animal model-ra therpy

Current Rheumatology Reviews, 2008, 4, 277-287 277

1573-3971/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd.

What Animal Models are Best to Test Novel Rheumatoid Arthritis Therapies?

Paul H. Wooley*

Orthopaedic Research Institute, Via Christi Healthcare System and Wichita State University, Wichita, KS, USA

Abstract: The relevance of animal models of rheumatoid arthritis and their relationship to the development of anti-

arthritic therapies is reviewed in depth. Different mechanisms for the induction of experimental arthritis, including

infectious processes, non-specific inflammation, autoimmune responses to cartilage components, and genetic

manipulation are discussed in context of pathological pathways relevant to rheumatoid arthritis. A variety of species,

including rats, mice, dogs, pigs, and monkey are examined for advantages and drawbacks in preclinical development of

anti-arthritic agents, and their capacity to mimic critical aspects of arthritis pathology. The history of anti-arthritic therapy

from non-steroidal anti-inflammatory agents to biological response modifiers is placed in context with the evolution of

animal models of arthritis. The potential of novel models based upon targeted gene manipulations and corresponding

pathway-specific drugs is examined as a new approach to identifying therapies relevant to rheumatoid disease.

Keywords: Adjuvant-induced arthritis, collagen-induced arthritis, rheumatoid arthritis, streptococcal cell wall arthritis, transgenic mouse.

INTRODUCTION

The question of the best animal model of rheumatoid arthritis (RA) has endured for decades, and is a pressing issue for major pharmaceutical companies, start-up biotechnologies, the FDA and basic researchers studying the pathophysiology of arthritis. There is, of course, no easy answer. First, no model truly resembles RA with respect to the complete pathology, immunology, and cellular biology of the human disease. Secondly, rheumatoid arthritis is not a monolithic disease entity, but rather a syndrome that varies widely from patient to patient with no reliable indications of the disease etiology. The many variations seen in clinical RA raise the question as to whether we are actually investigating a single disease entity, or a spectrum of signs and symptoms that may be loosely grouped together as an inflammatory, erosive joint disease with unknown origins. So the question must be rephrased when a novel therapeutic strategy for RA is considered for pre-clinical development. The query becomes: Is the pathological pathway targeted for therapeutic manipulation relevant to rheumatoid disease? If so, which animal model is most relevant to this pathological pathway?

RELEVANT PATHOLOGICAL PATHWAYS IN ANIMAL MODELS OF RA

One useful feature of most animal models of arthritis is that we do understand much of the underlying pathology of the joint disease. These mechanisms can be considered in four major categories:

*Address correspondence to this author at the Orthopaedic Research

Institute, 929 North St. Francis, Wichita, Kansas 67214, USA; Tel: 316

268 5486; Fax: 316 291 4998; E-mail: [email protected]

Infectious Arthritis and Reactive Arthritis

There are viruses, bacteria, and mycoplasma that have been identified as causative agents in animal arthritis. Although an infectious etiology for rheumatoid arthritis has not been demonstrated, infectious and reactive arthritis are well recognized in humans, and a pathogenic agent cannot be completely ruled out in playing a role in RA. Second, the immune response against pathogenic organisms can result in a joint disease, termed reactive arthritis in patients. There are several convincing models of this mechanism that have been demonstrated in animals.

Autoimmunity to Joint Components

The most widely recognized example of this mechanism is type II collagen-induced arthritis, although responses to cartilage proteoglycans can provoke a similar joint disease. These models do not arise spontaneously, but require immunization using adjuvants to provoke an aggressive immunological response to cartilage components.

