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Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; and
The Open University of Israel, Tel-Aviv, Israel
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) and deliver
costimulatory signals to autoreactive B cells, inducing them to produce
pathogenic autoantibodies. EAMG in rats mimics human MG in its clinical and immunopathologic manifestations and is a reliable model to investigate therapeutic strategies for myasthenia. In an attempt to develop an Ag-specific immunotherapy for MG, we have previously demonstrated that mucosal administration of recombinant fragments of human AChR prevents the induction of EAMG and suppresses ongoing EAMG in rats (1, 2). The mucosal tolerance was mediated by a shift from a Th1 to a Th2/Th3 AChR-specific response and down-regulation of costimulatory factors such as CD40 ligand (CD40L), B7-1, and B7-2 (3).
CD40L is expressed on activated CD4+ T cells, whereas CD40, the receptor for CD40L, is expressed on various APCs such as B cells, dendritic cells, and macrophages (4). CD40-CD40L interaction influences many T cell-mediated inflammatory responses as reviewed in detail elsewhere (5, 6). Binding of CD40L to CD40 triggers B cells to function as APC and up-regulates the expression of the costimulatory molecules B7-1 and B7-2 (7, 8). CD40-CD40L signaling also activates macrophages to produce inflammatory cytokines (9) and plays an important role in the in vivo activation and clonal expansion of Ag-specific T cells (10).
CD40-CD40L interactions were previously found to be essential for the development of several autoimmune diseases including collagen-induced arthritis (11), autoimmune oophoritis (12), experimental allergic encephalomyelitis (EAE) (13, 14), lupus nephritis (15, 16), experimental autoimmune thyroiditis (17), and spontaneous autoimmune diabetes (18).
The role of CD40-CD40L in EAMG was recently studied in CD40L knockout mice (CD40L-/-) (19). The mice were completely resistant to EAMG induction and had diminished Th1 and Th2 responses as well as severely impaired T cell-dependent AChR-reactive B cell responses (19). These observations suggested that signaling via CD40-CD40L plays an important role in the induction of EAMG. In this study we tested the effect of intervention in CD40-CD40L interactions on the progression of an already existing disease. We show that anti-CD40L treatment is an effective way of suppressing EAMG even when it is given during the chronic stage of disease. The underlying mechanism of this suppression seems to be mediated by down-regulation of B7-2 and up-regulation of CTLA-4 levels. Pathogenic Th1-type cytokines are decreased, but there are no significant changes in the levels of Th2- or Th3-type cytokines and no induction of regulatory cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female Lewis rats (6–7 wk of age) were purchased from the
Animal Breeding Center of the Weizmann Institute of Science (Rehovot,
Israel). Torpedo AChR was purified from Torpedo californica
by affinity chromatography as previously described (20).
Two recombinant human AChR fragments corresponding to the extracellular
domain of the 
-subunit were used to represent mammalian muscle AChR
for determination of AChR-specific responses. The homology between rat
and human muscle AChR in this region is 96%. H1-205, a fragment
corresponding to residues 1–205 of human AChR -subunit expressed
without a fusion partner was used for determination of IgG isotypes of
anti-AChR Abs. Trx-H1-210, which corresponds to residues 1–210
of the human AChR -subunit and is expressed as a fusion protein with
thioredoxin was used for determination of AChR-specific in vitro B cell
proliferation. Trx-H1-210 was applied for B cell proliferation
because it is similar in its conformation to native AChR, as assessed
by its reactivity with -bungarotoxin (-BTX) and with
conformation-dependent anti-AChR mAbs (3). All
recombinant AChR fragments were expressed in Escherichia
coli and purified as previously described (3, 21).
The purified recombinant proteins exhibited a single band on SDS-PAGE
when stained with Coomassie blue, and were estimated to be at least
95% pure.
Induction and clinical evaluation of EAMG
Rats were immunized once in both hind footpads by s.c. injection of Torpedo AChR (40 µg/rat) emulsified in CFA containing additional Mycobacterium tuberculosis (1 mg/rat; Difco, Detroit, MI). Clinical severity of EAMG was graded as follows: grade 0, no weakness or fatigability; grade 1, mildly decreased activity, weak grip, with fatigability; grade 2, weakness, hunched posture at rest, decreased body weight and tremor; grade 3, severe generalized weakness, marked decrease in body weight, moribund; grade 4, dead. Animals were evaluated weekly for 9–10 wk following immunization with Torpedo AChR.
