Animal models of rheumatoid arthritis
Richard Williams • Louise M. Topping 95
Key Points
n Arthritis may be induced in animals by immunization with cartilage components,
nonspecific immune stimuli, localization of antigens in the joint, or genetic mutations.
n Animal models are tools that mimic various aspects of rheumatoid arthritis (RA) but
do not fully resemble human disease.
n Models have a defined onset and are useful for studying initiating factors and kinetic
evaluation of disease processes.
n Animal models serve an important role in the evaluation of antiarthritic drugs but do
not always predict efficacy in man.
n There is increasing emphasis on implementation of the 3 R’s: replacement, reduction,
and refinement.
INTRODUCTION
Experimental animal models of arthritis have contributed to the understand-
ing of basic mechanisms of joint disease. Marked diversity is seen among the
numerous models, with arthritis being induced by the following:
n Immunization with cartilage components
n Injection of nonspecific immune stimuli
n Components of infectious agents
n Immune complexes
n Manipulation of genetic information in transgenic animals
n Spontaneous mutations
No single animal model of arthritis truly represents the human disease.
The wide variety of agents that can induce experimental arthritis with clinical
and histopathologic features close to those of human arthritides suggests that
disparate etiologic pathways could exist for rheumatoid arthritis (RA). Aspects
peculiar to individual models are of value but must be interpreted with cau-
tion. Much can be learned from the general validity of mediator involvement
and common concepts. Models provide valuable preclinical data for the devel-
opment of novel treatments, both pharmacologic and biologic, and insight
into relevant mechanisms common to both experimental arthritis and RA.
MECHANISMS OF INDUCTION OF
EXPERIMENTAL ARTHRITIS
IMMUNIZATION WITH CARTILAGE COMPONENTS
The most widely utilized mode of RA is collagen-induced arthritis (CIA),
which occurs in rats, mice, and primates following immunization with type
II collagen in adjuvant. The pathological features of the disease include
synovitis with infiltration of polymorphonuclear and mononuclear cells,
pannus formation, erosion of bone and cartilage, and fibrosis (Fig. 95.1).
CIA susceptibility is linked to the I-A region of the H-2q and H-2r hap-
lotypes in mice. Analysis of the I-A chains of alleles from susceptible and
resistant strain (B10.Q) indicated that susceptibility is associated with a
four–amino-acid sequence in the I-Aβ chain.1 This sequence is located in a
region associated with binding antigenic peptide, analogous to the genetic
susceptibility observed in RA in humans conferred by the DRβ chain. The
induction of arthritis in mice of a C57BL/6 (H-2b) background2,3 has facil-
itated the use of gene knockout mice and the generation of the congenic
C57Bl/6 N.Q strain that expresses the arthritis susceptible Q haplotype of
the MHC class II region.4
Humoral immune responses play a significant role in the pathogenesis
of CIA,5 which is likely to be true also for human RA, although elevated
circulating levels of antibodies to type II collagen are not detected in the
majority of patients with RA. Another important similarity between CIA
and RA is the expression of proinflammatory cytokines, including tumor
necrosis factor-alpha (TNF-α) and interleukin (IL)-1β, in the joints of mice
with arthritis6 and the fact that blockade of these molecules results in reduc-
tions in both the clinical and histological severity of disease.7–14 However,
CIA differs from human RA in that it is a relatively acute disease in which
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arachidonic acid metabolites play an important pathological role in the dis-
ease process. Thus, cyclooxygenase inhibitors are very effective in reducing
the severity of CIA but are less effective in RA.
As discussed above, convincing data have not yet emerged pointing
