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*
Department of Medicine, Inflammation Research Center, University of Melbourne, and
The Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria, Australia
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Abstract |
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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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Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease
for which there is evidence that GM-CSF may be involved. GM-CSF has
been found at elevated levels in RA lesions (13) and is produced in
vitro by resident joint cells (chondrocytes and synovial fibroblasts)
following their stimulation with inflammatory cytokines, such as IL-1
and TNF-
(14, 15). The latter observations led to the CSF network
hypothesis (16) that sought to explain the chronicity of rheumatoid
joint disease in terms of a positive feedback between joint cell CSF
secretion and monokine production. GM-CSF has also been implicated in
the adherence of neutrophils to cartilage and its subsequent
degradation by these cells (17). Finally, GM-CSF has been reported to
cause a flare-up of existing RA when administered (for correction of
neutropenia) to patients with Felty’s syndrome or following
chemotherapy treatment (18, 19).
Collagen-induced arthritis (CIA) in the mouse (20) is an autoimmune model of RA that is dependent upon both humoral and cellular immune responses to type II collagen (CII) (21); it is considered to be restricted to mouse strains bearing the H-2q or H-2r haplotypes and is generally performed in DBA/1 mice (22). We recently reported that GM-CSF, when injected i.p. into DBA/1 mice suboptimally primed to develop CIA, exacerbated the disease symptoms (23), suggesting a proinflammatory role for GM-CSF in this model. Although highlighting the importance that elevated circulating levels of GM-CSF could have on the course of disease, this study did not indicate whether endogenous GM-CSF was a necessary component of the CIA response.
Therefore, in the present study we have examined the role of endogenous GM-CSF in the CIA model using GM-CSF-deficient mice (24). For this purpose we have taken the unique approach of establishing the model in mice of a non-H-2q/non-H-2r background, thereby eliminating the need for backcrossing the GM-CSF-deficient mice onto the DBA/1 (H-2q) strain. We report that GM-CSF-deficient mice are relatively resistant to the induction of CIA compared with their littermate wild-type control mice. This study implicates GM-CSF as a key proinflammatory cytokine pivotal to the development of CIA in mice and adds further support to the idea of the involvement of GM-CSF in inflammatory joint diseases (e.g., RA).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice heterozygous for a disrupted GM-CSF gene (GM-CSF+/-) were provided by the Ludwig Institute for Cancer Research (Royal Melbourne Hospital, Melbourne, Australia) and bred at the Department of Medicine animal house. The derivation was previously reported (24). Briefly, chimeric mice were generated by microinjection of 129/OLA-derived ES cells (H-2b) with a disrupted GM-CSF gene into C57BL/6 (H-2b) host blastocysts. Germline transmitters of the mutated GM-CSF allele were crossed with C57BL/6 mice for 11 generations, giving GM-CSF+/- mice that were interbred to yield the GM-CSF-/-, GM-CSF+/-, and GM-CSF+/+ mice used for the experiments. In some experiments (see text) mice from the first C57BL/6 cross were interbred and used; these were confirmed as homozygous H-2b by FACS analysis of spleen cells using H-2b-specific mAb (I. K. Campbell and P. M. Hogarth, unpublished observations). GM-CSF genotype status was determined by PCR analysis of tail DNA as previously described (24). Animals were fed standard rodent chow and water ad libitum and were housed with same sex littermates in sawdust-lined cages. Mice of both sexes were consigned to experiments at 8 to 15 wk of age.
Collagen-induced arthritis
An emulsion was formed by dissolving 2 mg/ml chick CII (Sigma, St. Louis, MO) overnight at 4°C in 10 mM acetic acid and combining it with an equal volume of CFA containing 5 mg/ml heat-killed Mycobacterium tuberculosis (H37 Ra, Difco, Detroit, MI). Mice were injected intradermally at several sites into the base of the tail with a total of 100 µl of emulsion containing 100 µg of CII; this was repeated as a boost 21 days later. Mice immunized without the CII component did not develop arthritis during the period of investigation in this study.