In vivo Ab treatment
Rabbit Abs specific for recombinant human CD40L (Alexis Biochemicals, San Diego, CA) or for BSA were prepared by two immunizations with 4-wk intervals, each with 25 µg of Ag in CFA. The purified IgG fractions (600 µg/ml/dose) of anti-CD40L or anti-BSA were i.p. administered to rats at the chronic stage of EAMG four times per week starting 4 or 6 wk after AChR immunization and continued until the end of the experiment.
Ab assays
Abs to rat muscle AChR were measured by radioimmunoassay with
crude rat muscle extract labeled by 125I--BTX,
and results are expressed as nmol Ab/L serum (22).
Determination of AChR-specific IgG isotypes was performed as described
previously (2). Microtiter plates were coated with
recombinant human AChR fragment, H1-205, and reacted with tested
serum samples at proper dilutions (1/50 for IgG1; 1/300 for IgG2a; 1/10
for IgG2b and IgG2c). Biotinylated mouse mAbs to rat IgG isotypes
(1:1000; Caltag, South San Francisco, CA) were added, and bound
Abs were detected by activity of alkaline phosphatase expressed as OD
at 405 nm.
Delayed-type hypersensitivity (DTH)
Assessment of DTH was performed by s.c. injection of Torpedo AChR (20 µg) into the contralateral ear of rats. The difference in ear lobe thickness before challenge and within 30 h after challenge was recorded for each animal. Results are expressed as the mean of four animals for each experimental group ± SEM.
Lymphocyte proliferation assay
Proliferation of lymph node cells (LNCs) from treated rats was
performed essentially as described (3). Draining LNCs were
removed 4 or 5 wk after initiation of treatment and cultured (5 x
105 cells/well) in RPMI 1640 medium supplemented
with HEPES (25 mM), sodium pyruvate (1 mM), glutamine (2 mM), 2-ME (50
µM), penicillin (20 U/ml), streptomycin (20 µg/ml), amphotericin B
(0.05 µg/ml), nonessential amino acids (mg/L); (Ala, 8.9; Asn, 15;
Asp, 13.3; Glu, 14.7; Gly, 7.5; Pro, 11.5; Ser, 10.5), and 0.5% normal
rat serum, either alone or in the presence of Torpedo AChR (0.25
µg/ml). Proliferation was assessed by measuring
[3H]thymidine (0.5 µCi/well) incorporation
during the last 18 h of a 4-day culture period. Results are
expressed as 
cpm after subtraction of background counts of
unstimulated cultures from those of stimulated LNCs.
B cell proliferation assay based on alkaline phosphatase activity
B cell proliferation was assayed as described (3).
Draining LNCs (1 x 106/ml) were cultured in
the medium used for lymphocyte proliferation supplemented by 10% FCS.
Cells in 24-well plates were stimulated in vitro with Trx-H1-210 (50
µg/ml) alone, or in the presence of either anti-CD40L (200
µg/ml) or anti-BSA (200 µg/ml). LPS (5 µg/ml) was used as a
positive control. After 4 days in culture, the cells were harvested,
washed, and diluted in PBS. For the alkaline phosphatase assay,
100-µl cell suspensions containing different cell concentrations were
transferred to 96-well plates into which 100 µl/well of substrate
solution (p-nitrophenyl phosphate, disodium; 1
mg/ml) was added. The plates were incubated for 2–4 h at 37°C in 5%
CO2. Alkaline phosphatase activity was monitored
by OD at 405 nm.
Determination of cytokines and costimulatory factors
PCR-ELISA was used to assess the levels of mRNA specific for
cytokines (IL-2, IL-4, IL-10, IL-12, IFN-, and TGF-
) and
costimulatory factors (CD40, CD40L, CD28, CTLA4, B7-1, and B7-2).