definitively to a role for collagen autoimmunity in the bulk of patients with
RA. This has prompted the search for other potential joint antigens that
may be the target of the autoimmune response in RA. For example, a T cell–
driven arthritis has been described in BALB/c mice following immunization
with the G1 domain of human proteoglycan aggrecan.15,16 Histopathological
changes include edema, proliferative synovitis, infiltration of mononuclear
cells, pannus formation, and erosion of cartilage and bone.
RESPONSE TO NONSPECIFIC IMMUNOLOGIC STIMULI
Injection of nonspecific agents with adjuvant activity (the capacity to elicit
an indirect immunologic response) can provoke experimental arthritis in
certain species. The classic example is adjuvant arthritis (AA) in the Lewis
rat.17 The precise contributions of the oil and the mycobacterial components
of Freund’s complete adjuvant in the pathologic pathway of this experimen-
tal disease remain unclear, but both may contribute. An association between
immunity to 65-kDa heat shock proteins and the induction of AA has been
suspected,18 but no single mycobacterial immunogen has been shown to be
responsible.19 There is, however, convincing evidence of a role for a myco-
bacterial cell wall component, muramyl dipeptide, which is immunostimu-
latory but does not evoke a specific immune response.20
Adjuvant- and pristane-induced arthritis
In addition, a number of adjuvants that lack immunogenic properties have
been shown to induce arthritis in susceptible strains of rats, including avri-
dine,21 incomplete Freund’s adjuvant, and pristane.19 Arthritis has also been
observed in mice following administration of pristane.22 Confirmation of
the fact that these are T cell–driven diseases is provided by the fact that
(1) anti–T cell treatments prevent the induction of arthritis,19,23 (2) suscep-
tibility is associated with genes within the MHC,24,25 and (3) arthritis may
be adoptively transferred by T cells.26,27 It was also found that arthritis could
be induced in DA rats by percutaneous exposure of adjuvant oils28 or even
a mineral oil–containing cosmetic product.29 The mechanism of arthritis
induction following immunization with adjuvants is not fully understood,
but one possibility is that immunization leads to an increase in the activity
of APC,30 resulting in the presentation to T cells of a hitherto unrecognized
or “sequestered” endogenous antigen.
Expansion of autoreactive T- and B-cell populations can occur as a con-
sequence of the adjuvant activation process and result in the migration of
cells to the joint, leading to subsequent immune-mediated joint damage and
production of a spectrum of autoantibodies against cartilage antigens (Fig.
95.2). Disease onset is rapid in AA (2 weeks), often followed by spontaneous
remission. Pristane-induced arthritis is slower (months) and characterized by
remissions and relapses, with no indication of B-cell involvement at the onset.
The pristane model is highly suited to studying genes controlling onset, sever-
ity, and chronicity.31 The spontaneous remission and lack of susceptibility to
reinduction make AA a suitable model for studies on the regulation of T-cell
tolerance. Histopathologic analysis of AA shows major involvement of bone
marrow, bone erosion, extensive bone apposition, and minor direct cartilage
damage in the early stages (Table 95.1). Indirect cartilage damage occurs later,
mainly as a consequence of the loss of underlying bone. The latter may explain
the cartilage-protective effect of treatment with osteoprotegerin (OPG), which
is a selective inhibitor of the osteoclast activator RANKL (receptor activator of
nuclear factor κB ligand).32,33 Combined blocking of TNF and IL-1 is associ-
ated with optimal control of arthritis and joint destruction.
COMPONENTS OF INFECTIOUS AGENTS
The development of arthritis as a consequence of infection is apparent in
both natural and induced animal models. Infectious agents may be tropic for
799
800 SECTION 7  Rheumatoid Arthritis

