL by inducing experimental
primary antiphospholipid syndrome (APS) following
passive transfer of human and mouse monoclonal and
polyclonal aCL to the tail vein of BALB/c and ICR
mice (5,6), or by active immunization of mice with
human or mouse aCL monoclonal antibodies (MAb)
(6,7,10,11). The primary APS was characterized by
serologic markers (a panel of aPL, prolonged activated
partial thromboplastin time [APTT], indicating the
presence of the LAC), hematologic findings (thrombocytopenia), and clinical manifestations (recurrent fetal
resorptions [the equivalent of human fetal loss] and
thromboembolic phenomena in the placenta and fetus).
Little is known about the exact mechanisms
involved in the pathogenesis of this experimental APS
model (although many theories have been proposed).
Several authors have suggested that a defect in bone
marrow stem cells may be the mechanism, as has been
reported for other autoimmune diseases. Indeed,
transfer of bone marrow cells induced diverse autoimmune diseases in healthy animals (12-16): transplantation of bone marrow cells from New Zealand black
(NZB) mice (known to spontaneously develop an
BLANK ET AL
116
autoimmune hemolytic anemia) into irradiated H-2histocompatible mice induced hemolysis in t h e transplanted mice (12-15). Similarly, in another model of
lupus-prone mice, reciprocal bone marrow cell transfer between a novel mutant mouse strain (CBN
KIJms-lprcg/lprcg [CBA-lprcg]) and CBA+ mice
caused autoantibody production and lymphoproliferation in the healthy strain (16). T h e aim of t h e present
study was t o examine whether bone marrow cells
derived f r o m mice with experimental APS could transfer t h e syndrome to naive mice, and whether T cells
are crucial for t h e process.
MATERIALS AND METHODS
Mice. Female BALB/c mice age 8-12 weeks were
purchased from the Tel-Aviv University animal facility and
kept according to accepted procedures.
Monoclonal antibodies. A mouse aCL MAb, termed
CAM, was derived from a mouse with experimental systemic lupus erythematosus (SLE) associated with secondary
APS, induced by a mouse-mouse hybridoma technique (7).
As a control, MAb N40, a mouse MAb that was derived from
the same fusion as CAM but does not bind to cardiolipin,
was used. Both MAb were of the IgG2b isotype.
Induction of experimental APS. BALB/c mice were
immunized with 10 pg of affinity-purified mouse MAb (CAM
or N40) in Freund’s complete adjuvant, injected into the
hind footpads. Three weeks later, a boost injection of 10 pg
of the MAb in phosphate buffered saline (PBS) was administered to the hind footpads (6,7).
Detection of antiphospholipid antibodies. Sera of the
immunized mice were examined monthly for aCL activity by
enzyme-linked immunosorbent assay (ELISA), as detailed
elsewhere (7). Briefly, 96-well ELISA plates (Nunc,
Roskilde, Denmark) were coated with cardiolipin (50 pg/ml
in ethanol; Sigma, St. Louis, MO). Following blocking with
5% bovine serum albumin (BSA) in PBS, serial dilutions
(1:200-1:3,600) of mouse sera in PBS-2% BSA were added
and incubated for 2 hours. Bound antibodies were detected
using goat anti-mouse IgG conjugated to alkaline phosphatase (Sigma) and its substrate p-nitrophenylphosphate
(Sigma). The color reaction at 405 nm was read with a
Titertek ELISA reader. Each step was followed by extensive
washings with PBS. The detection of anti-phosphatidylserine
(anti-PS), anti-phosphatidylinositol (anti-PI), anti-phosphatidylethanolamine (anti-PEA), and anti-phosphatidylcholine
(anti-PC) antibodies in the sera of the tested mice was done by
the same method as for aCL.
Inhibition of anticardiolipin antibody binding. Sera at
a dilution giving 50% of maximal binding to the antigen
(cardiolipin) were preincubated with the antigen, at different
concentrations (0.1-50 pglml). Background optical density
(OD) values were subtracted from the recorded values. The
preincubation was carried out with cardiolipin (Sigma) or
with an irrelevant phospholipid (PC), in order to confirm
specific binding. After incubation of the sera, the remaining
activity was tested by ELISA as detailed above. The percent
inhibition was calculated as [(OD control - OD with inhibitor)/OD control1 x 100.
Blood cell counts. White blood cell and platelet
counts of individual blood samples were quantified in diluted
blood using a single optical cytometer (HC Plus Cell Control
Counter; Coulters Electronics, Luton, England).