Draining LNCs (1 x 106/ml) were cultured in
the medium used for lymphocyte proliferation and stimulated with
Torpedo AChR (0.25 µg/ml) for 40 h. Total RNA extraction was
performed by using a total RNA extraction kit (Roche Molecular
Biochemicals, Mannheim, Germany), and the extracted RNA was reverse
transcribed into cDNA using M-MuLV reverse transcriptase (New England
Biolabs, Beverly, MA) with oligo(dT) as a primer. PCR was performed in
the presence of digoxigenin (DIG)-dNTP and specific primer pairs for
specific cytokines and costimulatory factors as described
(2) by using a PCR-ELISA kit (Roche Molecular
Biochemicals). The sequences of primer pairs for PCR and internal
primers specific for cytokines and costimulatory factors were the same
as previously reported (3). The internal primers were all
biotinylated by Biotin-Chem-Link (Roche Molecular Biochemicals)
according to the manufacturer’s protocol. The amplified DIG-labeled
PCR products were quantified by a peroxidase-conjugated anti-DIG
Ab. PCR products were viewed with the peroxidase substrate ABTS, and
signals were quantified by absorbance at 405 nm (2).
Statistical analysis
Student’s two-tailed t test was used to determine the significance of differences between group means.
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Results |
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The interaction of CD40L on T cells with its receptor, CD40, on B
cells is critical for induction of T cell-dependent Ab production.
Because MG and EAMG are T cell-dependent Ab-mediated autoimmune
disorders, we reasoned that blocking of CD40-CD40L interaction could
result in an immunosuppressive effect on the production of pathogenic
autoantibodies. To test this hypothesis, anti-CD40L Ab was
administered to rats at the chronic stage of EAMG, which usually
appears 
4 wk after immunization with Torpedo AChR. Treatment was
initiated either 4 (Fig. 1
A)
or 6 wk (Fig. 1B) after EAMG induction. Rats were injected
four times a week with anti-CD40L Ab or anti-BSA as control Ab,
and treatment was continued for 4–5 more weeks. At the beginning of
treatment the mean clinical score of the rats was 1.5. Treatment with
anti-CD40L Ab had a therapeutic effect on the severity of EAMG
(Fig. 1 and Table I), in both protocols.
When treatment started 4 wk after disease induction (Fig. 1A), in the anti-CD40L-treated group none of the rats
died and two of eight rats recovered completely (Table I), whereas in
the anti-BSA-treated group there was an aggravation in the severity
of EAMG. Five weeks after initiation of treatment, two of eight rats
died, and four were severely sick (mean clinical score: 2.5). A similar
protective effect of anti-CD40L treatment was observed when
treatment started 6 wk after disease induction (Fig. 1B).
Three of seven rats recovered completely or partially, but none of the
anti-BSA-treated rats showed any signs of recovery. It should be
noted that the suppressive effect of anti-CD40L on the clinical
symptoms of EAMG lasted only for a short period (2 wk) after the
treatment has been discontinued. Also, adoptive transfer of splenocytes
from anti-CD40L-treated rats into naive rats did not protect the
recipients against subsequently induced EAMG (data not shown).
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). Rats in the
control, anti-BSA-treated group lost 8 ± 20 g/rat, between 5
and 9 wk following induction of EAMG, whereas rats in the
anti-CD40L-treated group gained 6 ± 14 g/rat at the same time
(Table I).
The effect of anti-CD40L Ab treatment on EAMG was accompanied by a
suppression of the AChR-specific humoral immune response (Table I).
Rats treated with anti-CD40L had a marked decrease in their
anti-self rat muscle AChR Ab titer (46% reduction) when tested
after 4 wk of treatment, whereas in the anti-BSA-treated group the
anti-self AChR titer increased by 75% as compared with the titer
at the initiation of treatment. However, as shown in Table I, treatment
with anti-CD40L Ab did not affect AChR-specific T cell
proliferation compared with the anti-BSA-treated group.
Effect of anti-CD40L treatment on AChR-specific DTH
The AChR-specific DTH response, a known Th1-regulated response,
was assessed in rats treated by anti-CD40L and in control rats
treated by anti-BSA. Three days after AChR injection, rats were
treated three times with either anti-BSA or anti-CD40L Abs, and
AChR-specific DTH responses were measured 30 h after AChR
injection into the ear lobes. Anti-CD40L treatment reduced DTH
responses to AChR as compared with anti-BSA-treated rats ( ear
lobe thickness was 16 ± 4 mm x 10-2
and 69 ± 12 mm x 10-2, respectively;
p < 0.002), indicating that anti-CD40L treatment
suppresses AChR-specific Th1 responses in vivo.