HYPOTHETICAL MECHANISM FOR THE DEVELOPMENT OF COLLAGEN-INDUCED AND PROTEOGLYCAN-INDUCED EXPERIMENTAL ARTHRITIS

High-density Immune-mediated
Cartilage aggrecan Type II joint damage
Autoantibodies
components proteoglycans collagen Antigen T-cell recognition
Immunization presentation (restricted by
(adjuvant) (MHC restricted) T-cell repertoire)
Th2
Chronic
arthritis
Th1,
Th17

Autoreactive T cells

FIG. 95.1  Animals are immunized with type II collagen or high-density aggrecan proteoglycans, and an autoimmune response results when specific epitopes are presented in
the context of major histocompatibility complex (MHC) class II antigens and recognized by autoreactive CD4+ T-cell populations. Autoantibodies and T effector cells reactive
against cartilage components develop via helper T-cell pathways and localize in synovial joints, which causes an immune-mediated inflammatory response. The immune
response is perpetuated by the release of cartilage antigens within the damaged joint, and chronic arthritis develops.

be induced in Lewis rats34 by the systemic injection of cell wall fragments

HYPOTHETICAL MECHANISM FOR THE DEVELOPMENT OF PRISTANE-
INDUCED AND ADJUVANT-INDUCED EXPERIMENTAL ARTHRITIS
Chronic antigen
stimulation
Joint antigen
Autoreactive and heat shock
B-cell activation protein release
Macrophage Immune-
stimulation mediated
(pristane, adjuvants)
joint damage
Autoreactive
Cytokine T-cell activation
production (MHC and Mls restricted)
Chondrocyte activation
Synovial cell activation
FIG. 95.2  Circulating macrophages become intensely activated by the nondegrad-
able oil components and produce high levels of proinflammatory cytokines (inter-
leukin-1 and interleukin-6, tumor necrosis factor-α, and interferon-α). Genetic
regulation governs the presence of autoreactive T cells and B cells, which become
activated and clonally expand. Joint-reactive lymphocytes migrate to the joint and
induce immune-mediated joint damage. The release of cartilage antigens and heat
shock proteins may feed back to the autoreactive lymphocytes and result in chronic
immune stimulation. Cytokines may also act directly on both synovial cells and
chondrocytes and thereby result in synovial hypertrophy, abnormal expression of
major histocompatibility complex (MHC) class II antigens and adhesin molecules,
and atypical production of matrix components. Arthritis develops as a result of the
chronic nature of the inflammatory stimulation.
the joint as a result of expression of adhesins or other molecules that pro-
mote sequestration within synovial tissue. Bacterial cell wall and Mycoplasma
membrane components may also provide nonspecific immune activation
through mitogenic activity. Viral infection of synovial cells may elicit novel
cell-surface antigens or abnormal expression of activation antigens and the
overproduction of autoantigens. Viral infection may also disrupt immune
regulation and increase proinflammatory cytokines and immune activity
against normally immunologically privileged components of the joint.
Streptococcal cell wall arthritis
Persistence of antigens from microorganisms within the joint can be critical
for the induction of arthritis. Streptococcal cell wall (SCW) arthritis can
of group A streptococci, which are highly resistant to biodegradation. A
similar disease can be induced with fragments from other bacteria, such as
Lactobacillus casei or Eubacterium aerofaciens. The underlying principle of
this model resides in the poor degradability of the fragments, thereby creat-
ing a persistent stimulus.
The Lactobacillus and Eubacterium models are of particular interest for
human disease because these bacteria are part of the normal gastrointestinal
flora. An enormous amount of potential arthritogenic stimuli is continu-
ously present in the normal gastrointestinal tract; fragments may spread in a
noninfectious manner to other tissues, and this may provoke arthritis when
immunoregulatory control is insufficient.
Within 24 hours of administration of cell wall fragments to rats, acute
inflammation develops in peripheral joints, coincident with dissemina-
tion of the cell wall fragments in blood vessels of the synovium and sub-
chondral bone marrow. The acute, complement-dependent inflammation
subsides over the next week, followed within 2 weeks by a chronic, T cell–
dependent erosive polyarthritis involving mainly peripheral joints. Chronic
joint inflammation develops only in susceptible strains that are unable to
maintain tolerance and therefore display SCW-specific T-cell responses.
Lewis rats are highly vulnerable to this arthritis. The mouse strains studied
thus far are not susceptible to the single intraperitoneal injection model, and
repeated dosing is needed to break tolerance. It is tempting to speculate that
similar loss of tolerance may occur in patients with RA with age, combined
with costimulatory environmental factors.
Studies of the involvement of cytokines in SCW arthritis show a combined
role of TNF and IL-1, as found in AA.35 In mice, a chronic relapsing SCW
model can be induced by repeated weekly injection of SCW fragments directly
into the knee joint, which displays a gradually increasing role of T cell–derived
IL-17 and synovial IL-17 receptor–bearing cells with every flare.36
Bacterial DNA can induce arthritis. In particular, the CpG motifs are
arthritogenic, and substantial amounts can be found in joint tissues.37
Macrophages play a major role in this arthritis through TNF production.
However, in comparison to cell wall fragments, the cytokine-inducing
capacity of bacterial DNA is weak. Normal joints of individuals contain both
bacterial fragments and bacterial CpG (CP61) motifs, and it is conceivable
that both factors contribute to arthritis.
Antigen-induced arthritis
Antigen-induced arthritis (AIA) provides a designed model of the develop-
ment of chronic erosive arthritis that reflects a sustained immune reaction to
a persistent trigger in joint tissues, in this case a planted protein antigen. It is
elicited by local injection of a high dose of antigen into the knee joint of an
animal previously hyperimmunized with that antigen in Freund’s complete
adjuvant. Such a model was first developed by Dumonde and Glynn38 in
rabbits. In principle, it can be induced in any species, provided that proper
immunity to a particular antigen can be mounted. Applications have since
been developed in mice, rats, and guinea pigs.
In contrast to the polyarthritis models described thus far, AIA remains
confined to the injected joint. Commonly used antigens are ovalbumin,
bovine serum albumin (BSA), fibrin, and cationic forms such as methylated
BSA. Cationic antigens are preferred due to their increased retention in the
joint.39 Preimmunization with antigen in complete Freund adjuvant induces
strong humoral and cell-mediated immunity. Arthritis is usually induced 3