Detection of lupus anticoagulant. The presence of
LAC was determined by measuring the prolongation of the
APTT in a mixing test (5): 1 volume of plasma (from whole
blood mixed with sodium citrate 0.13 moles/liter, in a 9:l
ratio) was added to 1 volume of cephalin and incubated for 2
minutes at 37°C. Another volume of 0.02M CaCl, was added,
and the clotting time was recorded in seconds.
Evaluation of pregnancy outcome. The finding of
vaginal plugs (indicating mating) was counted as day 0 of
pregnancy. The weights of the placentas and embryos were
recorded. The percentage of resorption of embryos in utero
was calculated as [resorbed fetuses/(resorbed fetuses +
full-term fetuses)] x 100.
Total body irradiation. Mice were positioned in radiation chambers and exposed to a single dose of 900 rads of
total body irradiation (TBI), from a y beam 150-A 6oCo
source (produced by Atomic Energy of Canada, Kanata,
Ontario, Canada). Skin-to-source distance was 105 cm, and
the dose rate was 65 cGy/minute.
Bone marrow cell preparation. Bone marrow cells
were prepared by flashing the femur and humerus, using a
25-gauge needle connected to a syringe containing RPMI
1640 medium. Viability of cells was determined by trypan
blue staining. T cell depletion was done by a I-hour panning
procedure, repeated 3 times, utilizing anti-Thy-1 antibody
(Becton Dickinson, Palo Alto, CA)-coated 9-cm petri dishes
on ice.
Bone marrow cell transplantation. Recipient naive
BALB/c mice (80 mice) were subjected to TBI. Two kinds of
bone marrow cell transplantation were employed: (a) from
mice in which experimental primary APS had been induced
by immunization with MAb CAM, and (b) from mice immunized with control mouse IgG MAb N40.
The bone marrow cell transfer was performed 4
months after disease induction, when all of the CAMimmunized mice had serologic and clinical evidence of APS.
The donors with experimental APS and the control donor
mice were killed, their femurs and tibias were removed, and
lo7 bone marrow cells were injected intravenously into each
recipient mouse, which previously had received TBI.
Spot ELISA. Mouse splenocytes ( lo6 cells/ml) were
assayed for their ability to secrete aPL in vitro. Splenocytes
were prepared by crushing the spleen and passing the
fragments through 0 . 4 5 ~nylon mesh. The erythrocytes were
lysed with 0.83% Tris buffered ammonium chloride. The
cells were seeded into 24-well tissue culture plates (Nunc),
precoated with various phospholipids. The plates were incubated for 6 hours at 37°C in the presence of 8% CO, in air.
Alkaline phosphatase-conjugated anti-mouse IgG or IgM
was added to the washed plates for 2 hours at room temperature. The enzymatic reaction was finished by adding BCIP
(Sigma) in 2-aminopropanol-Triton 405-MgC1, buffer to 3%
agar (type I, low electroendosmosis; Sigma) heated and
diluted in BCIP buffer at a 1:4 ratio, resulting in a 0.6% agar
solution. Overnight incubation at 37°C resulted in blue spots,
BONE MARROW TRANSPLANTATION AND EXPERIMENTAL APS
117
Table 1. Serologic findings in mice after transplantation of bone marrow cells derived from mice with experimental antiphospholipid
syndrome*
Recipient mice
~~~
Antibody infused
CAM-immunized
(n = 80)
N40-immunized
(n = 60)
Whole BMT from
CAM-immunized
donors
(n = 20)
Double-stranded DNA
Cardiolipin
Phosphatidylserine
Phosphatidylinositol
Phosphatidylcholine
Phosphatid ylethanolamine
124 2 17
989 t 75
903 t 94
879 f 103
347 f 97
225 +. 66
134 f 4
103 f 5
124 f 7
94 f 3
85 f 2
95 f 3
172 f 644
849 k 93
804 2 121
811 2 132
441 t 75
352 f 92
Donor mice
BMT-TCD from
CAM-immunized
donors
(n = 20)
Whole BMT from
N40-immunized
donors
(n = 20)
104 2 42
89 f 31
75 24
121 f 42
93 ? 39
112 31
135 f 27
92 2 24
83 2 71
72 2 24
89 2 31
93 2 24
*
*
* Recipient mice underwent bone marrow transplantation (BMT) of cells (whole population or T cell-depleted [TCD]) derived from mice with
experimental antiphospholipid syndrome or control donor mice, 4 months after immunization with CAM monoclonal antibody (MAb)
(anticardiolipin) or N40 MAb (irrelevant IgG). Sera were tested at a dilution of 1:200. Values are expressed as the mean f SD optical density
at 405 nm x lo3. Values of autoantibodies in the sera of preimmunized mice ranged from 76 % 19 to 134 2 32. Statistical analysis by Student's
t-test demonstrated that the groups of mice immunized with CAM MAb or transfused with whole bone marrow cells from mice immunized with
CAM had significantly higher titers of antiphospholipid antibodies (P< 0.01 to P < 0.05) in comparison with mice immunized with control N40,
mice transfused with T cell-depleted bone marrow cells from mice immunized with CAM, or mice transfused with whole bone marrow cells
from mice immunized with N40.