Non-Specific Inflammatory Stimulants and Immune Reactions

Adjuvant-induced arthritis (AIA) and pristane-induced arthritis (PIA) are the classic models related to inflammatory stimuli. Adjuvant arthritis is essentially confined to rats, and represented the ideal model for the development of COX inhibitors. The extreme sensitivity of the model to COX inhibitors can be argued as a weakness of this model: since this compound class can ‘cure’ the rat arthritis, but not the human condition, it is likely that the overall mechanism in AA is distinct from RA. Animals with PIA exhibit a broad range of autoimmune responses, which is a curious sequel to a non-specific stimulus, and therefore may also represent a model of systemic lupus erythematosous. The mechanism by which non-specific inflammation provoked by a mineral oil results in rheumatoid factor, anti-collagen antibodies, and hyper-gammaglobulinemia remains unclear. AIA is non-specific

278 Current Rheumatology Reviews, 2008, Vol. 4, No. 4 Paul H. Wooley

immune response within the joint can also result in inflammatory, erosive disease. Induction of this model requires systemic immunity established by repeated immunization against a soluble antigen (typically a foreign serum albumin), and then joint inflammation is induced by intra-articular challenge with the antigen. Arthritis is confined to the injected joint, and this model can be established in most laboratory animal species.

Transgenic Manipulation of Genes Relevant to Inflammatory and Immune Responses

Transgenic animals represent a powerful tool when considering appropriate models for developing biological response modifiers. The use of the TNF transgenic mouse in the development of TNF inhibitors represented a milestone in novel strategies of pre-clinical research. In this instance, Keffer et al. [1] demonstrated that unregulated production of TNF in transgenic mice resulted in a realistic inflammatory joint disease. This was accompanied by surprisingly little tissue inflammation in the major organs, although the mice exhibited signs of cachexia and died early in life. This model was ideal for the pre-clinical development of anti-TNF therapies, particularly infliximab, since treatment of the transgenic mice with this anti-TNF construct also permitted an extension of the lifespan and facilitated breeding. Several other transgenic mouse strains have exhibited joint disease, and some might not have been predicted to exhibit signs of arthritis from the genetic material under modification. Notably, the K/BxN transgenic strain fits this category. This category could also consider the chimeric model established by surgical implantation of RA tissue into immunodeficient animals. Although this does not provide a model of an arthritic joint, it does represent a potential model to examine of drug effects in viable human synovial tissue.

SELECTION OF AN APPROPRIATE ANIMAL SPECIES

In general, the FDA prefers the demonstration of pre-clinical anti-arthritic effects in two animal species prior to NDA approval. With the proliferation of murine collagen arthritis and transgenic mouse strains tailored to the proposed mechanism of action, it is common that mice will occupy one of the requisite species. It is then considered preferable to avoid rats (due to the overwhelming similarities in biology, toxicology, etc) as a second species, which can lead to a difficult choice to fulfill the development requirement. Ideally, primates would serve as the closest relevant species to humans, and if cost containment presents no obstacle, primate models are available. Squirrel monkeys, rhesus monkeys and cerebus monkeys have all been reported to develop collagen-induced arthritis [2, 3], and the resemblance to the patho-logy of RA is fairly good. The systemic reaction to immunization in primates (which may be related to the use of complete adjuvant rather than actual autoimmunity to type II collagen) appears to be very severe, and early reports contained descriptions of debilitating and cachetic effects. Despite these initial difficulties, and the fact that primate use is frequently prohibitory expensive and a