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 CHAPTER 95  Animal models of rheumatoid arthritis 801

Table 95.1
Models of Arthritis
Model Abbreviation Speciesa Feature IC T Cell References
Induced models
Collagen-induced arthritis CIA DBA/1 mouse CII + + 73

Proteoglycan-induced arthritis PGA BALB/c mouse PG + + 74

Adjuvant-induced arthritis AA Lewis rat Autoimmune − + 17

Oil-induced arthritis OIA DA rat Autoimmune − + 19

Pristane-induced arthritis PIA Mouse, DA rat Autoimmune − + 75,76

Streptococcal cell wall–induced arthritis SCW-A Lewis rat Persistent bacteria − + 34

Flare SCW Mouse T cell–derived IL-17 − + 35

Antigen-induced arthritis AIA Rabbit, mouse Persistent antigen + + 38,40

Flare AIA Mouse T cell–derived IL-17 − + 41

Transgenic models
K/BxN arthritis KRN K/BxN mouse GPI + + 46

TNF transgenic arthritis TNFtg Mouse TNF overexpression − − 61,62

IL-1 transgenic arthritis IL-1tg Mouse IL-1 overexpression − − 65

IL-1ra transgenic arthritis IL-1ra−/− BALB/c mouse Autoimmune T cells ± + 69,71

SKG arthritis SKG Mouse T-cell defect − + 58

gp130-induced arthritis gp130 Mouse STAT3 defect − + 60

gp130, Glycoprotein 130; GPI, glucose-6-phosphate isomerase; IC, immune complexes; IL-1, interleukin 1; TNF, tumor necrosis factor.
a
Mostly used.