which were counted using a light microscope. Results are
presented as the percent antibody-forming cells (AFC),
calculated as (no. of aPL AFC/no. of total IgG AFC) x 100.
Proliferation response. Before and after bone marrow
cell transfusion into recipient BALB/c mice, the effect of the
treatment on proliferative activity was assayed. Paraaortic
and inguinal lymph nodes were collected under aseptic
conditions, and single-cell suspensions were prepared.
Lymph node cells (LNC) were washed and resuspended in
RPMI 1640 supplemented with 1% autologous serum, 2 mM
sodium pyruvate, 2 mM glutamine, 2 mM non-essential
amino acids, 10 mM HEPES, 100 units/ml penicillinmM 2mercaptoethanol. LNC (2
streptomycin, and 5 X
x lo5 celldwell) were cultured with 5 pg/well aCL MAb;
irrelevant IgG and concanavalin A (2 pg/well) were used as
controls. Triplicate cultures were incubated at 37°C in the
presence of 8% CO, for 4 days. Eighteen hours before
harvesting, 'H-thymidine was added to each well (1 pCi/well
of 5 rnCilmmole; Nuclear Research Center, Negev, Israel).
Results are expressed as the mean counts per minute in
triplicate cultures.
RESULTS
Bone marrow cells derived from mice immunized with the aCL MAb, all of which developed
Table 2. Clinical parameters in mice after transplantation of bone marrow cells derived from mice with experimental antiphospholipid
syndrome*
Recipient mice
Parameter
CAM-immunized
(n = 80)
N40-immunized
(n = 60)
Whole BMT from
CAM-immunized
donors
(n = 20)
APTT (seconds)
Platelet count (x 1o3mm3)
Fetal resorption (%)
Placental weight (mg)
Embryo weight (mg)
83 ? 7 t
671 1228
49 2 8 t
133 t 118
745 f 93
27 t 4
998 2 112
7 2 2
191 t 33
1,432 f 104
94 f 8$
549 f 72$
45 7$
124 ? 67
801 t 87
Donor mice
*
* Values are the mean f SD. APTT = activated partial thromboplastin
t P < 0.005 versus N40-immunized mice.
BMT-TCD from
CAM-immunized
donors
(n = 20)
Whole BMT from
N40-immunized
donors
(n = 20)
27 f 5
1,201 f 289
4 5 8
184 f 22
1,301 t 39
30 f 4
1,141 f 189
5 22
195 f 42
1.347 f 218
*
time. See Table 1 for details.
2 P < 0.005 versus mice receiving T cell-depleted bone marrow cell transplantation (BMT-TCD) from CAM-immunized donors and versus
mice receiving whole BMT from N40-immunized donors.
§ P < 0.05 versus N40-immunized mice.
7 P < 0.05 versus mice receiving T cell-depleted bone marrow cell transplantation (BMT-TCD) from CAM-immunized donors and versus mice
receiving whole BMT from N40-immunized donors.
BLANK ET AL
118
loo
r
80
60
40
20
I
0
5
10
I
I
I
I
I
I
15 20 25 30 35 40
CARDlOLlPlN (ug/ml)
1
45
1
50
Figure 1. Inhibition of cardiolipin (CL) binding in sera from mice
transfused with bone marrow cells from mice with the antiphospholipid syndrome (APS). Each point represents the mean from a pool
of 20 mice. CL (C) and PS (C) = cardiolipin and phosphatidylserine,
respectively, as inhibitor, sera of mice transfused with bone marrow
cells from control mice immunized with IgG; C L (BMT-TCD) and
PS (BMT-TCD) = CL and PS, respectively, as inhibitor, sera of
mice transfused with T cell-depleted bone marrow cells from mice
with the APS; CL (BMT) and PS (BMT) = CL and PS, respectively,
as inhibitor, sera of mice transfused with whole bone marrow cells
from mice with the APS.
