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and IL-1 Blockade in Collagen-Induced Arthritis and Comparison with Combined Anti-TNF-/Anti-CD4 Therapy1
Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, London, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, anti-IL-1,
and combined anti-TNF-/anti-CD4 therapy in collagen-induced
arthritis. Blockade of TNF- or IL-1 before disease onset delayed,
but did not prevent, the induction of arthritis. When treatment was
initiated after onset of arthritis, anti-TNF-, anti-IL-1ß,
and anti-IL-1R (which blocks IL-1 and IL-1ß) were all found to
be effective in reducing the severity of arthritis, with anti-IL-1R
and anti-IL-1ß showing greater efficacy than anti-TNF-.
Anti-IL-1ß was equally as effective as anti-IL-1R, indicating
that IL-1ß plays a more prominent role than IL-1 in
collagen-induced arthritis. An additive effect was observed between
anti-TNF- and anti-IL-1R in the prevention of joint erosion
and in normalization of the levels of serum amyloid P. Combined
anti-TNF-/anti-CD4 therapy also caused normalization of
serum amyloid P levels. The therapeutic effect of anti-TNF- plus
anti-CD4 was comparable to that of anti-TNF- plus
anti-IL-1R, suggesting that combined anti-TNF-/anti-CD4
therapy prevents both TNF-- and IL-1-mediated pathology.
Anti-TNF- treatment reduced IL-1ß expression in the joint and,
conversely, anti-IL-1ß treatment reduced TNF- expression.
Combined anti-TNF-/anti-CD4 treatment almost completely
blocked the expression of IL-1ß, thereby confirming the ability of
this form of combination therapy to prevent IL-1ß-mediated
pathology. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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therapy is effective in reducing disease activity in rheumatoid
arthritis (RA)3
(1, 2, 3, 4, 5). The decision to test anti-TNF- therapy in
RA was based on a variety of diverse findings that, taken together,
provided compelling evidence that TNF- was playing a dominant
pathological role in the disease. For example, it was shown that
blockade of TNF- in RA synovial cell cultures led to reduced
production of another important pro-inflammatory cytokine, IL-1,
suggesting that the production of IL-1 in RA is driven by TNF-
(6). Subsequently, the beneficial effects of
anti-TNF- therapy were demonstrated by a number of groups in
collagen-induced arthritis (CIA), an animal model of RA
(7, 8, 9, 10, 11). A further piece of evidence that confirmed the
arthritogenic capacity of TNF- was the observation that
TNF--transgenic mice, which express human TNF- in a disregulated
fashion, spontaneously develop severe erosive arthritis that can be
prevented by anti-human TNF- mAb (12). However,
more recently it was shown that arthritis could also be prevented in
TNF--transgenic mice by the administration of a blocking
anti-IL-1R (type I) mAb, indicating that the induction of arthritis
by TNF- in this model is dependent on IL-1 (13). Studies of cytokine blockade also point to an important pathological role for IL-1 in CIA (14, 15, 16, 17). However, some doubt as to the pathological significance of IL-1 remains as continuous infusion with IL-1R antagonist (IL-1Ra) was found to be relatively ineffective in adjuvant arthritis (17) and neutralization of IL-1 in streptococcal cell wall-induced arthritis failed to affect the clinical severity of disease, although a reduction in cartilage proteoglycan depletion was observed microscopically (18). In human RA, clinical trials with IL-1Ra have shown only modest reductions in disease activity (19) although in view of the poor pharmacokinetics, this may be due to incomplete neutralization of IL-1 (17).
We report here on a comparative study to evaluate the effect of
neutralizing both IL-1 and IL-1ß (using a mAb that blocks
signaling via the type I IL-1R), IL-1ß (using anti-IL-1ß mAb),
or TNF- (using anti-TNF- mAb) in CIA. In addition, we compare
the effects of two different forms of combination therapy,
anti-TNF- plus anti-IL-1R and TNF- plus anti-CD4. In
this study we are able to confirm and extend previous findings
suggesting that IL-1, like TNF-, represents a promising therapeutic
target for RA. In addition, we provide data indicating that IL-1ß,
rather than IL-1, is the major contributor to joint pathology in CIA
in DBA/1 mice. Finally, we demonstrate that combined
anti-TNF-/anti-CD4 therapy leads to effective suppression of
both TNF- and IL-1ß expression.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Bovine type II collagen was purified from articular cartilage as described (20). Male DBA/1 mice (8–12 wk of age) were immunized intradermally with type II collagen (200 µg/mouse), emulsified in CFA.
mAb treatment
All mAbs were administered by i.p. injection. Isotype controls for all of the mAbs used in this project have been shown to have no discernable effect on the progression of arthritis (8, 14, 21, 22). The mAbs that were used are described below.