weeks later by local injection of a large amount of antigen into the knee
joint. Initially, an immune complex (IC) type of reaction dominates, fol-
lowed by T cell–mediated chronic inflammation. In the rabbit, chronicity
may last for years. Histopathologic examination shows a granulocyte-rich
exudate in the joint space, thickening of the synovial lining layer, and, at
later stages, a predominantly mononuclear infiltrate in the synovium, which
later includes numerous T cells and clusters of plasma cells making anti-
bodies to the inciting antigen, thus implying that retained antigen is still a
driving force in chronic arthritis. Intense IC formation is seen in superficial
layers of the articular cartilage, which may contribute to localized cartilage
destruction. Early loss of PG, followed by pannus formation and cartilage
and bone erosion, is a common finding.
Two important principles emerge from this model: first, chronicity
occurs only in the presence of sufficient antigen retention in joint tissues,
in combination with proper T cell–mediated delayed hypersensitivity, and,
second, joints contain numerous noncollagenous and avascular collagenous
tissue such as cartilage, ligaments, and tendons, which allows prolonged
antigen retention by antibody-mediated trapping and charge-mediated bind-
ing.39,40 Chronicity is caused by the generation of local antigen-specific T-cell
hyperreactivity, which allows flares in response to tiny amounts of antigen.
In rabbits, antibody responses are generally high and allow sufficient
IC-mediated trapping of antigen in the joint. Because antibody levels are
lower in mice, cationic antigens are needed as suitable arthritogens because
of their ability to stick to the negatively charged collagenous structures of
the joint and to accumulate IC formation at the surface.39,40 Of interest, this
principle may extend to cationic bacterial or viral components and appears
to be of importance in the KRN model of arthritis, in which anti-glucose-6-
phosphate isomerase (anti-GPI) antibodies stick to GPI antigen trapped at
cartilage surfaces.
In AIA in the rabbit and the mouse, elimination of TNF and IL-1 was
poorly effective in suppressing joint inflammation, thus pointing to substan-
tial “overkill” by other mediators in this severe onset of arthritis. However,
elimination of IL-1 did yield impressive protection against cartilage destruc-
tion. The AIA model is most suited to studies of the mechanism of cartilage
destruction as induced by a mix of ICs and T-cell reactivity. It is assisted
by knowledge of the exact time of onset, accessibility of the knee joint (as
compared with the ankles), and the presence of a contralateral control joint.
Moreover, the model can be used to evaluate the regulation of local T-cell
hyperreactivity against a retained foreign antigen.
Flares of arthritis
In contrast to the chronicity of human RA, most animal models have a rela-
tively short duration of severe and rapidly destructive inflammation. In this
respect, models of repeated flares of arthritis, with slower development of
lesions, provide a valuable extension.
An arthritic joint bearing retained antigen and a chronic antigen-specific
T-cell infiltrate displays a state of local hyperreactivity. This situation is not
restricted to retained antigen but also applies to new antigen entering the
sensitized joint from the circulation. Flares of smoldering arthritis can be
induced with as little as 10 ng of antigen, and T cell–derived IL-17 plays a
dominant part in such exacerbations.41
Similar flare models have been developed in rats and mice with bacte-
rial cell wall constituents. Bacterial fragments may function as an antigen
but also directly trigger TLRs, in particular, TLR2. The ensuing reactions
are a mixture of T cell– and macrophage/fibroblast-driven processes. In the
mouse model of repeated SCW rechallenge, the swelling response of every
flare remains dependent on TNF. However, the chronic erosive infiltrate in
the synovial tissue that occurs after repeated challenges is dependent on
IL-1. Cartilage erosion is absent in IL-1-deficient mice but does occur in
TNF-deficient mice. This model is more severe and erosive in DBA/1 mice
than in C57Bl/6 mice, erosion is absent in T/B cell–deficient RAG−/− mice,
and blocking of IL-17 prevents an erosive phenotype. The repeated-chal-
lenge model becomes Th17 dependent, and IL-1 is a major cytokine driving
this process of Th17 generation.36
Of note, considerable cross-reactivity occurs between cell walls from
different bacterial origins, and flares may result from homologous and het-
erologous fragments. This may extend to cross-reactive autoantigens from
cartilage, which underlines the fact that arthritis can start in response to a
particular antigen but may spread to other antigens, including autoantigens.
TLRs have been identified as recognition sites for bacteria. TLR2 is
involved in SCW recognition, whereas TLR4 is triggered by lipopolysaccha-
ride but also by the damaged connective tissue components released in ero-
sive stages. The acute SWC arthritis model is dependent on TLR2, whereas
the more chronic rechallenge model loses TLR2 dependence and becomes
dependent on TLR4.42 These principles open up a wide range of putative
stimuli involved in exacerbations, which simultaneously complicates the
search for the driving “antigen” in humans. Flares can be blocked efficiently
with a combination of antibodies to TNF, IL-1, and IL-1741 in particular.
Evaluation of the efficacy of TLR blockers is warranted.
IMMUNE COMPLEX–INDUCED ARTHRITIS
Autoantibodies such as rheumatoid factor and anticitrullinated peptide anti-
bodies (ACPAs) are a key feature of RA, and the success of treatment with an
anti–B cell drug (rituximab) enhanced interest in their pathogenic role. In
some of the models discussed earlier such as collagen-, PG-, and antigen-in-
duced arthritis, IC formation at joint tissues is a major element (see Table
95.1). Although excessive IC formation can cause destructive arthritis, chro-
nicity is limited, unless augmented by T cells.43 Minute amounts of antigen
suffice to stimulate T cells, whereas considerable amounts of ICs are neces-
sary to stimulate the release of inflammatory mediators from phagocytes. It
is likely that IC models mimic part of the RA pathology.
There is interest in the use of passive IC models, along with the avail-
ability of a range of transgenic knockouts, to identify crucial pathways of
inflammation and tissue destruction. The advantage of passive systems is
the lower dependence on genetic background, thereby avoiding excessive