Effect of anti-CD40L treatment on cytokines and costimulatory factors
To study the possible effect of anti-CD40L treatment on Th1 and Th2/Th3 cells and on costimulatory factor expression, we monitored the levels of cytokines and costimulatory molecules in the treated rats. Draining LNCs from rats treated with anti-BSA or anti-CD40L were removed 4 or 5 wk after initiation of treatment and cultured for 40 h in the presence of Torpedo AChR. Total RNA was then prepared from the cells and subjected to PCR-ELISA with cytokine-specific or costimulatory factor-specific primers.
As shown in Fig. 2, anti-CD40L
treatment resulted in significant down-regulation
(p < 0.001) of IL-12 and IFN- with no
effect on the level of Th2-type (IL-4 and IL-10) or Th3-type (TGF-)
cytokine mRNA levels, suggesting that anti-CD40L treatment induces
a selective suppression of Th1-type differentiation. The fact that
adoptive transfer of splenocytes from anti-CD40L-treated rats into
naive rats did not protect the recipients against subsequently induced
EAMG, together with the unchanged level of Th2- and Th-3 type
cytokines, suggests that anti-CD40L treatment affects EAMG via
suppression of Th1-type regulation of the AChR-specific response
without the induction of Th2/Th3 regulatory cells.
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, anti-CD40L treatment
resulted in up-regulation of CTLA-4 and down-regulation of B7-2 levels
compared with anti-BSA-treated rats (p <
0.001). Other costimulatory factors such as CD28, B7-1, and CD40L were
similarly expressed in anti-CD40L- and anti-BSA-treated
rats.
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Unlike our previous observation following oral tolerance with AChR
recombinant fragments (2), we did not observe a deviation
from Th1 to Th2/Th3 regulation of the AChR-specific response in
anti-CD40L-treated rats. The analysis of IgG isotype profile of
anti-AChR Abs confirmed these observation. The IgG isotypes of Abs
to AChR were measured 4–5 wk after initiation of treatment. H1-205,
a recombinant human AChR fragment (96% homologous to the respective
rat sequence), was used as a mammalian AChR Ag in this assay
(2). As shown in Fig. 4, total anti-H1-205 IgG levels, as well as the levels of IgG1 and
all IgG2 subtypes, were lower in anti-CD40L-treated rats as
compared with control anti-BSA-treated rats. These data are in line
with the observed cytokine profile and suggest that anti-CD40L
treatment does not induce a shift from Th1 to Th2/Th3 regulation of the
anti-AChR response. Such a shift would be expected to lead to an
increase in IgG1, which in the rat is regulated by Th2-type cells.
IgG2b and IgG2c, which have been previously suggested to be involved in
rat EAMG (2, 23), are regulated by Th1 cells.
