Inflammation Research Centre, The University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia
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Key Words: rheumatoid arthritis • hematopoiesis • cytokines • inflammatory mediators • in vivo animal models
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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There is increasing evidence that CSFs may play a major part in chronic
inflammatory autoimmune diseases, such as rheumatoid arthritis (RA).
Three of the four known CSFs (M-CSF, G-CSF, and GM-CSF) are produced by
human-joint tissue cells (chondrocytes, synovial fibroblasts) in
vitro in response to the inflammatory cytokines, IL-1 and tumor
necrosis factor 
(TNF-) [3
4
5
6
]. Certain CSFs have
also been identified in RA joint exudates [7
,
8
] and in RA synovial tissues by in situ
hybridization [9
]. We recently obtained more direct
evidence of a role for CSFs in inflammatory arthritis by demonstrating
that GM-CSF can exacerbate disease symptoms when injected into mice
sensitized to develop collagen-induced arthritis (CIA)
[10
] and that GM-CSF-deficient mice are resistant to the
induction of CIA [11
]. Because GM-CSF can affect cells
of the monocytic, granulocytic, and dendritic cell lineages, its key
target cell in autoimmune arthritis remains obscure.
The ability of M-CSF and G-CSF to affect specific haemopoietic cell lineages presents a unique opportunity to dissect and assess the relative contributions of two major cellular pathways of GM-CSF action in CIA and to gain a better understanding of their separate contributions to disease. Although a previous study [12 ] described exacerbation of disease in the Streptococcus agalactiae rat model of arthritis by intravenous (i.v.) injection of recombinant human (rh) M-CSF, little is known of the actions of this cytokine in an autoimmune model of arthritis, such as CIA, or whether endogenous M-CSF is required for disease development. Also, to our knowledge, there is only one study describing the effect of G-CSF on an animal arthritis model [13 ]. This is surprising given that it has been administered to patients with Felty’s syndrome (a variant of RA) for treatment of neutropenia [14 15 16 17 18 ] and is being used for the mobilization of haemopoietic stem cells in patients with severe RA prior to myeloablation [19 ].
The aim of this study was to obtain a better understanding of the role of M-CSF and G-CSF in autoimmune arthritis. Several approaches were used to investigate the involvement of M-CSF, and to a lesser extent G-CSF, in CIA. We show that exogenous M-CSF and G-CSF can exacerbate arthritis symptoms when injected into mice suboptimally primed to develop CIA. We also show that endogenous M-CSF is required for CIA development, because disease severity is reduced in arthritic mice treated with neutralizing monoclonal antibodies (mAbs) to M-CSF, and CIA could not be established in M-CSF-deficient (op/op) mice. These findings extend the proinflammatory potential of the CSF family. Our results also suggest possible new targets for therapeutic intervention in RA and suggest caution should be exercised when using G-CSF for therapeutic purposes in RA.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Mice
Male DBA/1 mice (7–11 weeks old) were purchased from the Animal
Resources Centre (Canning Vale, Western Australia) and allowed to
acclimate for 1 week before experimentation. DBA/1 mice were fed
standard rodent chow and water ad libitum and were housed in
sawdust-lined cages in groups of five. Osteopetrotic (op/op)
mutant mice and their littermate wild-type controls, each on the
C57BL/6 and C3HeB/FeJ background, were obtained from the Ludwig
Institute for Cancer Research (Parkville, Victoria, Australia) and
maintained in micro-isolators within the Ludwig Institute’s animal
house facility. Following weaning, the op/op mice, which
lacked incisors, were maintained on a diet containing equal amounts of
powdered chow and Ensure nutritional powder (VHA Trading Co., Mulgrave,
Victoria, Australia), mixed in sterile water.