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802 SECTION 7  Rheumatoid Arthritis
backcrossing to create transgenics in suitable, susceptible mouse strains.
Passive transfer of collagen-induced arthritis can be performed with a criti-
cal mixture of a number of anti-CII monoclonal antibodies, including com-
plement-binding IgG2a. Sets are now commercially available, and accepted
concepts of inflammation pathways include IC-mediated complement acti-
vation and Fcγ receptor triggering on phagocytes.

K/BxN and serum transfer models

An intriguing model of arthritis was described in the offspring of KRN TCR
transgenic mice crossed with NOD mice.44 KRN TCR transgenic mice express
a TCR specific for bovine pancreas ribonuclease presented in the context of
I-Ak.45 However, when KRN mice are crossed with NOD mice (I-Ag7), the
resulting (K/BxN) offspring develop arthritis spontaneously. Further studies
showed that arthritis in K/BxN mice was dependent on I-Ag7 MHC class II
molecules and CD4+ T cells.44,46,47 B lymphocytes were required for arthri-
tis development,44,46 and arthritis could be transferred by injecting naive
mice with serum IgG from arthritic mice in a complement-dependent and a
FcγR-dependent manner.46,48,49 These antibodies recognize endogenous GPI,
which seems to associate preferentially with the cartilage surface.50
However, the KRN model differs from human RA in one important
respect: its lack of dependence on TNF-α.51 Another point that is worth
emphasizing is that GPI is unlikely to be the critical autoantigen in RA as
antibodies to GPI are no more common in RA than in other diseases.52,53
As an adaptation of this model, Kamradt and colleagues54 immunized
mice with GPI and showed the development of arthritis after a few weeks.
This direct immunization model is a mix of GPI-specific T cells and anti-GPI
antibodies; serum from these mice cannot transfer arthritis. The latter makes
the direct immunization model different from classic KRN arthritis.