Anti-TNF-. TN3-19.12, a neutralizing hamster IgG1
anti-TNF-/ß mAb (23) was a gift from Robert
Schreiber (Washington University Medical School, St. Louis, MO), in
conjunction with Celltech (Slough, U.K.). The concentration of
TN3-19.12 required to cause 50% inhibition of killing of WEHI 164
cells by 15 pg/ml TNF- is 62.0 ng/ml (24). In vivo
administration of TN3-19.12, at doses of 300 µg/mouse given once
every 3 days, was earlier shown by us to be effective in reducing the
severity of CIA (8).
Anti-IL-1R. 35F5 is a rat IgG1 mAb that
blocks the binding of IL-1 and IL-1ß to the mouse type I IL-1R and
hence neutralizes IL-1 bioactivity. A concentration of 100 ng/ml 35F5
caused a 50% inhibition of proliferation of the D19.G4.1 cell line,
stimulated with 12 ng/ml IL-1 (25). Pretreatment with
35F5 at a dose of 200 µg completely prevented weight loss and
attenuated the acute phase response in mice following challenge with
turpentine (26). 35F5 was generated and supplied by
Richard Chizzonite (Hoffmann-LaRoche, Nutley, NJ).
Anti-IL-1ß. 1400.24.17 is a mouse IgG1 mAb
that neutralizes IL-1ß but not IL-1. The concentration of
1400.24.17 required to induce a 50% inhibition of proliferation of the
D10S cell line, stimulated with 100 pg/ml IL-1ß, was 50 ng/ml
(14). Treatment of DBA/1 mice with 1400.24.17, at doses of
100 µg/mouse (three times per week) from the time of collagen
immunization, was earlier shown to produce a marked reduction in the
severity of CIA (14). 1400.24.17 was generated and
supplied by Harry Towbin (Novartis Pharmaceuticals, Basel,
Switzerland).
Anti-CD4
Lytic anti-CD4 mAb (rat IgG2b) consisted of a mixture (1:1) of YTS 191.1.2 and YTA 3.1.2 (27, 28, 29). YTA 3.1.2 was a gift from Herman Waldmann (then at the University of Cambridge, U.K.) and YTS191.1.2 was obtained from the European Collection of Animal Cell Cultures (Salisbury, U.K.).
Clinical assessment of arthritis
Following immunization with type II collagen, mice were monitored for the first signs of arthritis (redness and/or swelling in one or more paws, or limping). To compare the severity of arthritis in the different treatment groups, clinical score and paw-swelling were monitored over a 10 day treatment period. A scoring system was used with the following scale: 0, normal; 1, slight swelling and/or erythema; and 2, pronounced edematous swelling. Each limb was graded, giving a maximum score of 8 per mouse. Paw thickness in affected hind-paws was measured with calipers throughout the treatment period and a value for total paw-swelling over this period was obtained by determining the area under the curve, using the trapezoidal method.
Histological assessment of arthritis
At the end of the treatment period the mice were killed, bled, and their joints were processed for histology. The first limb to show clinical evidence of arthritis was removed, fixed, decalcified, and embedded before sectioning and staining with hemotoxylin and eosin. Saggital sections of the proximal interphalangeal (PIP) joint of the middle digit were examined by microscopy in a blinded fashion for the presence or absence of erosions, as defined (21). Thus, comparisons were made of the same joints and the arthritis was of identical duration in each case. The PIP joint was chosen because in previous studies, erosions have been found to be present in this joint in 90–100% of untreated arthritic mice on day 10 of arthritis. A significant reduction in this figure is taken to represent a beneficial therapeutic effect on joint erosion.
Immunohistochemistry
Joints from treated arthritic mice were analyzed for TNF- and
IL-1ß expression using a previously described procedure
(30). In brief, joints were embedded in OCT embedding
matrix, snap-frozen, and stored at -70°C until use. Sagittal
sections (6 µM thick) were air-dried then fixed in 4%
paraformaldehyde. After blocking endogenous peroxidase activity the
slides were incubated with anti-TNF- mAb (MP6-XT22; PharMingen,
San Diego, CA) or anti-IL-1ß mAb (B122; Genzyme, Cambridge, MA).