Clinical and histologic assessment of arthritis
Animals were assessed for redness and swelling of limbs, and a clinical score was allocated for each mouse two to three times per week for up to 60 days as previously described (23). The maximum score per mouse was 12. At termination, the rear paws of the mice were removed, fixed, decalcified, and paraffin embedded as previously described (23). Frontal sections (5 µm) were stained with hematoxylin and eosin and evaluated without knowledge of the treatment groups, based on the histologic assessment of Williams et al. (25).
ELISA for detection of Abs to CII
ELISA assays were performed for the detection of Abs to CII by coating 96-well flat-bottom plates (Immunoplate Maxisorp, Nunc, Copenhagen, Denmark) with 50 µl of CII (2 µg/ml in PBS) overnight at 4°C. The wells were then blocked by 1-h incubation at 37°C with 200 µl of PBS containing 1% (w/v) BSA. Next, 50 µl of serial fourfold dilutions (beginning at 1/1000 dilution) of mouse sera in PBS supplemented with 0.05% (v/v) Tween-20 were applied and incubated for 2 h at 37°C. Horseradish peroxidase-conjugated goat anti-mouse whole IgG (Sigma) or isotype-specific (IgG1, IgG2a, IgG2b, and IgG3; Southern Biotechnology, Birmingham, AL) antisera (50 µl) were next applied for 2 h at 37°C followed by o-phenylenediamine dihydrochloride substrate (Sigma) in phosphate-citrate buffer (50 µl), and color development was monitored after a standard period by measurement in a microplate reader (model 450, Bio-Rad, Richmond, CA) at 450 nm. Three washes in PBS/0.05% (v/v) Tween-20 were applied between all steps. Standard curves were constructed as follows: for total IgG, protein G-Sepharose affinity-purified mouse anti-CII IgG fraction (serial 1/4 dilutions beginning at 7 µg/ml); for others, mouse anti-CII sera (serial 1/4 dilutions beginning at 1/1000). In each case the anti-CII sera were derived from a pool obtained from CII-hyperimmunized DBA/1 mice. Arbitrary units were assigned to the standards, such that 1 U/ml gave an OD of 0.5 with the different antisera.
Delayed-type hypersensitivity (DTH) reaction
Mice were immunized, as before, by intradermal injection into the base of the tail with chick CII in CFA. Ten days later the mice were anesthetized and injected s.c. into the right hind footpad with 20 µl of a solution containing 2 mg/ml CII in PBS; the left footpad received the same volume of vehicle. Immediately before injection and 24 and 48 h thereafter, the thicknesses of the left and right footpads were measured using spring callipers (Mitutoyo, Tokyo, Japan) accurate to 0.01 mm. The Ag-specific DTH response was determined as the increase in right footpad thickness minus the increase in left footpad thickness at the given time points. Injection of CII into the paws of naive mice produced negligible swelling. Following the 48 h measurement, the mice were sacrificed, and the hind footpads were removed and processed for histologic analysis as described above, except that decalcified specimens were halved in the sagittal plane, and paraffin-embedded sections were cut in this plane from the center of the footpad outwards. Sections were stained with hematoxylin and eosin to confirm cellular infiltration into the dermis and s.c. regions.
Statistics
For clinical scores the Mann-Whitney two-sample rank test was
used to determine the level of significance between means of groups.
For data pertaining to Ab levels in serum samples and the DTH reaction,
Student’s t test for the difference between two means was
employed, while the paired t test was used for comparison of
mouse weights over the course of the experiments. The incidence of
arthritis between different groups and the proportion of joints in
different histologic categories were assessed by the 
2
test. For each test p < 0.05 was considered
statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To evaluate the requirement for endogenous GM-CSF for the development of CIA, GM-CSF-deficient mice (GM-CSF-/-) and their littermate controls (GM-CSF+/+ and GM-CSF+/-), each on the C57BL/6 (H-2b) background, were primed to develop CIA by intradermal immunization with chick CII in CFA followed by a repeat of the primary injection 21 days later. This immunization schedule successfully elicits CIA in the wild types of these and certain other non-H-2q/non-H-2r mouse strains with an incidence only slightly lower than that in DBA/1 mice (our manuscript in preparation).