ANTICITRULLINATED PROTEIN ANTIBODIES

AND ARTHRITIS MODELS
Anticitrullinated protein antibodies (ACPAs) are a serologic hallmark of
human RA, but their role in animal models of arthritis has been difficult to
confirm. In one study, a range of monoclonal antibodies specific for citrulli-
nated CII were generated and found to induce arthritis on passive transfer.55
A potential association was identified between periodontal infection and
RA via bacteria-dependent induction of a pathogenic autoimmune response
to citrullinated epitopes. Thus, infection with the periodontal pathogen
Porphyromonas gingivalis exacerbated CIA, and this was dependent on pepti-
dylarginine deiminase (PPAD), which converts arginine residues in proteins
to citrulline. Infection with wild-type P. gingivalis caused increased levels
of autoantibodies to type II collagen type II, whereas a PPAD-null mutant
strain was ineffective.56 However, in another study, immunization of various
mouse strains with citrullinated fibrinogen, myelin basic protein, and type
II collagen failed to induce or aggravate arthritis despite eliciting ACPAs.57
GENE MANIPULATION AND TRANSGENIC MODELS
Transgenic animals and spontaneous mutant mice have provided models of
arthritis, often unexpectedly. For example, Sakaguchi et al. showed that a
spontaneous point mutation of the gene encoding an SH2 domain of ZAP-
70 resulted in the development of chronic autoimmune arthritis in mice.58
The result of this is that T cells in SKG mice respond weakly to antigenic
stimulation, and it is proposed that suboptimal signal transduction via the
TCR as a result of aberrant ZAP-70 leads to a change in the threshold of T
cells to thymic selection, resulting in a failure to delete self-reactive T cells.
This model challenges another commonly held belief that autoimmune dis-
eases arise as a result of hyperresponsive T cells. Another interesting facet
of the SKG model of arthritis is the requirement for stimulation through
the innate immune system, which can be provided by housing the mice in
a microbially rich environment or by administration of fungal β-glucans,
such as zymosan.59 This demonstrates how genetic factors can interact with
environmental stimuli to generate autoimmune disease.
Mice with a homozygous mutation in the gp130 IL-6 receptor subunit
show enhanced signal transduction and STAT3 activation, and a lympho-
cyte-mediated RA-like joint disease develops. The increased proliferation of
CD4+ T cells is due to elevated production of T cell–activating IL-7 by non-
hematopoietic cells.60
Keffer et al. generated a strain of mice overexpressing a human TNF-α
transgene (including its endogenous promoter region) that had been dys-
regulated by the replacement of the 3′ AU-rich region with the 3′ untrans-
lated region of the human β-globin gene. TNF overexpression resulted in
chronic polyarthritis with a 100% incidence.61 The disease could be pre-
vented by continuous administration of antihuman TNF-α mAb, confirming
b
FIG. 95.3 Joint damage in hTNF-α-transgenic mice. (a) Erosive changes in
the cartilage–bone–pannus region of a proximal interphalangeal joint from an
hTNF-α-transgenic mouse with arthritis. Note the focal erosion of subchondral bone.
(b) Normal joint from a nontransgenic littermate. Hematoxylin and eosin.
the role of the transgenically expressed TNF-α in the induction of arthritis.
Histopathological analysis of the joints of hTNF-α transgenic mice revealed
that the disease was highly erosive in nature, with subchondral bone, rather
than cartilage, being mostly affected (Fig. 95.3).
TNF-α expression in hTNF-α transgenic mice was not confined to the
joint and was found to be overexpressed in various tissues, including lung,
spleen, and the joint. The reason why the joint should be affected while
other tissues are spared is not known and, in fact, a second strain of TNF-α
transgenic mice was generated in which the TNF-α transgene lacked an
AU rich region. These mice were found to develop not only arthritis but
also inflammatory bowel disease.62 It is interesting to note that TNF-α-
overproducing mice can be backcrossed to RAG−/− mice without altering the
arthritis phenotype, indicating that the adaptive immune system plays no
role in the development of arthritis in this model.
This model is of interest in identifying pathways of TNF-induced arthri-
tis and screening the efficacy of various TNF-directed therapies. A signifi-
cant finding was that treatment of hTNF-α transgenic mice with anti-IL-1R
antibody prevented the development of spontaneous arthritis,63 demon-
strating that IL-1 is an important downstream pathological mediator in this
model. This is consistent with findings in human RA synovial cell cultures
in which TNF-α inhibition was found to block IL-1 production,64 indicating
the dependence of IL-1 production on TNF-α.
Another transgenic model that confirms the arthritogenic potential of IL-1
is the IL-1α-transgenic mouse that spontaneously develops severe arthritis at
around one month of age.65 Unlike TNF-α-transgenic mice, severe degrada-
tion of cartilage was observed in IL-1α-transgenic mice, thereby confirming
previous findings, published over 30 years ago, regarding the important role
of IL-1 in cartilage breakdown.66–68
The opposite approach, elimination of IL-1 control by gene targeting of
the endogenous IL-1 receptor antagonist (IL-1ra), also yielded a model of
arthritis. IL-1ra deficiency in a BALB/ca background resulted in pronounced
arthritis at the age of 8 weeks.69 Marked synovial and periarticular inflam-
mation with invasion of granulation tissue and articular erosion was noted.