minority of animal facilities can serve as primate centers, there are several successful reports of primate use in novel therapy development. Brok et al. [4] reported on the trial of Daclizumab (a humanized monoclonal antibody against the -chain of the CD25 IL-2 receptor) using CIA in rhesus monkeys. When Daclizumab treatment was commenced before the onset of CIA, a significant reduction of inflammation and joint erosion was observed. In a therapeutic protocol, joint-degradation was abrogated, and the overall trial indicated positive pre-clinical findings. Yamamoto et al. [5] recently reported on the treatment of CIA in cynomolgus monkey using a chimeric anti-osteopontin antibody. Blocking of the interaction of a cryptic epitope within osteopontin with its integrins has been show to inhibit CIA in mice, and a murine monoclonal antibody specific for a cryptic epitope of human osteopontin, fused with human IgG1 constant region (C2K1) was shown to ameliorate established collagen-induced arthritis in cynomolgus monkeys. Inhibition of joint swelling by C2K1 was observed at 4 to 5 weeks after onset of arthritis, coincidental with peak blood levels of C2K1. Joint swelling reappeared following a sharp decline of C2K1 blood levels at 6 weeks. However, erosion of bone and cartilage in joints was still significantly reduced, and this novel approach to therapy appears promising. Vierboom et al. [6] used CIA in rhesus monkeys to test a small molecular weight antagonist of CCR5 (SCH-X). Treatment was initiated on the day of CIA induction and continued for 45 days. Monkeys were monitored for signs of clinical arthritis and markers of inflammation and joint degradation. Two of five animals in the SCH-X-treated group displayed prominent soft-tissue swelling, compared with all 5 saline-treated monkeys, and SCH-X treatment resulted in an suppression of the C reactive protein acute-phase reaction, a reduction in the excretion of cartilage breakdown products and blocking of the erosion of joint cartilage: Overall, the use of a CCR5 antagonist appears to have potential for treatment of active RA. Saito et al. [7] have used cynomolgus monkeys with collagen-induced arthritis to examine the tissue distribution of R-125224 (a humanized anti-human Fas monoclonal antibody), and discovered a high signal in the bone marrow, thymus, lungs, liver, adrenals, spleen, ovaries, axillary lymph node and mesenteric lymph node compared to the signal in plasma. Although the experiment demonstrated that R-125224 cross-reacted with the monkey Fas antigen, the influence on arthritis was not the focus of this study. Feasibility studies for gene therapy in primate CIA have also been published by Bessis et al. [8]. In addition to the close genetic relationship of primates to humans, the physical size of most monkeys is a considerable advantage if an intra-articular injection is the most pertinent mode of administration. In this report, cell cultures of skin fibroblasts were transfected with a plasmid carrying the lacZ gene, and then injected into metacarpophalangeal, metatarsophalangeal, and interphalan-geal joints. Synovial tissue X-gal labeling showed significant reporter gene activity in transfected cells up to 6 days after intra-articular injection. These are clearly early indications, and considerable work remains to perfect a sustained but controllable vector expression system to develop an anti-arthritic gene therapy approach. Primates have also been employed to address potential side effects of biological response modifiers, since the capacity to develop an adverse immune response against the protein therapeutic (however well engineered) remains a constant problem. Rojas et al. [9]

Novel Rheumatoid Arthritis Therapies Current Rheumatology Reviews, 2008, Vol. 4, No. 4 279

used cynomolgus monkeys to assess the in vivo formation, distribution, and elimination of immune complexes resulting from a low-level immune response to Infliximab (IFX), a chimeric IgG1 monoclonal antibody to TNF . They observed a rapid formation of immune complexes comprised of IFX and radiolabeled anti-IFX IgG antibody, with a terminal half-life of approximately 38 hours compared with 86 hours for a non-immune antibody control. There were no macroscopic or microscopic histological findings, but the results indicate that immune complexes between IFX and anti-IFX IgG antibodies do form in vivo. This experiment was not conducted during the treatment of primate CIA with IFX, and therefore may not accurately represent the risk of a response to the biological response modifier during an ongoing autoimmune disease. However, the study illustrates the potential of this approach for risk assessment, as well as therapeutic evaluation, using animal model systems.

Given the desire for a non-rodent model of arthritis with a large synovial joint, it is perhaps surprising the porcine models have not been thoroughly investigated, particularly since mini-pigs and micro-pigs are attractive alternatives to large animal husbandry [10]. Beyond one early description of carrageenin-induced arthritis in the SPF pig [11], reports on porcine arthritis have been confined to infectious joint disease [12, 13] and no commonly accepted model of rheumatoid disease has emerged. Caprine encephalitis/arthritis due to lentiviral (CAEV) infection [14, 15] is an intriguing model that has undergone steady investigation for two decades, but studies are currently focused upon the molecular mechanisms underlying the viral activity [16, 17]. Although there are no current publications on the effects of anti-arthritis therapies in this model, there are reports that indicate the participation of TNF [18], IL-16 [19] and nitric oxide [20] in the pathology of CAEV arthritis.

