BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO.

11 1041
ANIMAL MODELS OF RHEUMATOID ARTHRITIS
THE use of animals to model human diseases arouses
understandable concerns regarding the relevance of the
findings. However, recent insights into the striking
degree of sequence homology that occurs between
comparable proteins from different mammals (and
even between some mammalian and microbial pro-
teins) have given new respectability to experimental
studies in animals. In any case, conservation of
functionally important sequences within proteins has
long allowed the therapeutic use of animal homologues
of human hormones (e.g. insulin). The long-term
survival of rheumatoid synovial xenografts within
severe combined immunodeficient (scid) mice further
highlights the essential metabolic similarity between
humans and rodents [1]. Thus, while humans and other
mammals differ obviously in appearance at a superficial
level, there are very close similarities in the general
system of their organs, as well as in their structural and
signalling proteins, lipid mediators and general cell
metabolism. This congruence underpins the suitability
of animals for studies requiring whole-body systems,
including studies of the altered homeostasis that
characterizes chronic polyarthritis. Such investigations
can be especially valuable when they address key issues
which are not accessible in human studies.
Most studies of experimentally induced polyarthritis
are undertaken in rats and mice, with the most
frequently used models being adjuvant-induced
arthritis (AA) in rats and type II collagen-induced
arthritis (CIA) in mice or rats [2]. While these models
differ in the manner in which polyarthritis is induced,
disease expression is broadly similar, albeit with some
consistent differences. They have in common with RA
the occurrence of symmetrical, predominantly periph-
eral polyarthritis with signs of systemic inflammation
(acute-phase protein response, weight loss). The
synovial inflammation seen, which includes erosive
pannus formation, also resembles that seen in RA.
Over the years, these models have been used to assess
the efficacy of novel chemotherapies. More recently,
the therapeutic effects of monoclonal antibodies
against targets of interest (e.g. T cells, adhesion
molecules) or of cytokines or their inhibitors have
been evaluated [2,3]. The specificity of biological
agent therapies is such that their use can yield
important information about mechanism as well as
about efficacy.
Clearly, neither AA nor CIA can be regarded as
involving the specific immunological trigger puta-
tively responsible for RA since the nature of the
antigen(s) responsible for inducing and maintaining
joint inflammation in RA has not been established.
However, there are many features of polyarthritis that
are not likely to be antigen specific. Examples include
the leucocyte-endothelial cell adhesive events involved
in the recruitment of leucocytes to inflamed synovium
[4] and the effector mechanisms responsible for the
cumulative tissue damage seen in chronic polyarthritis
[5]. Thus, there are important aspects of RA which are
shared generically by other forms of polyarthritis and
which can be modelled adequately in experimental
animals.
A relatively recent development has been the use of
mice and rats bearing human or rodent transgenes to
display the pathological effects of constitutive over-
expression of particular proteins, including inflammat-
ory cytokines. The physiological relevance of findings
must be inferred with some caution, particularly when
effects depend on high copy numbers of the transgene
or when promoter constructs allow expression within
an unusually broad range of cells and tissues, or in a
manner which escapes the normal regulatory mechan-
isms. An- example of this approach is mice bearing
tumour necrosis factor a (TNFa) transgenes. These
mice develop polyarthritis spontaneously at an early
age [6], suggesting that TNFa, when present in
sufficient amounts, may be intrinsically arthritogenic.
The availability of embryonic stem cells in mice also
makes possible the generation of stock in which
particular genes have been rendered defective by
disruptive homologous recombination [7]. In these
'gene knockout' (KO) mice, the genetic deficiency can
affect development (sometimes with lethal effects),
as well as the homeostatic responses of mature
animals.
Experiments which utilize cross-bred multiple trans-
genic and/or KO mice deficient at different loci can
be especially instructive. The studies of David and
co-workers provide examples [8, 9]. They have assessed
the role of transgenes for human DQ and DR alleles
in susceptibility for CIA in mice in which the
corresponding H-2 genes have been disabled or are
otherwise defective. Their salient conclusions were that
certain HLA-DQ alleles (DQ8, DQ7, DQ5) and their
murine homologues predispose to CIA. The DR
molecules DR4, DR14 and DR1,.which are regarded
as susceptible genes (or severity risk factors) for RA in
humans, appear to play a permissive role (as does
absence of the murine equivalent of this locus), whereas
DR alleles not associated with arthritis appear to be
protective. In humans, the susceptibility-inducing DQ
alleles are co-expressed with the RA-associated DR
alleles, with which they are in linkage disequilibrium.
The notion is thus introduced that a disease
susceptibility haptotype (susceptibility-inducing DQ,
permissive DR) may predispose to RA, with the
importance of particular DQ alleles having been
overshadowed hitherto by the presence of the DR