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Moreover, elevated levels of antibodies against immunoglobulins, CII, and
double-stranded DNA were found, suggestive of autoimmune responses.
Overexpression of a range of cytokines, including IL-1β, TNF, and IL-6, was
observed in the joints before the onset of arthritis.
In sharp contrast to the TNF transgenic model, the arthritis in IL-1ra−/− mice
is strongly dependent on T cells, in line with the remarkable genetic restriction.
It is consistent with the view that IL-1 is a crucial regulator of T-cell function.
Undisturbed IL-1 action, in the absence of IL-1ra, apparently permits activation
of IL-17-producing T cells directed against exogenous triggers or endogenous
autoantigens. The spontaneous arthritis in IL-1ra−/− mice does not develop in
germ-free conditions and is reduced in TLR4-deficient mice.70 Both TNF and
IL-17 deficiency prevent the onset of arthritis.71
THE 3 R’s
Animal models of arthritis will continue to be used to address scientific
questions and to test novel therapeutic approaches due to the unmet need
in human disease. The implementation of the 3 R’s—replacement, reduction,
and refinement—is encouraged at all levels; that is, within research establish-
ments and companies and by regulators, funding bodies, and journals. There
is considerable scope for the refinement of animal models of RA, including
the use of analgesia, use of less severe models (e.g., not requiring the use of
CFA), and the inclusion of humane endpoints and improved husbandry.72
Refinement in RA research can easily be employed through the choice of
model used. Polyarthritis models—that is, models in which multiple joints
are affected, such as CIA and K/BxN—are associated with an overall higher
severity than monoarthritic models, such as AIA.72 The involvement of only
one joint means mice can redistribute their weight to the three unaffected
limbs. Furthermore, the presence of an unaffected contralateral joint acts
as an internal control in these models, which for many readouts reduces
the need for additional mice as controls. Although polyarthritis models are
scientifically justified due to their apparent similarity to human RA, monoar-
thritis models possess many relevant disease processes and are encouraged
to be used in place of polyarthritis models wherever possible.
The use of analgesia is also highly encouraged to reduce pain and suffer-
ing in RA models but is often not employed due to the lack of literature asso-
ciated with model progression and drug interaction. Analgesics that inhibit
COX-2 enzymes, such as nonsteroidal antiinflammatories, are not appro-
priate for use due to their interference with inflammation and the model
progression. Recommended analgesics include the nonopioid analgesic met-
amizole and aniline analgesics, and there is growing encouragement for their
use as rescue therapy in animal models.
The use of CFA in animal models is associated with a variety of side
effects, including localized injection site granulomas and ulceration. The
immunostimulatory ability of CFA means it is still commonly used in RA
murine models; however, researchers are encouraged to explore alternatives
to CFA to reduce pain and suffering in mice. If CFA is to be employed,
measures can be taken to minimalize ulceration of the injection site, includ-
ing subcutaneous injection instead of intradermal, monitoring injection site
after immunization, and treating with topical antiseptic creams daily (e.g.,
Sudocrem).
Another important refinement is to limit the duration of arthritis to the
shortest possible time required to answer a given experimental question. A
broader discussion of potential refinements is included in Hawkins et al.72
CONCLUSIONS
Arthritis may be induced in animals by immunization with cartilage compo-
nents, nonspecific immune stimuli, bacterial or viral components, or trans-
genic manipulation. Animal models are research tools that mimic various
aspects but never fully resemble human RA. Animal models have a defined
onset and are useful for kinetic evaluation of arthritis, cell and mediator
involvement, and detailed analysis of joint erosion. Animal models serve an
important role in the evaluation of antirheumatic treatments and provide
direction for novel approaches to treatments such as cytokine inhibition.
The implementation of the 3 R’s is of particular relevance for animal models
of RA, and there is scope for refinement of existing models to improve ani-
mal welfare.
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