BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 11 1041

ANIMAL MODELS OF RHEUMATOID ARTHRITIS

THE use of animals to model human diseases arousesunderstandable concerns regarding the relevance of thefindings. However, recent insights into the strikingdegree of sequence homology that occurs betweencomparable proteins from different mammals (andeven between some mammalian and microbial pro-teins) have given new respectability to experimentalstudies in animals. In any case, conservation offunctionally important sequences within proteins haslong allowed the therapeutic use of animal homologuesof human hormones (e.g. insulin). The long-termsurvival of rheumatoid synovial xenografts withinsevere combined immunodeficient (scid) mice furtherhighlights the essential metabolic similarity betweenhumans and rodents [1]. Thus, while humans and othermammals differ obviously in appearance at a superficiallevel, there are very close similarities in the generalsystem of their organs, as well as in their structural andsignalling proteins, lipid mediators and general cellmetabolism. This congruence underpins the suitabilityof animals for studies requiring whole-body systems,including studies of the altered homeostasis thatcharacterizes chronic polyarthritis. Such investigationscan be especially valuable when they address key issueswhich are not accessible in human studies.

Most studies of experimentally induced polyarthritisare undertaken in rats and mice, with the mostfrequently used models being adjuvant-inducedarthritis (AA) in rats and type II collagen-inducedarthritis (CIA) in mice or rats [2]. While these modelsdiffer in the manner in which polyarthritis is induced,disease expression is broadly similar, albeit with someconsistent differences. They have in common with RAthe occurrence of symmetrical, predominantly periph-eral polyarthritis with signs of systemic inflammation(acute-phase protein response, weight loss). Thesynovial inflammation seen, which includes erosivepannus formation, also resembles that seen in RA.Over the years, these models have been used to assessthe efficacy of novel chemotherapies. More recently,the therapeutic effects of monoclonal antibodiesagainst targets of interest (e.g. T cells, adhesionmolecules) or of cytokines or their inhibitors havebeen evaluated [2,3]. The specificity of biologicalagent therapies is such that their use can yieldimportant information about mechanism as well asabout efficacy.

Clearly, neither AA nor CIA can be regarded asinvolving the specific immunological trigger puta-tively responsible for RA since the nature of theantigen(s) responsible for inducing and maintainingjoint inflammation in RA has not been established.However, there are many features of polyarthritis thatare not likely to be antigen specific. Examples include

the leucocyte-endothelial cell adhesive events involvedin the recruitment of leucocytes to inflamed synovium[4] and the effector mechanisms responsible for thecumulative tissue damage seen in chronic polyarthritis[5]. Thus, there are important aspects of RA which areshared generically by other forms of polyarthritis andwhich can be modelled adequately in experimentalanimals.

A relatively recent development has been the use ofmice and rats bearing human or rodent transgenes todisplay the pathological effects of constitutive over-expression of particular proteins, including inflammat-ory cytokines. The physiological relevance of findingsmust be inferred with some caution, particularly wheneffects depend on high copy numbers of the transgeneor when promoter constructs allow expression withinan unusually broad range of cells and tissues, or in amanner which escapes the normal regulatory mechan-isms. An- example of this approach is mice bearingtumour necrosis factor a (TNFa) transgenes. Thesemice develop polyarthritis spontaneously at an earlyage [6], suggesting that TNFa, when present insufficient amounts, may be intrinsically arthritogenic.The availability of embryonic stem cells in mice alsomakes possible the generation of stock in whichparticular genes have been rendered defective bydisruptive homologous recombination [7]. In these'gene knockout' (KO) mice, the genetic deficiency canaffect development (sometimes with lethal effects),as well as the homeostatic responses of matureanimals.

Experiments which utilize cross-bred multiple trans-genic and/or KO mice deficient at different loci canbe especially instructive. The studies of David andco-workers provide examples [8, 9]. They have assessedthe role of transgenes for human DQ and DR allelesin susceptibility for CIA in mice in which thecorresponding H-2 genes have been disabled or areotherwise defective. Their salient conclusions were thatcertain HLA-DQ alleles (DQ8, DQ7, DQ5) and theirmurine homologues predispose to CIA. The DRmolecules DR4, DR14 and DR1,.which are regardedas susceptible genes (or severity risk factors) for RA inhumans, appear to play a permissive role (as doesabsence of the murine equivalent of this locus), whereasDR alleles not associated with arthritis appear to beprotective. In humans, the susceptibility-inducing DQalleles are co-expressed with the RA-associated DRalleles, with which they are in linkage disequilibrium.The notion is thus introduced that a diseasesusceptibility haptotype (susceptibility-inducing DQ,permissive DR) may predispose to RA, with theimportance of particular DQ alleles having beenovershadowed 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 isan example of a deeper level of understanding achievedthrough animal studies in relation to the complex roleof HLA factors in human diseases.

And so, in an era in which experimental biology isdominated by molecular genetics and molecular cellbiology, animal models of polyarthritis have acquiredincreased rather than diminished respectability. Onthe one hand, there is a broader appreciation of thefundamental similarity between mammals in bothmetabolism and fine structure. On the other hand, thereis a growing need to marry the precision of studiesin molecular cell biology with more integrated, butinevitably less precise, studies of homeostasis andpathophysiology in intact animals. Concern for thewelfare of animals demands that studies of arthritis inlaboratory animals be scrutinized rigorously to ensurethat questions being addressed are scientifically andmedically important, and that all reasonable attemptsare made to avoid unnecessary suffering of experimen-tal animals. However, the need to strike an appropriatebalance between reductionist insights into molecularmechanisms, and a more holistic understanding ofhealth and disease, requires experiments on intactanimals.

L. G. CLELAND

Rheumatology Unit, Royal Adelaide Hospital, NorthTerrace, Adelaide, South Australia

REFERENCES

1. Geiler T, Kriegsmann J, Keyszer G et al. A new modelfor rheumatoid arthritis generated by engraftmcnt ofrheumatoid synovia! tissue and normal human cartilagein SCID mice. Arthritis Rheum 1994^7:1664-71.

2. Yoshino S, Cleland LG. Depletion of alpha/beta T cellsby a monoclonal antibody against the alpha/beta T cellreceptor suppresses established adjuvant arthritis, butnot established collagen-induced arthritis in rats. J ExpMed 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 OpinRheumatol 1994;6:281-6.

4. Imhof BA, Dunon D. Leukocyte migration andadhesion. Adv Immunol 1995^8:345-416.

5. Harris ED Jr. Rheumatoid arthritis, pathophysiologyand implications for therapy. N Engl J Med 1990;322:1277-89.

6. Keffer J, Probert L, Cazlaris H et al. Transgenic miceexpressing human tumour necrosis factor: a predictivegenetic model of arthritis. EMBO J 1991; 10:4025-31.

7. Galli Taliadoros LA, Sedgwick JD, Wood SA, KornerH. Gene knockout technology. A methodologicaloverview for the interested novice. / Immunol Methods1995;181:1-15.

8. David CS, Gonzales Gay M, Zhou P et al. Mouse andhuman MHC class II genes H-2A/HLA-DQ mediatesusceptibility while H2-E/HLA-DR molecules mediateprotection in collagen induced arthritis. Lessons forhuman RA. Rheumatol Europe 1995;24{suppl. 2):2-4.

9. Zanelli E, Gonzales Gay MA, David CS. CouldHLA-DRB1 be the protective locus in rheumatoidarthritis. Immunol Today 1995;6:274-8.

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