Collagen-induced arthritis
An emulsion was formed by dissolving 2 mg/ml chick CII overnight
at 4°C in 10 mM acetic acid and combining it with an equal volume of
complete Freund’s adjuvant (CFA), prepared by adding heat-killed
M. tuberculosis to incomplete Freund’s adjuvant at 5 mg/ml.
All mice were injected intradermally (i.d.) at several sites into the
base of the tail with a total of 100 µl emulsion containing 100 µg
CII and 250 µg M. tuberculosis. Depending on the
experiment, mice were then treated in one of three ways.
(1) Exacerbation studies (suboptimum CIA)
Mice in this group received no further injections of CII. This
procedure followed that previously described [10
], where
omission of a booster injection resulted in suboptimal induction of
CIA. After different periods of time, mice were given 4–5 daily
injections of M-CSF or G-CSF, or the same volume of vehicle at the
doses, routes, and times indicated in the text.
(2) Neutralizing mAb studies (optimum CIA)
In experiments to examine the effect of neutralizing mAbs, mice
were immunized for maximum CIA response by administration of a repeat
of the primary CII injection as a boost at day 21, as previously
described [11
]. Mice were then assessed daily for
clinical signs of CIA and, from 27 days postprimary immunization
onward, newly arthritic mice were randomly assigned to one of two mAb
treatment groups—5A1 or DX48. The arthritic mice were then given 10
consecutive daily intraperitoneal (i.p.) injections of mAb (300 µg),
and the arthritis was assessed clinically throughout.
(3) IL-1 enhancement of CIA (optimum CIA)
In some experiments (indicated in text), the rapid onset of CIA
was induced, as described [20
], by four consecutive
daily subcutaneous (s.c.) injections into the rear footpad with IL-1ß
(20 ng, 104 units). The injections were initiated at 21
days postprimary CII immunization, and no CII boost was given.
Clinical and histological assessment of arthritis
Mouse limbs were assessed for redness and swelling, and a
clinical score was allocated 2–3 times per week for up to 60 days. The
scoring system was as previously described [10
], where
0 = normal, 1 = slight swelling, 2 = extensive swelling,
and 3 = joint distortion and/or rigidity. The maximum score per
mouse was 12. When killed, the limbs of the mice were removed, fixed,
decalcified, and processed for histological assessment of haematoxylin
and eosin-stained sections, as previously described
[11
].
Detection of Abs to CII by enzyme-linked immunosorbent assay
(ELISA)
ELISAs for Abs to CII were performed as previously described
[11
]. Horseradish peroxidase-conjugated goat anti-mouse
IgG (Sigma) detection Ab was used. Standard curves were constructed
from sera of CII hyperimmunized DBA/1 mice (arbitrarily set at 1000
units/ml).
Statistics
The following statistical tests were used to compare different
groups for the parameters indicated: Mann-Whitney two-sample rank test
(clinical scores), Student’s t-test for the difference of
two means (anti-CII Ab levels), and the 
2 test
(arthritis incidence). For each test, P < 0.05 was
considered statistically significant.
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View this table: [in a new window] |
Table 1. Effect of M-CSF on Murine CIAa
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2
analysis). The variation observed is unlikely to be a result of
endotoxin contamination in the M-CSF, because this was < 0.1
ng/mg M-CSF (limulus lysate assay). Furthermore, no effect of LPS was
observed, alone or with M-CSF, when CII-immunized mice were given four
daily s.c. injections (days 20–23) of M-CSF (15 µg), or vehicle,
with and without the addition of 100 ng LPS (unpublished results). The kinetics of the enhanced CIA response to M-CSF is shown for Experiment 3 in Figure 1 , as incidence (A) and clinical score (B). In that experiment, mice were given four consecutive daily i.p. injections of M-CSF, beginning 20 days postimmunization with CII. It is evident in these suboptimally immunized mice that, although M-CSF generated an earlier and more severe form of CIA compared with the control mice, its effect was not immediate but delayed, with no notable response occurring until five days after the initial M-CSF injection. The mean clinical scores peaked at day 43.