Sections were then washed and incubated with biotinylated secondary Ab
(Vector Laboratories, Burlingame, CA). Ab-biotin conjugates were
detected with an avidin-biotin-HRP complex (Vectastain Elite ABC;
Vector Laboratories) and developed with diaminobenzidine.
Quantification of cytokine immunostaining
Sections stained for TNF- or IL-1ß were examined using an
Olympus BH-2 microscope (New Hyde Park, NY) and analyzed by computer
image analysis (AnalySIS; Soft Imaging System, Munster, Germany). Six
digital images (magnification, x200) per specimen were recorded and
quantitative analysis was performed according to color separation. The
data are presented as the area within a region of interest covered by
positively stained cells, expressed as a percentage of the total area
covered by cells.
Measurement of anti-type II collagen IgG
Circulating levels of anti-collagen IgG were measured by solid phase ELISA, as described (8).
Measurement of serum amyloid P (SAP)
Serum levels of SAP were measured by a solid phase ELISA that uses the Ca2+-dependent binding of SAP to trinitrophenylated keyhole limpet hemocynanin (31).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1 blockade before the onset of CIA
To determine the effect of blocking TNF- and/or IL-1 during the
induction of arthritis, but before the onset of clinical disease, mice
were given two injections on days 14 and 16 after collagen immunization
with 300 µg anti-TNF- alone, 200 µg anti-IL-1R alone, or
300 µg anti-TNF- plus 200 µg anti-IL-1R. Controls
received PBS. Mice started to develop arthritis 17 days after
immunization in the PBS-treated group, compared with 22 days in the
group treated with anti-TNF- and 24 days in the groups treated
with anti-IL-1R or anti-IL-1R/anti-TNF- (Fig. 1
). This suggests that either
TNF--blockade or IL-1-blockade during this prearthritic period is
capable of protecting mice from disease for a short period after
injection. However, this protection was short-lived as arthritis
developed very rapidly in the groups of mice treated with
anti-TNF- and/or anti-IL-1R mAbs, such that 100% incidence
of arthritis was reached in all groups (Fig. 1). This clearly indicates
that neither TNF- blockade, IL-1 blockade, or combined TNF-/IL-1
blockade had a long-lasting protective effect, although all three
treatments delayed the start of arthritis.
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We had earlier demonstrated a dose-dependent beneficial influence
of anti-TNF- mAb after the onset of clinical arthritis, a
finding that helped to establish the validity of the therapeutic effect
of TNF-blockade (8). Consequently, we set out to
demonstrate a comparable effect for IL-1 blockade in established CIA.
Mice were immunized with type II collagen and monitored for the first
signs of arthritis. On days 1, 4, and 7 of arthritis, the mice were
treated with different doses of anti-IL-1R mAb (20, 100, or 200
µg/mouse). The experiment was terminated on day 10. Anti-IL-1R
treatment had a dose-dependent therapeutic effect, as judged by
clinical score, paw-swelling and joint erosion (Table I). Thus, a dose of 20 µg/mouse of
anti-IL-1R failed to modulate any of the disease parameters,
whereas doses of 100 µg and 200 µg reduced clinical score,
paw-swelling, and joint erosion, although the small number of mice used
in the study (4 mice/group) precluded statistical analysis of the data.
For all further studies, doses of 200 µg/mouse were used.
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and IL-1 blockade in established CIA
One of the principle objectives of this study was to compare the
effects TNF- blockade, IL-1 blockade and combined TNF-/IL-1
blockade in established arthritis. Therefore, mice were treated with
anti-TNF- alone, anti-IL-1R alone or anti-TNF- plus
anti-IL-1R. Additional groups were given anti-IL-1ß alone,
anti-IL-1ß plus anti-TNF-, or anti-TNF- plus
anti-CD4. Controls were given PBS. The first injection was given on
day 1 of arthritis (the first day that clinical arthritis was detected)
and repeated on days 4 and 7. The experiment was terminated on day 10.