cell population and T cell-depleted bone marrow cells
to secrete aCL, anti-PS, and anti-PI. The number of
AFC was increased in mice that received the whole
bone marrow cell population, while none of these
antibodies were found in elevated titers in mice that
received T cell-depleted bone marrow cells. Furthermore, LNC derived from mice treated with whole
bone marrow cells proliferated in the presence of aCL
(Figure 3). Four months after whole bone marrow cell
transplantation, all of the mice developed clinical and
hematologic markers of primary APS (Table 2), including significant prolongation of the APTT (94 seconds
and 83 seconds in mice transfused with whole bone
marrow cells from CAM-treated mice and in CAMtreated mice, respectively, compared with 27-30 seconds in controls “40-treated mice, mice transfused
with T cell-depleted bone marrow cells from CAMtreated mice, and mice transfused with whole bone
marrow cells from N40-treated mice]), reduction in
platelet counts (549 x 103/mm3and 671 x 103/mm3,
respectively, compared with 998-1,201 in controls), a
high rate of fetal resorptions (45% and 40%, respectively, compared with 6 7 % in controls) (representative uteri are shown in Figure 4), lower mean placenta
00
,
T
I
70 -
serologic markers of experimental APS as well as
thrombocytopenia, prolonged APTT, and high rates of
fetal resorption (Tables 1 and 2), were infused into the
tail vein of naive irradiated (900 rad) BALB/c mice.
The data presented in Table 1 demonstrate that when
the irradiated naive BALB/c mice were transplanted
with bone marrow cells derived from mice with experimental APS, high levels of antibodies to CL, PS, PI,
PC, and PEA had developed in all recipient mice 4
months after transplantation. High levels of &glycoprotein I also developed (data not shown). The
aPL were specific, as can be seen from the competition
experiments presented in Figure 1. The transfer of T
cell-depleted bone marrow cells did not induce aPL
production. No specific antibody production was
noted when bone marrow cells of N40 (irrelevant
1gG)-immunized mice were transferred.
Analysis of the AFC in the mice that received
bone marrow cell transplantation (Figure 2) demonstrated a difference in the ability of the bone marrow
60
-
50 -
1
-
+
40
9s?
30-
2
20
-
10
-
0BMT
BMT-TCD
D
Figure 2. Antiphospholipid antibody-forming cell (AFC) activity in
mice transfused with bone marrow cells from mice with the APS.
Each point represents the mean from 3 different experiments (5 mice
in each group tested). PI = phosphatidylinositol; PEA = phosphatidylethanolamine; D = donor mice with the APS. See Figure 1 for
other definitions.
BONE MARROW TRANSPLANTATION AND EXPERIMENTAL APS
119
weights (124 mg and 133 mg, respectively, compared
with 184-195 mg in controls), and lower mean embryo
weights (801 mg and 745 mg, respectively, compared
with 1,301-1,432 mg in controls).
DISCUSSION
The importance of bone marrow cells in the
development of autoimmunity has been previously
shown, in studies in which autoimmune-prone animals
were successfully treated with bone marrow transplantation (12-15). In the present study we assessed the
pathogenic potential of bone marrow cells in inducing
experimental antiphospholipid syndrome, by transplanting bone marrow cells from mice with experimental APS into naive, total body-irradiated, syngeneic
mice. Our results demonstrate that APS can be transferred to syngeneic irradiated recipient mice through
whole-population bone marrow cells. The transplanted
mice developed high titers of aPL (CL, PS, PI), in
association with elevated levels of specific AFC. In
addition, specific proliferation response of the recipient lymphocytes in response to aCL was observed.
Other investigators have also reported on the
ability of bone marrow transplantation to induce auto-
0
0
X
I
a
0
ANTIBODY (ug/rnl)
Figure 3. Anti-CAM activity of lymph node cells in mice transfused
with bone marrow cells from mice with the, APS. Each point
represents the mean 2 SD from 3 different experiments (5 mice in
each group tested). See Figure l for definitions.
Figure 4. Representative pictures of uteri from A, a mouse transfused with T cell-depleted bone marrow cells from mice with
experimental antiphospholipid syndrome (APS) and B, a mouse
transfused with a pool of whole bone marrow cells from a group of
mice with experimental APS. The recipient mice were killed on day
15 of pregnancy.
immune disease in experimental animals (12-22) although there have been conflicting results (23). In an
interesting study reported by LaFace and Peck (24),
reciprocal allogeneic bone marrow transplantations
were carried out between diabetes-susceptible
nonobese diabetic (NOD) and non-diabetes-susceptible
mice. The results showed that lethally irradiated NOD
mice reconstituted with bone marrow from normal
mice remained free of diabetes; in contrast, lethally
irradiated non-diabetes-susceptible mice reconstituted
with a NOD hematopoietic cell system all developed
insulitis which, in lo%, progressed to overt diabetes.