 View larger version (17K): [in a new window] |
Figure 1. Kinetics of the effect of exogenous M-CSF on CIA incidence and
severity. DBA/1 mice were immunized by i.d. injection of CII in CFA and
20 days later, were given four consecutive daily i.p. injections of
M-CSF (30 µg) or the same volume of vehicle (n=10 mice per
group). Mice were assessed and scored for clinical signs of arthritis,
as described in Materials and Methods. The maximum clinical score per
mouse was 12. Results show the percent cumulative incidence (A) and
mean ± SEM clinical scores (B) of the two groups of
mice up to day 60. The average clinical scores of the M-CSF-treated
mice were significantly greater than for the vehicle-treated mice
over the 21–60-day period (P<0.005).
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 View larger version (25K): [in a new window] |
Figure 2. Neutralizing mAbs to M-CSF reduce the severity of established CIA.
DBA/1 mice were immunized by i.d. injection of CII in CFA at days 0 and
21. Mice were clinically assessed daily for signs of arthritis, and
from day 27 onward, newly arthritic animals (shown as day 1 of
arthritis) were assigned to one of two mAb-treatment groups—anti-M-CSF
(5A1) or isotype control (DX48). Each group received 10 consecutive
daily i.p. injections of mAb (300 µg per day), beginning the first
day of arthritis symptoms. Results show the mean ±
SEM (n=10 mice per group) clinical scores of the
two groups of mice over the first 11 days of CIA. The
anti-M-CSF-treated group had significantly lower clinical scores than
the control group over the 4–7-day period (P<0.05).
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View this table: [in a new window] |
Table 2. M-CSF-Deficient (op/op) Mice Are Resistant to CIA
Inductiona
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2
analysis). Therefore, G-CSF increased the incidence and severity of
CIA. Figure 3
shows the kinetics of the G-CSF effect on CIA incidence (A) and
severity (B) (Experiment 3 from Table 3
). Again, in contrast to M-CSF,
the effect of G-CSF was rapid (within 2 days of the first G-CSF
injection), and the mean clinical score peaked earlier (day 27). |
View this table: [in a new window] |
Table 3. G-CSF Exacerbates Murine CIAa
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 View larger version (20K): [in a new window] |
Figure 3. Kinetics of the effect of exogenous G-CSF on CIA incidence and
severity. DBA/1 mice were immunized by i.d. injection of CII in CFA and
20 days later, were given four consecutive daily i.p. injections of
G-CSF (30 µg) or the same volume of vehicle (n=10 mice per
group). Mice were assessed and scored for clinical signs of arthritis,
as described in Materials and Methods. Results show the percent
cumulative incidence (A) and mean ± SEM clinical
scores (B) of the two groups of mice up to day 60. The average clinical
scores of the G-CSF-treated mice were significantly greater than for
the vehicle-treated mice over the 21–60-day period
(P<0.005).
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 View larger version (20K): [in a new window] |
Figure 4. Effect of M-CSF and G-CSF on serum anti-CII IgG levels. In two separate
experiments (A and B), DBA/1 mice were immunized by i.d. injection of
CII in CFA, as described in Materials and Methods, without boost. At
days 20–23, mice (n=10) were injected daily i.p. with 30
µg of M-CSF or G-CSF, or with vehicle (control). Sera were prepared
from blood collected at 26 and 60 days postimmunization and assayed for
anti-CII IgG levels by ELISA. *P < 0.05 compared with
vehicle control.
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The requirement for endogenous M-CSF for CIA was demonstrated by a reduction in the severity of established disease by M-CSF-neutralizing mAb (Fig. 2) and by the resistance of M-CSF-deficient (op/op) mice to arthritis development (Table 2) . M-CSF could be functioning in CIA through effects on monocyte-macrophage infiltration into the joints, on type-A synovial lining (macrophage lineage) cells, or on osteoclasts [28 ]. Because administration of rhM-CSF at the doses used in this study elicits up to a 10-fold increase in circulating blood monocyte levels in mice [22 ], this, in turn, could result in increased numbers of monocytes/macrophages entering the joint. The importance of monocyte/macrophage infiltrate in CIA has been demonstrated by the requirement for macrophage migration inhibitory factor (MIF) function in the model [29 ] and by the prevention of adoptive transfer of CIA by Mac-1 blockade [30 ]. Enhanced numbers of activated macrophages are present in the synovium at the earliest preclinical stages of CIA [27 ] and are an important source of cytokines for disease development [31 , 32 ]. In addition, macrophages may function as antigen-presenting cells for CII [33 ].