The existence of canine rheumatoid arthritis (CRA) has been recognized for decades [21, 22], but is considered to arise spontaneously and no breed of “RA susceptible dog” has been established for experimental purposes. Ohashi et al. [23] have shown that antigen-induced arthritis may be elicited in the joints of beagles sensitized and challenged intra-articularly with bovine serum albumin, but this model has not been further developed for pre-clinical use. Early studies of anti-arthritic therapy of spontaneous canine RA made an important observation; while cytotoxic agents are effective in canine RA, COX inhibitors are contraindicated due to safety concerns [24]. The presence and significance of canine rheumatoid factor remains controversial, although the preponderance of publications suggested that most canine RA is seropositive [25-28]. Inflammatory cytokines appear to contribute to the joint disease [29], elevated levels of MMP-9 [30], MMP-3 and TIMP-1 [31] in arthritic joints have been described, and antibodies to both type II collagen [32] and heat shock proteins [33] have been reported. The immunohistochemistry of the rheumatoid joint depicts an accurate model of human RA. Hewicker-Trautwein et al. [34] reported that synovial membrane biopsies from dogs with CRA exhibited numerous diffusely and perivascularly distributed CD5

+

lymphocytes in the subsynovium, with CD4+ cells

outnumbering CD8+ cells in the perivascular areas. CRA

resulted in higher numbers of / TCR+ cells compared with

/ TCR+

cells, and a marked increase of MHC class II antigen expression was noted, with 50% to 90% of the synovial lining cells strongly MHC class II

+. Overall, CRA appears to

resemble human RA to a great degree. No structured pre-clinical trials of anti-arthritic agents have been reported in CRA, and although the model appears both accurate and relevant, it would difficult to design a trial given the low frequency of CRA in the dog population, and the absence of an available arthritis breed [24].

Rabbits may provide the best compromise between reasonable joint size and readily available RA model systems when intra-articular joint manipulations are required. For some gene therapy approaches, it may be desirable to obtain synovial cells for culture and ex vivo gene transfection, prior to re-implantation within the synovial cavity to evaluate the therapeutic benefits. The ex vivo approach provides useful information on transfection efficacy, transgene stability, and the rate of target protein production. The rabbit represents the animal with the minimum donor joint size that can provide a reasonable number of synovial cells upon harvest, with strains that exhibit a sufficient degree of inbreeding to alleviate allograft rejection upon re-introduction to a recipient. The majority of researchers utilize AIA in the rabbit, a well documented technique usually employing immunization and intra-articular challenge to mBSA [35, 36], although inflammatory arthritis has been elicited in the rabbit joint via the intra-articular introduction of human gliostatin - platelet-derived endothelial cell growth factor [37], transforming growth factor -2 [38], recombinant human IL-8 [39, 40], Phospholipase A2 (PLA2) enzymes [41] and lipopoly-saccharide (LPS) [42]. A recent evaluation of rabbit AIA has shown a significant concordance between the genes typically seen activated in rheumatoid synovial tissue and joint tissues from rabbits with AIA [43]. Four days after disease induction rabbits were injected with glucocorticoids and 24 hours later synovial tissue, menisci, and cartilage from the knee were collected. Changes in mRNA levels were assessed using reverse transcription-polymerase chain reaction with primers for collagen I, collagen II, biglycan, decorin, matrix metallo-proteinases-3 and -13 (MMP-3 and MMP-13), COX-1 and COX-2, TNF , IL-1 , inducible nitric oxide synthase (iNOS), hyaluronan synthase-2 (HAS-2). While most genes were up-regulated in arthritic tissues, iNOS, HAS-2, COX-1 were down-regulated. Gene activities of collagen II, MMP-3, and MMP-13 were further down-regulated by glucocorticoids in both normal and arthritic tissues, but other genes showed a variety of responses. Overall, the gene activity pattern appeared promising for the evaluation of arthritic events, and the ability to use gene array analysis suggests that this type of approach may permit detailed analysis of the pathways involved in novel therapeutics. Another advantage of the rabbit in RA drug development is the potential for the use of novel formulations that require accurate delivery of a reasonable volume of material within the synovial cavity. The rabbit knee has been recently employed for testing liposome, niosome, lipogelosome and niogelosome formulations of diclofenac sodium [44], and the size of the joint permitted drug retention analysis by radiolabeling with Tc-99m and gamma scintigraphy. The scintigraphic imaging studies revealed that radiolabelled lipogelosome formulation containing DF-Na retained much longer in the experimentally arthritic knee joints