Anti-TNF- treatment alone caused a significant reduction in
paw-swelling although anti-IL-1R treatment had a much more
pronounced therapeutic effect (Fig. 2 and
Table II). Combined treatment with
anti-TNF- and anti-IL-1R was more effective than
anti-IL-1R alone, although the differences between the two groups
were not statistically significant. Clinical scores were significantly
reduced in the mice treated with anti-TNF- and even more so in
the mice given anti-IL-1R (Table II). Finally, the extent of joint
erosion was compared by histological evaluation of the erosive changes
in the PIP joints. Of the control arthritic mice, 86% of the joints
showed erosive changes, compared with 52% for the mice given
anti-TNF- alone, 36% for the mice given anti-IL-1R alone,
and only 8% in the group given anti-TNF- plus anti-IL-1R
(Table II).
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therapy, and a combination of
anti-IL-1R and anti-TNF- showed a trend toward even greater
suppression of disease. A similar result was obtained when TNF-
blockade was compared with IL-1 blockade using anti-IL-1ß mAb.
Thus, anti-IL-1ß was more effective than anti-TNF- in
reducing paw-swelling, clinical score, and joint erosion (Table II
).
However, combined treatment with anti-TNF- plus anti-IL-1ß
resulted in even further reductions in paw-swelling and joint erosion
than anti-IL-1ß alone (Table II).
The anti-IL-1R mAb used in these experiments neutralizes the
activity of both IL-1 and ß through its interaction with the type
I IL-1R. In view of the potent ameliorative effect of anti-IL-1R
mAb in this study, the question is raised of which cytokine, IL-1 or
IL-1ß, plays the dominant pathological role in CIA. In this study,
very similar levels of suppression of clinical score, paw-swelling, and
joint erosion were observed in the groups treated with anti-IL-1R
mAb or anti-IL-1ß mAb (Table II). This finding indicates that
IL1ß plays a more important role in the pathogenesis of CIA than
anti-IL-1.
This study has established that most of the pathology in CIA can be
attributed to either TNF- or IL-1, and in an earlier study we had
reported that combined treatment with anti-TNF and anti-CD4
prevented mice from much of the pathology associated with CIA. These
two findings suggest that combined anti-TNF/anti-CD4 treatment
results in the suppression of both TNF- and IL-1 activity. To
further support this hypothesis, a direct comparison was made of
combined treatment with anti-TNF- plus anti-CD4 and
anti-TNF- plus anti-IL-1R/anti-IL-1ß. As judged by
clinical score, paw-swelling, and joint erosion, the magnitude of the
therapeutic effect of combined anti-TNF-/anti-CD4 treatment
was very similar to, or greater than, that of
anti-IL-1R/anti-IL-1ß alone or anti-TNF- plus
anti-IL-1R/anti-IL-1ß (Table II). This suggests that
treatment with anti-TNF- plus anti-CD4 leads to the
suppression of IL-1 activity.
Effect of therapy on the acute phase response
It is reported that the pro-inflammatory cytokines, TNF-, IL-1,
and IL-6, are major mediators of the acute phase response
(32). Furthermore, serum levels of at least one acute
phase protein, SAP, have been found to be elevated in CIA
(33). Therefore, an additional study was conducted to
compare levels of SAP in mice treated with anti-TNF- and/or
anti-IL-1R or anti-TNF- plus anti-CD4. Neither
anti-TNF- nor anti-IL-1R treatment alone had any significant
effect on levels of SAP although there was a trend toward reduced
levels in the anti-IL-1R-treated group (Table III). However, there was a significant
reduction in SAP levels in the group given anti-TNF- plus
anti-IL-1R and an even more pronounced reduction in the group given
anti-TNF- plus anti-CD4. Thus, SAP levels found in
anti-TNF-/anti-CD4-treated mice were similar to or less than
those found in a group of age- and sex-matched, unimmunized DBA/1 mice.
These data suggest that TNF- and IL-1 are not direct inducers of
SAP, but act through another mediator, such as IL-6 (34),
and this further supports the concept that combined
anti-TNF-/anti-CD4 treatment results in suppression of other
pro-inflammatory cytokines in addition to TNF-.