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To examine whether the observed effects of anti-CD40L
treatment on EAMG and anti-self-AChR levels, are associated with
changes in AChR-specific B cell proliferation, we compared the in vitro
response to AChR of cells from myasthenic rats. LNCs were removed from
myasthenic rats at the chronic phase of disease (mean clinical score:
2–3) and cultured for 4 days in the presence of Trx-H1-210 alone or
together with either anti-CD40L or anti-BSA. Trx-H1-210 was
applied for this assay because of the similarity of its conformation to
native AChR, as assessed by its reactivity with -BTX and with
conformation-dependent anti-AChR mAbs (3). The level
of B cell proliferation was determined by alkaline phosphatase
activity, which is known to be specific for activated B cells
(24, 25). As shown in Fig. 5
the presence of anti-CD40L strongly suppressed in vitro B cell
proliferation, whereas anti-BSA Abs did not
(p < 0.001). In contrast, in vitro
anti-CD40L treatment did not induce suppression of T cell
proliferation in response to AChR (data not shown). This is in
agreement with the observation that anti-CD40L treatment in vivo
down-regulates the anti-self AChR Ab levels but has no effect on
AChR-specific T cell proliferation (Table I), and implies that
anti-CD40L treatment suppresses proliferation of B cells but not of
T cells. The lack of effect on the overall T cell proliferation and
IL-2 levels, as well as the diminished Th1-dependent DTH response and
reduced levels of Th1-type cytokines, suggests that anti-CD40L
treatment affects Th1 differentiation rather than proliferation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-12 but no changes
in IL-4, IL-10, and TGF- as well as in a decreased DTH response to
AChR and in reduced anti-self-AChR Ab titers of all IgG
isotypes. Anti-CD40L treatment affected the expression of
specific costimulatory factors (B7-2 levels were reduced, whereas
CTLA-4 levels were increased) but did not affect the levels of the
other costimulatory factors (B7-1, CD28, CD40, and CD40L). The production of autoreactive Abs in EAMG is regulated by AChR-specific CD4+ and CD8+ helper T cells (26), and interaction of T and B cells is crucial for disease pathogenesis (27). B cells express both MHC II and costimulatory molecules on their cell surface and can work as APCs and provide costimulatory signals for Ag-specific T cell activation (28). In turn, the activated T cells express CD40L and secrete cytokines that provide costimulatory signals for B cell proliferation and differentiation. T cell activation, and B cell proliferation and differentiation, through this two-way T-B cell interaction can be a self-perpetuating process during disease progression.
The specificity of T cell help for B cell activation and
differentiation is maintained by the expression of CD40L on the surface
of T cells. Interaction of CD40L on T cells with CD40 on B cells
induces B cell activation, cell surface expression of activation Ags,
proliferation, and initiation of immunoglobulin isotype switch. This
CD40L/CD40 costimulation is also an important regulator of Th1
responses. It enhances IFN- production by direct induction of
IL-12p40 mRNA expression and accumulation of bioactive IL-12 production
(29), or by activation of IL-1-converting enzyme
(caspase-1), which in turn activates IL-1 or IL-18, an IFN--inducing
factor (30). The suppressive effect of anti-CD40L Ab
in suppression of ongoing chronic EAMG in our study was associated with
down-regulation of the pathogenic inflammatory cytokine IFN- and of
IL-12 (Fig. 2), both of which have been previously demonstrated to be
directly or indirectly involved in induction of EAMG
(31, 32, 33, 34, 35). The selective suppressive effect on Th1-type
differentiation by anti-CD40L treatment is consistent with models
of other autoimmune diseases such as multiple sclerosis, diabetes, and
thyroiditis (17, 18, 36, 37), and with graft-vs-host
disease and graft rejection (38, 39).
Blockade of CD40L induced up-regulation of CTLA-4 expression levels and
down-regulation of B7-2 but not of B7-1 (Fig. 3). It is known that B7-2
expression on B cells is rapidly induced by CD40 and by IFN- that
increases transcription and stability of B7-2 mRNA (40).
Reduced IFN- levels associated with down-regulation of B7-2
expression (Figs. 2 and 3) have been previously reported
(41). Repression of B7-2 on self-reactive B cells is known
to be crucial for the elimination of autoreactive B cells by Fas in B-T
cell interactions (41). In addition, the effectiveness of
Ag-specific B cells as APCs depends on immediate up-regulation of B7-2
(42). B7-2 also induces IL-12R expression and accumulation
of IL-12R1 and IL-12R2 mRNA in CD4+ T cells
(43). In MG patients, the expression level of B7-2 on
CD4+ and CD8+ T cells is
higher than in healthy individuals (44). Based on the role
of B7-2 as a promoter for humoral responses, lowering B7-2 levels by
anti-CD40L treatment may contribute to decreased anti-self Ab
levels and suppression of EAMG.
CTLA-4 present on CD4+ and
CD8+ T cells acts as a key negative
immunomodulator of immune responses by blocking CD28-dependent T cell
activation (45). CTLA-4 is also involved in the induction
of peripheral T cell tolerance in vivo (46), and its
blockade exacerbates clinical symptoms of EAE (47). The
CTLA-4 gene is polymorphic, and certain alleles are
linked to MG and other autoimmune diseases (48, 49, 50, 51, 52, 53, 54).