Figure 1
shows results from the pooled
data of two experiments performed using 8- to 14-wk-old mice from the
11th C57BL/6 backcross (99.95% C57BL/6); in these experiments the
entire litters of GM-CSF+/- cross-matings were tested.
Immunized mice were examined regularly over a 60-day period for signs
of redness and/or swelling of the paws, and a clinical score (maximum
of 12/mouse) was assigned as previously described (23). The majority of
the GM-CSF+/+ mice exhibited clinical signs of
CIA, with 9 of 13 mice having swollen joints beginning on days 24 to 39
(Fig. 1a) and the mean clinical score peaking on day 43
(Fig. 1b). In Table I, which
summarizes the data from Figure 1, it is evident that the
GM-CSF+/+ mice demonstrated a broad range of
responses, as we and others have observed using DBA/1 mice in this
model (23, 26); these varied from minor swelling of digits to severe
swelling and ankylosis in all four paws (severity range, 1–12; median,
9).
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a). The
arthritis in the GM-CSF-/- mice was restricted
to the swelling of single digits on the affected limbs. The mean
clinical score was consistently lower in the
GM-CSF-/- mice than in the
GM-CSF+/+ mice throughout the course of the
experiment (Fig. 1b), and this was reflected in the
significantly lower average clinical scores of the mice over the period
from days 22–60 (p < 0.005; see Table I). The
lower clinical scores of the GM-CSF-/- mice
compared with those of the GM-CSF+/+ mice were
thus a combination of reduced incidence of arthritis as well as
considerably lessened severity of disease in responsive mice, shown by
the restricted range of 1 to 2 (Table I).
Interestingly, overall the GM-CSF+/- mice exhibited an
intermediate response between the other two genotypes for both
incidence and clinical score (see Fig. 1) with 17 of 28 mice developing
signs of arthritis, although the severity range was comparable to that
in the GM-CSF+/+ mice (Table I).
As an additional measure of CIA severity, the weights of the GM-CSF+/+ and GM-CSF-/- mice were compared over the period from CII boost (day 21) to sacrifice (day 60). Over this time frame the GM-CSF+/+ mice failed to gain weight, while the weights of the GM-CSF-/- mice increased by an average of 5% (p < 0.0001, by paired t test), suggesting reduced morbidity and severity of disease in the latter genotype.
A further experiment was performed using age- and sex-matched GM-CSF+/+ and GM-CSF-/- mice (n = 12) of mixed C57BL/6 and 129/OLA background (single C57BL/6 cross; see Materials and Methods). Using this cohort, CIA, manifested as a solitary swollen digit, was observed in only one GM-CSF-/- mouse. Again, the severity (based on maximum clinical score) of the responsive GM-CSF+/+ mice had a broad range from 1 to 12 (median 9); the means (±SEM) of the clinical scores averaged over days 23–60 differed significantly for GM-CSF+/+ and GM-CSF-/- mice (2.18 ± 0.79 and 0.02 ± 0.02, respectively; p < 0.01).
Histologic assessment
To confirm the clinical assessments, at sacrifice the clinically
positive hind paws of the two responding
GM-CSF-/- mice as well as the hind limbs of two
other GM-CSF-/- mice and those of four
clinically positive GM-CSF+/+ mice from the
experiments detailed in Figure 1 were removed and processed for
paraffin embedding and sectioning. Histologic grading of hematoxylin-
and eosin-stained sections was performed for each joint based on the
procedure of Williams et al. (25), and the results are summarized in
Table II. The
GM-CSF-/- mice exhibited a significantly
reduced proportion of joints in the severe histopathologic category
compared with that in the GM-CSF+/+ mice (4 vs
72%, respectively; p < 0.001) and were more
frequently normal in histologic appearance (91% compared with 12% for
GM-CSF+/+ mice; p < 0.001). The
GM-CSF-/- mouse joints were typically normal in
appearance (Fig. 2a), while
inflammatory cell infiltrate of granulocytes and mononuclear cells,
subsynovial inflammation and hyperplasia, as well as cartilage and bone
degradation resulting in loss of joint architecture were common
features of the GM-CSF+/+ mouse joints (Fig. 2, b and c).