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1042 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 11
alleles with which they are associated. Clearly, this is
an example of a deeper level of understanding achieved
through animal studies in relation to the complex role
of HLA factors in human diseases.
And so, in an era in which experimental biology is
dominated by molecular genetics and molecular cell
biology, animal models of polyarthritis have acquired
increased rather than diminished respectability. On
the one hand, there is a broader appreciation of the
fundamental similarity between mammals in both
metabolism and fine structure. On the other hand, there
is a growing need to marry the precision of studies
in molecular cell biology with more integrated, but
inevitably less precise, studies of homeostasis and
pathophysiology in intact animals. Concern for the
welfare of animals demands that studies of arthritis in
laboratory animals be scrutinized rigorously to ensure
that questions being addressed are scientifically and
medically important, and that all reasonable attempts
are made to avoid unnecessary suffering of experimen-
tal animals. However, the need to strike an appropriate
balance between reductionist insights into molecular
mechanisms, and a more holistic understanding of
health and disease, requires experiments on intact
animals.
L. G. CLELAND
Rheumatology Unit, Royal Adelaide Hospital, North
Terrace, Adelaide, South Australia
REFERENCES
1. Geiler T, Kriegsmann J, Keyszer G et al. A new model
for rheumatoid arthritis generated by engraftmcnt of
rheumatoid synovia! tissue and normal human cartilage
in SCID mice. Arthritis Rheum 1994^7:1664-71.
2. Yoshino S, Cleland LG. Depletion of alpha/beta T cells
by a monoclonal antibody against the alpha/beta T cell
receptor suppresses established adjuvant arthritis, but
not established collagen-induced arthritis in rats. J Exp
Med 1992;175:907-15.
3. Kalden JR. Biologic agents in the therapy of inflam-
matory rheumatic diseases, including therapeutic anti-
bodies, cytokines, and cytokine antagonists. Curr Opin
Rheumatol 1994;6:281-6.
4. Imhof BA, Dunon D. Leukocyte migration and
adhesion. Adv Immunol 1995^8:345-416.
5. Harris ED Jr. Rheumatoid arthritis, pathophysiology
and implications for therapy. N Engl J Med 1990;
322:1277-89.
6. Keffer J, Probert L, Cazlaris H et al. Transgenic mice
expressing human tumour necrosis factor: a predictive
genetic model of arthritis. EMBO J 1991; 10:4025-31.
7. Galli Taliadoros LA, Sedgwick JD, Wood SA, Korner
H. Gene knockout technology. A methodological
overview for the interested novice. / Immunol Methods
1995;181:1-15.
8. David CS, Gonzales Gay M, Zhou P et al. Mouse and
human MHC class II genes H-2A/HLA-DQ mediate
susceptibility while H2-E/HLA-DR molecules mediate
protection in collagen induced arthritis. Lessons for
human RA. Rheumatol Europe 1995;24{suppl. 2):2-4.
9. Zanelli E, Gonzales Gay MA, David CS. Could
HLA-DRB1 be the protective locus in rheumatoid
arthritis. Immunol Today 1995;6:274-8.

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