The absence of CIA in op/op mice (Table 2) possibly provides support for the importance of the type-A synovial lining cells in this model. Although op/op mice have normal T-cell-dependent immune responses [34 ], they lack type-A synovial cells [28 ]; thus, the latter are considered an M-CSF-dependent cell population. Interestingly, unlike some macrophage populations, type-A synovial cell deficiency in op/op mice cannot be overcome by the systemic injection of M-CSF from birth [28 ]. These cells may, therefore, be dependent on local rather than systemic M-CSF production for their survival and development. This could be supplied by the fibroblast-like (type B) synovial cells or chondrocytes, which produce basal levels of M-CSF at least in vitro [4 , 6 , 35 ]. Our findings with the op/op mouse are in agreement with previous studies in which depletion of type-A cells from the synovial lining by injection of liposome-encapsulated clodronate resulted in protection from CIA [36 ]. However, the inability of circulating rhM-CSF to restore type-A synovial cells in the op/op mouse [28 ] suggests that the effect of exogenous M-CSF on CIA could be at the level of circulating monocytes/macrophages (see above). In short, the numbers and function of resident and infiltrating monocyte-macrophage populations could be affected by M-CSF in CIA [27 ]. Finally, M-CSF is essential for osteoclast production [37 ] and function [28 ], and these cells could be contributing to the bone destruction observed in the late stages of CIA. The osteopetrosis of the op/op mouse is a direct result of the absence of osteoclasts in these mice.
A threshold anti-CII IgG response is considered a necessary but alone insufficient requirement for CIA development [25 , 26 , 38 ]. The anti-CII IgG levels of the M-CSF-treated mice were higher than those of control mice (Fig. 4A) , but whether this increase actually contributed toward the exacerbation of CIA by M-CSF is uncertain. The effect of M-CSF on anti-CII IgG levels could be through elevated levels of cytokines, such as IL-6, possibly because of increased numbers of "primed" monocytes/macrophages capable of producing them [39 40 41 ]. In keeping with previous studies in the op/op mouse [34 ], these mice developed normal levels of anti-CII IgG (unpublished results), similar to our observations with the GM-CSF-deficient mouse, which showed resistance to CIA but a normal humoral response to CII [11 ]. The inability of exogenous G-CSF to modulate anti-CII IgG levels (Fig. 4B) yet still exacerbate CIA (Table 3 , Experiment 3) suggests that the threshold Ab level for subsequent disease development was already achieved, even in these suboptimally immunized mice. Therefore, G-CSF would appear to enhance disease through a separate process. Further experimentation is required to clarify the mechanisms involved, but these observations concur with other studies [42 ] in which it was shown that anti-CII Ab levels do not necessarily correlate with disease.
Data from various animal models suggest that M-CSF may be a key mediator of certain autoimmune diseases. The MRL/lpr mouse has elevated M-CSF serum levels, which precede spontaneous glomerulonephritis [43 ]. Splenic mononuclear phagocytes of the autoimmune motheaten mouse spontaneously produce M-CSF [44 ] and have an enhanced proliferative capacity in vitro [45 ]. In a rat model of experimental allergic encephalomyelitis (EAE), spinal chord extracts showed elevated mRNA expression for M-CSF and c-fms (M-CSF receptor), which correlated with the clinical incidence of disease [46 ]. The present study extends this list to autoimmune arthritis. Perhaps in support of our findings, a recent gene-mapping study in B10.RIII x RIIIS/J mice identified a non-MHC CIA susceptibility gene (Mcia2) on chromosome 3 in the region of the M-CSF locus—a region previously linked to EAE [47 ].