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a). However, the interphalangeal and metatarsal-phalangeal
joints of the digits showing clinical signs of arthritis in some
instances (2 of 57 joints) exhibited histopathology comparable to that
observed in the most severely affected GM-CSF+/+
mice. Inflammatory cell infiltrate, synovial hyperplasia, pannus
formation, and associated cartilage and bone degradation were evident
with loss of joint architecture. Humoral response to CII of GM-CSF-deficient mice
Since CIA development is dependent on both B and T cell responses
(21), the almost complete absence of CIA in the
GM-CSF-/- mice could be due either to their
inability to develop Abs to CII or to a weakened cellular response to
CII. To address the first possibility, sera were collected from all
mice at sacrifice and examined by ELISA for Abs to CII. The total IgG
Abs to CII were comparable for the different mouse genotypes (Table I).
Since the IgG2a and IgG2b isotypes, rather than the total IgG, are
considered to be of prime importance in the Ab response to CII (27),
sera from GM-CSF-/- and
GM-CSF+/+ mice were also examined for possible
differences in the IgG isotype responses to CII. This further level of
investigation did not reveal any statistically significant differences
between the two groups of mice in the Ab responses to CII (Fig. 3).
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The cellular response to CII was next investigated by the DTH
reaction based on footpad swelling. While
GM-CSF-/- mice were capable of a DTH response
to CII, as indicated by the significantly greater degree of swelling in
their CII-injected footpads vs that in vehicle-injected footpads
(p < 0.005, by paired t test; data
not shown), there was a significant reduction
(p < 0.05) in its magnitude compared with that
in GM-CSF+/+ mice at 24 and 48 h after Ag
challenge (Fig. 4). Histologic assessment
of footpad sections from each group of mice confirmed that the swelling
observed was indeed due to mononuclear cell infiltration into the
dermis and not simply edema.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study, GM-CSF knockout mice on a C57BL/6
(H-2b) background were employed to test the requirement for
endogenous GM-CSF in the development of CIA. We found that 70% of
wild-type mice on this background developed CIA within 40 days of
primary CII immunization (Fig. 1a,
GM-CSF+/+). This discovery dispensed with the
putative requirement to backcross the GM-CSF null mice onto the DBA/1
background to attain a CIA-susceptible strain. By comparing, in the CIA
model, GM-CSF-deficient and wild-type control mice on this background
we showed that the absence of the GM-CSF gene product protected against
disease development. Only 2 of 15 GM-CSF-deficient mice developed very
mild clinical symptoms of CIA, and this was shown histologically to be
confined to the interphalangeal and metatarsal-phalangeal joints of the
digits. In contrast, the GM-CSF-competent mice showed a significantly
greater incidence of disease and clinical responses ranging from mild
(score 1) to severe (score 12), with swelling and ankylosis of all four
paws.
Histologic analyses of arthritic paws confirmed the clinical
assessments: the joints of the GM-CSF-deficient mice were most often
normal in histologic appearance, whereas those of the wild-type mice
were frequently severely disrupted, with pannus tissue formation and
associated cartilage and bone loss (Table II and Fig. 2).
Interestingly, in 2 of the 57 joints examined from the GM-CSF-deficient
mice the degree of joint damage was comparable to that observed in the
most severely affected wild-type mice. It would therefore appear that
GM-CSF is not absolutely required for the development of CIA and that
in a small number of individuals disease within isolated joints can
proceed to the end stage in its absence. Rather, GM-CSF may be needed
for the rapid systemic progression of CIA toward polyarthritis, since
during the course of this study (up to 60 days) arthritis appeared to
be confined to isolated digits on the affected limbs of
GM-CSF-deficient mice. In further delineating the role of GM-CSF in
this model it would be of interest to compare the effects of systemic
and local GM-CSF reconstitution in the GM-CSF null mice.