CTLA-4 normally acts as a negative regulator of T cell activation;
therefore, up-regulation of CTLA-4 levels by anti-CD40L treatment
may attenuate Th1-type cell activation (55). Up-regulation
of CTLA-4 was also found during remission periods in EAE
(56), which is consistent with the role of CTLA-4 in the
termination of immune responses. Therefore, the increased levels of
CTLA-4 and down-regulated B7-2 levels induced by anti-CD40L
observed in our study may lead to impaired T cell activation, which is
necessary for the proliferation and differentiation of autoreactive B
cells and may thus result in reduced Ab production. The unchanged
levels of costimulatory factors other than B7-2 and CTLA-4 and the lack
of effect on T cell proliferation by anti-CD40L treatment suggest
that anergy is not induced and seems not to be involved in suppression
of EAMG. Also, this may suggest that the up-regulation of CTLA-4 and
down-regulation of B7-2 are not sufficient to affect T cell
proliferation probably due to the activity of other cytokines such as
IL-2 and costimulatory factors such as B7-1 and CD28. Nevertheless,
they did affect T cell differentiation, resulting in specific
down-regulation of IL-12 and IFN- levels.
It is noteworthy that the protective effect of anti-CD40L Abs disappeared within 2 wk after cessation of Ab treatment. This indicates that the immunosuppressive effect of anti-CD40L is reversible and does not induce any regulatory T cells. Indeed, adoptive transfer of splenocytes from anti-CD40L-treated rats did not provide protection against EAMG induction in the recipients, supporting the notion that no regulatory cells were induced by anti-CD40L treatment. This is in contrast to the long-lasting effect we have observed in rats in which mucosal tolerance was induced by recombinant AChR fragments (1, 2, 21). In addition, repetitive i.p. administration of rabbit anti-CD40L Abs to rats elicited an immune response to rabbit IgG. It is clear that when considering an analogous treatment of MG patients, one should avoid the repetitive administration of xenogeneic immunoglobulins, for instance, by the use of humanized anti-CD40L Abs.
In summary, treatment of chronic EAMG by anti-CD40L attenuates
disease progression by suppressing Th1 differentiation and effector
functions. The decreased level of anti-self-Ab was associated with
reduced expression of B7-2, IL-12, and IFN- levels, and increased
CTLA-4 levels, which may contribute to down-regulation of T cell
effector functions. The effect of anti-CD40L treatment during the
chronic phase of experimental myasthenia is of special relevance to
human MG, which is a chronic disease. It is encouraging that an
appropriate antagonist of CD40L-CD40 signaling could alleviate the
symptoms of the chronic autoimmune process in EAMG. Therefore,
targeting of CD40L-CD40-mediated signaling may be potentially suitable
for immunotherapy of myasthenia especially when combined with our
previously described long-lasting Ag-specific effect of oral tolerance
induced by AChR-derived fragments.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Sara Fuchs, Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. E-mail address: sara.fuchs{at}weizmann.ac.il
3 Abbreviations used in this paper: MG, myasthenia gravis; EAMG, experimental autoimmune MG; AChR, acetylcholine receptor, DTH; delayed-type hypersensitivity; -BTX, -bungarotoxin; CD40L, CD40 ligand; EAE, experimental allergic encephalomyelitis; LNC, lymph node cell; DIG, digoxigenin.
Received for publication January 9, 2001. Accepted for publication March 19, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit. Proc. Natl. Acad. Sci. USA 96:8086.-converting enzyme (caspase-1) activity in vascular smooth muscle and endothelial cells and promotes elaboration of active interleukin 1. J. Biol. Chem. 272:19569. (IFN-) is necessary for the genesis of acetylcholine receptor-induced clinical experimental autoimmune myasthenia gravis in mice. J. Exp. Med. 186:385. or IL-12 has different effects on experimental myasthenia gravis in C57BL/6 mice. J. Immunol. 164:5236.. Clin. Immunol. Immunopathol. 87:15.[Medline]
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 S.-H. IM, D. BARCHAN, P. K. MAITI, L. RAVEH, M. C. SOUROUJON, and S. FUCHS Suppression of experimental myasthenia gravis, a B cell-mediated autoimmune disease, by blockade of IL-18 FASEB J, October 1, 2001; 15(12): 2140 - 2148. [Abstract] [Full Text] [PDF]
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