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and IL-1ß expression
following therapy
We next set out to address the question of the extent to which
anti-IL-1 therapy affects the level of TNF- expression and,
conversely, the extent to which anti-TNF-, or combined
anti-TNF-/anti-CD4 therapy, affects the level of IL-1
expression. Mice with established CIA were treated on days 1 and 4 of
arthritis with anti-IL-1R, anti-TNF-, or anti-TNF-
plus anti-CD4. The mice were killed on day 6 of arthritis and
undecalcified joints were cryosectioned and stained for TNF-/IL-1ß
expression. The proportion of positively stained cells was quantified
using image analysis. Both anti-IL-1R and anti-TNF- gave
significant reductions in the proportions of TNF--positive cells and
IL-1ß-positive cells (Table IV).
Combined anti-TNF-/anti-CD4 therapy caused even greater
suppression of TNF-, and particularly IL-1ß expression. This
confirms the ability of combined anti-TNF-/anti-CD4
treatment to profoundly suppress the level of IL-1ß expression at the
site of disease activity.
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None of the different treatments tested had any significant effect on circulating anti-type II collagen IgG levels, assayed at day 10 (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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blockade
and IL-1 blockade in CIA. In the first experiment, mAbs to TNF- or
to the type I IL-1R were administered during the induction phase of CIA
and it was found that both forms of treatment caused a delay of 5–7
days in the manifestation of clinical arthritis (Fig. 1). After this
delay, arthritis developed rapidly in treated mice, presumably as a
consequence of the clearance of mAbs from the circulation. From this it
was concluded that both TNF- and IL-1 are required for the induction
of CIA but a brief pulse of anti-TNF- or anti-IL-1R
treatment during this prearthritic phase fails to modulate the ongoing
autoimmune response as all mice eventually developed arthritis.
A second set of experiments was then performed in which the effect of
TNF- blockade and/or IL-1 blockade were assessed in established
arthritis. Two different IL-1 blocking mAbs were used, anti-IL-1R
and anti-IL-1ß. Anti-TNF- treatment alone was found to reduce
the clinical and histological severity of arthritis, a finding that is
consistent with previously published reports (7, 8, 9, 10, 11).
However, anti-IL-1 treatment, using either anti-IL-1R mAb or
anti-IL-1ß mAb, resulted in significantly greater suppression of
disease, both clinically and histologically than anti-TNF-
(Table II). The findings presented here are consistent with previous
findings by Van den Berg and colleagues (15, 16), which
reported marked amelioration of established CIA following treatment
with polyclonal Abs against IL-1 and IL-1ß, anti-IL-1ß alone
or high doses of IL-1Ra. However, the results of comparisons between
different mAbs should be interpreted with caution, as the mAbs may
differ appreciably in their ability to neutralize their target cytokine
or to penetrate the site of disease activity. Nevertheless, these
findings may suggest that IL-1, like TNF-, represents a potential
therapeutic target for RA.
A question that we have addressed in this report is whether combined
treatment of CIA with a TNF- neutralizing mAb plus an IL-1
neutralizing mAb provides greater therapeutic effect than either mAb
alone. Anti-TNF- treatment combined with anti-IL-1R or
anti-IL-1ß was found to provide increased suppression of
arthritis than anti-IL-1R alone or anti-IL-1ß alone, though
the differences were not statistically significant. Histologically, an
additive effect was indeed observed between anti-TNF- and
anti-IL-1R or anti-IL-1ß in the protection against joint erosion
(Table II). In addition, there was clear evidence of an additive
therapeutic effect between anti-TNF- and anti-IL-1R in
suppression of the acute phase response, as judged by circulating
levels of SAP (Table III).
In previous studies we demonstrated synergy between anti-TNF-
and anti-CD4 in the amelioration of established CIA and it was
postulated that an important mechanism underlying this synergy was the
suppression, not just of TNF-, but also of other pro-inflammatory
cytokines, including IL-1 (21). In the present study we
have demonstrated, first, that most of the pathology associated with
CIA can be attributed to either IL-1 or TNF- and second, that the
magnitude of the therapeutic effect of combined
anti-TNF-/anti-CD4 treatment was comparable to combined
treatment with anti-TNF- plus anti-IL-1R/anti-IL-1ß.