There are even a few case reports of adoptive
transfer of autoimmunity after bone marrow transplantation in humans: Holland et a1 (25) reported on a
brother and sister who presented with classic findings
of Graves’ disease within a year of each other. Eight
years previously, the brother had received transplantation of bone marrow from his sister due to a lifethreatening aplastic anemia. After the procedure, all of
his peripheral blood leukocytes had the genotype
46XX. It thus appears that the brother passively
acquired clone-programmed or activated lymphocytes
from his sister, which led to the development of
Graves’ disease. Similarly, Vialettes et a1 (26) reported on the development of autoimmune hypothyroidism and type I diabetes mellitus in a patient after
allogeneic bone marrow
from her
HLA-identical sister. The donor later developed autoimmune hypothyroidism and signs of pre-type I dia-
120
betes. Other cases of transfer of autoimmune diseases,
including myasthenia gravis (27), hypothyroidism (28),
and autoimmune thrombocytopenic purpura (29), following bone marrow transplantation have also been
reported.
The mechanism of adoptive transfer of autoimmune diseases via bone marrow transplantation
could involve the expression of disease susceptibility
genes in hematopoietic cells, coupled with the transfer
of autoreactive lymphocytes. Indeed, in our study,
APS was not transferred by T cell-depleted bone
marrow. Another possibility is that the emergence of
the clinical picture of APS following transplantation of
bone marrow from mice with the disease might be due
to abnormalities of bone marrow stem cells responsible for autoantibody production. Such abnormalities
have been reported in the mutant mouse strain CBAlprcg (16), and in NZB mice (9,13,3&33): the marrow
cell population of NZB mice had 30-fold more colonyforming cells than did this population in control mice
(30). These cells may play a role in autoimmune
diseases. Moreover, from the results obtained in previous studies on the germinal center in the bone
marrow, it has been suggested that in secondary
antibody responses, antigen processing and presentation occur in secondary lymphoid organs, while most
serum antibodies are produced by cells in the bone
marrow (32). Germinal-center B cells, which acquire
antigen from follicular dendritic cells in draining lymph
nodes during the first few days of the secondary
response, migrate to the bone marrow to terminally
differentiate and produce specific antibodies (32).
Our results also demonstrate the pathogenic
role of T cells in inducing experimental APS, since the
disease was not transferred by T cell-depleted bone
marrow. The T cells may play a role in the pathogenesis of experimental APS by providing help to B cells
in producing the pathogenic autoantibodies (e.g.,
aCL), or through effector T cells which directly cause
the disease. T cells are key mediators of many organspecific autoimmune diseases, such as autoimmune
thyroiditis, gastritis, and insulitis in insulin-dependent
diabetes mellitus (34-38). Indeed, in SLE, which is
regarded as a classic autoantibody-induced disease, T
cells seem to play an important role in disease generation. Indeed, we were able to induce experimental
SLE in naive mice by transfer of T cell clones specific
for a pathogenic idiotype (39-41).
The role of T cells in the induction and progression of APS is not yet known. In the autoimmune
BLANK ET AL
mouse strain MRL-lpr, depletion of T cells (by
thymectomy) prevented the development of the autoimmune condition, including the production of aCL
(42). Since T cells have been shown to play a major
role in autoimmune diseases, it was suggested that a
deletion in the T cell receptor (TCR) p region might
explain susceptibility of SJL mice to collagen-induced
arthritis (43), or a deletion in the Vp2-Cp2 region in
NZW mice might predispose to the development of
lupus in this strain (44). Furthermore, germline expression of rearranged TCR a-chain transgenes with the
immunoglobulin H-chain enhancer reproducibly elicits
T cell-mediated autoimmune disease in the thyroid
gland, gastric mucosa, Langerhans’ islets, salivary
gland, ovaries, and testes in selected strains of normal
mice (45).
In summary, our study shows the importance of
bone marrow T cell populations in the transfer of
experimental APS to naive mice. These findings demonstrate the importance of T cells in the induction of
APS, which up till now has been regarded as an
autoantibody-induced disease. Our results also may
raise the possibility of the therapeutic benefit of bone
marrow transplantation in cases of severe APS that
has been unresponsive to other treatments (“catastrophic” APS).
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