Investigations were undertaken to examine why GM-CSF-deficient mice were resistant to CIA induction. Given the importance of GM-CSF in dendritic cell development in vitro (2) and the reported dependence of the CIA model on both humoral and cell-mediated immunities to CII (21), GM-CSF-deficient and wild-type mice were compared for their immune responses to CII. No differences were observed between the two genotypes in the serum levels of either the total IgG or IgG subclass responses to CII at 60 days postprimary immunization, suggesting a normal humoral response to this Ag in the GM-CSF-deficient mice. Since complement fixing Abs of the IgG2 subclass are considered critical for CIA development (27), the latter result precluded the possibility that, although the total IgG levels were comparable between the two genotypes, other IgG subclasses may have been generated by the GM-CSF-/- mice at the expense of the IgG2 subclasses, thereby accounting for their reduced CIA incidence. The further possibility that a temporal difference between the humoral responses to CII of the two genotypes may account for the subsequent differences in CIA development is unlikely given that one of the two GM-CSF-deficient mice that developed CIA was the first mouse to show signs of joint swelling (on day 22). Instead, in accordance with the work of others (21, 33), it would appear that the capacity of mice to raise Abs to CII is alone insufficient to result in CIA.
In contrast, while the GM-CSF-deficient mice were capable of eliciting
cell-mediated immunity to CII, as determined by the DTH response, it
was at a significantly reduced level compared with that in the
wild-type control mice (Fig. 4), suggesting suppression of T cell
function. Whether this reduction is sufficient to account for the
minimal arthritic response in these mice remains uncertain. Recent
studies (34) examining the T cell function of immunized
GM-CSF-deficient mice reported a reduced CD4+ proliferative
response to specific Ags; the mechanism was thought to involve a
GM-CSF-induced dendritic cell-derived factor capable of enhancing the T
cell proliferative response, rather than an intrinsic malfunction in
the T cells. The reported incapacity of dendritic cells to either
process or present CII (35) suggests that another explanation may be
needed for the reduced cellular response to CII in the present study.
For instance, it could reflect the inability of the GM-CSF-deficient
mouse T cells to activate macrophages through GM-CSF production.
Finally, it must be acknowledged that these studies compared the immune
responses to chick CII; the possibility remains that differences exist
between the GM-CSF-deficient and wild-type mice in their abilities to
develop an autoimmune reaction to murine CII.
The absence of GM-CSF in the knockout mice could, based on in vitro
studies, have ramifications for granulocyte, monocyte-macrophage, or
dendritic cell responses in the CIA model. Interestingly,
GM-CSF-deficient mice have normal hemopoiesis up to 12 wk of age (24)
and normal levels of both myeloid-related and lymphoid-related
dendritic cells in the major lymphoid organs (spleen, lymph node, and
thymus) (36). However, these are under steady state conditions where
mice have not been elicited to develop autoimmune inflammatory disease,
such as CIA. Local or systemic differences between the
GM-CSF+/+ and GM-CSF-/-
mice in either the numbers or levels of activation of any of the three
cell lineages listed above may still account for the observations
reported herein. Recent functional studies with the GM-CSF-deficient
mouse have demonstrated an increased tolerance to endotoxin-mediated
septic shock that was related to reduced circulating levels of the
cytokines IFN-
, IL-1, and IL-6 (37). Moreover, LPS-stimulated
peritoneal macrophages from GM-CSF-/- mice
produced less IL-1 and nitric oxide than those from wild-type mice.
Thus, while GM-CSF knockout mice have normal steady state levels of
circulating monocytes, they may be impaired in their ability to respond
to certain stimuli. Studies of the local (joint) and systemic cytokine
levels of CII-immunized GM-CSF-deficient mice may provide further
insight into how they are protected from CIA development.
The results of this study taken together with our previous report of exacerbation of the CIA model by exogenous GM-CSF (23) support the idea of GM-CSF as a proinflammatory mediator and provide a strong argument for a pivotal role for GM-CSF in CIA development and inflammatory joint disease.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Ian K. Campbell, Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute, P.O. Royal Melbourne Hospital, Victoria 3050, Australia. E-mail address:
3 Abbreviations used in this paper: GM-CSF, granulocyte-macrophage CSF; RA, rheumatoid arthritis; CIA, collagen-induced arthritis; CII, collagen type II; DTH, delayed-type hypersensitivity.
Received for publication February 12, 1998. Accepted for publication May 26, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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