These two findings provide evidence to support the concept that
combined anti-TNF-/anti-CD4 treatment results in the
effective elimination of the pathology attributable to both TNF- and
IL-1. Further evidence in support of this concept is provided by the
finding that combined anti-TNF-/anti-CD4 treatment led to
normalization of SAP levels as elevated levels of SAP are reported to
be induced by a number of pro-inflammatory cytokines, including
TNF-, IL-1 and most importantly, IL-6 (34). The fact
that combined anti-TNF-/anti-CD4 treatment caused a greater
reduction in SAP levels than combined anti-TNF/anti-IL-1R
treatment raises the possibility that treatment with anti-TNF-
plus anti-CD4 resulted also in the suppression of additional
cytokines, such as IL-6. Finally, we were able to confirm using
immunohistochemistry that combined anti-TNF-/anti-CD4
therapy leads to marked suppression in the level of expression of both
TNF- and IL-1ß at the site of disease activity (Table IV).
The mechanism by which combined anti-TNF-/anti-CD4 treatment
could conceivably give rise to the suppression of IL-1 activity is a
matter for conjecture. One possibility is that there are two major
pathways involved in the induction of TNF- and IL-1 in CIA. The
first pathway may involve the production of pro-inflammatory cytokines
by cells in the synovium, following their activation by
CD4+ T cells. The second pathway may function
independently of T cells and may involve the induction of TNF- and
IL-1 production by TNF itself in an autocrine/paracrine fashion. This
is supported by the observation that the spontaneous production of IL-1
by human synovial cells in vitro is effectively blocked by the addition
of anti-TNF- Abs (6). This would account for the
fact that anti-CD4 treatment alone is relatively ineffective in
ameliorating already established arthritis. In contrast, combined
anti-TNF-/anti-CD4 treatment would modulate cytokine
production elicited by both pathways.
The impressive therapeutic effect achieved by IL-1-blockade in this study raises the possibility that this form of treatment is immunosuppressive as well as anti-inflammatory. However, circulating anti-type II collagen IgG levels were not significantly altered by anti-IL-1R/anti-IL-1ß therapy (data not shown). This is consistent with the results of a previous study in which anti-IL-1ß mAb, administered continuously from the time of collagen immunization, had no effect on anti-collagen IgG levels (14).
In conclusion, we have demonstrated that IL-1, in addition to TNF-,
is a potential target for therapeutic intervention in RA. Increasingly,
the goal in RA therapy is to prevent joint damage, as in the case of
anti-TNF-. In CIA, previous findings have shown that IL-1 plays
an important role in cartilage degradation (15, 16, 35)
and our findings indicate that IL-1 blockade is highly effective in
limiting joint erosion. These findings strengthen the case for further
evaluation and optimization of anti-IL-1 therapy in the clinic.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Richard Williams, Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, 1 Aspenlea Road, London W6 8LH, U.K.
3 Abbreviations used in this paper: RA, rheumatoid arthritis; CIA, collagen-induced arthritis; IL-1Ra, IL-1R antagonist; PIP, proximal interphalangeal; SAP, serum amyloid P; AUC, area under the curve.
Received for publication May 19, 2000. Accepted for publication September 11, 2000.
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References |
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, and interleukin-6 in cartilage proteoglycan metabolism and destruction: effect of in situ blocking in murine antigen- and zymosan-induced arthritis. Arthritis Rheum. 38:164.[Medline]
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 J.-Y. Choe, B. Crain, S. R. Wu, and M. Corr Interleukin 1 Receptor Dependence of Serum Transferred Arthritis Can be Circumvented by Toll-like Receptor 4 Signaling J. Exp. Med., February 17, 2003; 197(4): 537 - 542. [Abstract] [Full Text] [PDF]
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 B. Krishnadasan, B. V. Naidu, K. Byrne, C. Fraga, E. D. Verrier, and M. S. Mulligan The role of proinflammatory cytokines in lung ischemia-reperfusion injury J. Thorac. Cardiovasc. Surg., February 1, 2003; 125(2): 261 - 272. [Abstract] [Full Text] [PDF]
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J. M. Labasi, N. Petrushova, C. Donovan, S. McCurdy, P. Lira, M. M. Payette, W. Brissette, J. R. Wicks, L. Audoly, and C. A. Gabel Absence of the P2X7 Receptor Alters Leukocyte Function and Attenuates an Inflammatory Response J. Immunol., June 15, 2002; 168(12): 6436 - 6445. [Abstract] [Full Text] [PDF]
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O. H. Hultgren, L. Svensson, and A. Tarkowski Critical Role of Signaling Through IL-1 Receptor for Development of Arthritis and Sepsis During Staphylococcus aureus Infection J. Immunol., May 15, 2002; 168(10): 5207 - 5212. [Abstract] [Full Text] [PDF]
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