This study has also provided evidence that cells of the granulocytic lineage, specifically neutrophils, are important in CIA. Only one study has described the effect of G-CSF in an arthritis model [13 ], where it was found that i.v. injection of rhG-CSF into rats enhanced the passive transfer of arthritis using suboptimal doses of anti-CII rat sera with an associated induction of peripheral blood neutrophilia. We have now shown an effect of G-CSF on actively immunized murine CIA. The effect of G-CSF in the current study could be a result of an increased number of circulating neutrophils mobilized from haemopoietic stem cells, an enhanced functional ability of the neutrophils, and/or enhanced haemopoietic progenitor stem-cell numbers in the circulation. In vivo administration of G-CSF is known to cause rapid systemic neutrophilia and haemopoietic stem-cell mobilization [48 ]. G-CSF, when given at the elicitation but not the priming phase, enhances delayed-type hypersensitivity possibly through an effect on mononuclear cell recruitment [49 ]. Because mononuclear cells lack G-CSF receptors, this recruitment occurs indirectly through the granulocytes, possibly via chemokine production. A similar mechanism could be operating in the present study. Thus, in addition to a direct effect on granulocyte levels/activation, there may be an indirect effect on mononuclear cell recruitment leading to accelerated CIA in the already-CII-primed mice. As well as monocytes/macrophages and neutrophils, GM-CSF stimulates the proliferation of eosinophils [1 ], and so the latter cells could also be contributing to the exacerbation of CIA in our studies with GM-CSF [10 ]. However, the absence of receptors for G-CSF and M-CSF on eosinophils precludes a direct effect on these granulocytes in the present study.
Several studies have demonstrated arthritis flare in RA patients following administration of G-CSF for correction of the neutropenia occurring as a complication of Felty’s syndrome [15 16 17 18 ] or as a consequence of drug treatments [50 ]. In view of this, two recent studies have addressed the safety of G-CSF administration to RA patients for haemopoietic stem-cell mobilization and subsequent autologous stem-cell transplantation. In one study [51 ], no arthritis flare was noted, although only low G-CSF doses were used (5 µg/kg), and all five patients had received corticosteroid treatment before therapy. A second study described arthritis flare in two of five patients receiving 10 µg/kg G-CSF, the optimum dose of two doses tested for satisfactory stem-cell mobilization [52 ]. Even higher doses of G-CSF may be required to adequately mobilize haemopoietic stem cells in RA patients. We showed that G-CSF doses as low as 0.3 µg per mouse (10 µg/kg) had detectable effects on CIA severity (Table 3 , Experiment 1), observations consistent with the latter study. Our findings further highlight the need for caution in administering G-CSF to arthritis patients, particularly if doses beyond 10 µg/kg are to be considered. Additional studies are required to determine whether endogenous G-CSF is necessary for CIA development. An approach using neutralizing Abs to G-CSF and/or G-CSF gene-knockout mice similar to that described herein for M-CSF and elsewhere for GM-CSF [11 ] would address this.
In summary, we have shown that the lineage-specific CSFs, M-CSF,
and G-CSF can exacerbate CIA, findings supporting roles for
monocytes/macrophages and granulocytes in autoimmune inflammatory
arthritis. We further showed that M-CSF blockade can alleviate disease
and that M-CSF-dependent cells are required for CIA. The presence of
CSFs in rheumatoid joints and their mutual modulation in
vitro by the proinflammatory cytokines, IL-1 and TNF-, led to
the proposal of a local "CSF network" within joints that might help
explain the chronicity of inflammatory joint disease
[53
]. Together with our previous findings
[10
, 11
], the present study highlights the
potent proinflammatory potential of the CSFs and suggests they may be
targets for therapeutic intervention in rheumatoid disease.
Received November 29, 1999; revised February 29, 2000; accepted March 1, 2000.
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