of the rabbits, and appeared to result in improved efficacy. Microsphere delivery of methotrexate has been evaluated using a similar model system [45], and this type of novel technology may improve established therapeutics or permit novel approaches by retaining the active mediator within the joint space, thus both improving efficacy and reducing the chance of unwanted systemic effects. While such a technical approach is theoretically possible in mouse and rat models, the maximum volume that may be injected into a mouse knee using a Hamilton needle and 27g needle that does not result in significant leakage (personal experience using contrast medium) is 25 μl. It would be predicted that the rat knee would retain ~100ul without significant leakage. Intra-articular injection is typically more difficult to accomplish in normal mice compared with arthritic animals, since the distended joints in the latter group provide a larger target. However, the accumulation of synovial fluid during joint edema probably increases the rate of fluid loss from the injected arthritic joint. Due to the limits of experimental accuracy of intra-articular injection in the mouse, the term ‘peri-articular’ injection is preferred to describe the delivery of local factors or gene therapy to the murine arthritis joint [46].

Rabbits also provide an opportunity for minimally invasive procedures in the arthritic joint. Beischer et al. [47] examined a technique for ablating inflamed synovium in joints using photo-dynamic therapy. The photosensitizer Haematoporphyrin Derivative (HpD) was injected into periarticular tissues, and pharmacokinetic studies revealed that inflamed synovium accumulated HpD. Activation of HpD by intra-articular light administration resulted in selective ablation of the inflamed synovium. Histological examination of the knees indicated that selective destruction of inflamed synovium was achieved at light doses 100 joules/cm2 and above. Photodynamic therapy in rabbit AIA was also utilized by Bagdonas et al. [48], who demonstrated the accumulation of endogenously produced porphyrins after administration of exogenous 5-amino-levulinic acid (ALA), with the highest fluorescence intensity of endogenously produced porphyrins occurring in the tissues of the inflamed joints. The authors concluded that this observation supports the application of photodynamic therapy for the treatment of arthritis and the use of optical non-invasive methods based on fluorescence detection of endogenously produced porphyrins for diagnostics of inflamed tissues. It appears that the rabbit model does provide an opportunity to model these types of techniques, which would be extremely challenging in mice and rats. This is supported by the studies of radiation synovectomy in the AIA rabbit model [49], where a rhenium-188 (188Re)-tin colloid improved the macro-scopic appearance and reduced the knee joint diameter, which was consistent with a reduction of the histological score compared to untreated arthritic controls. Yao et al. [50] used rabbit AIA to demonstrate that intra-articular injection of an adenoviral vector expressing human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) stimulated synovial apoptosis and reduced inflammation. Gene transfer of TRAIL induced apoptosis in cells within the synovial lining, reduced leukocytic infiltration and stimulated new matrix synthesis by cartilage. This study [51] was extended using a rabbit arthritis model induced by

intra-articular introduction of allogeneic fibroblasts genetically engineered to secrete human IL-1ß. This novel approach to engineering a pathway-specific arthritis appears highly useful, and demonstrated that recombinant chimeric human TRAIL protein (rTRAIL) also induces apoptosis of proliferating rabbit synovium and reduces inflammation. Apoptosis of the synovial lining was demonstrated using TUNEL analysis, and leukocyte infiltration into the synovial fluid of the inflamed knee joints was reduced by more than 50% following rTRAIL treatment. Apoptosis induction in the rabbit AIA model has also been investigated by Mi et al. [52] using a synovial-targeted transduction peptide, HAP-1, which is able to facilitate specific internalization of protein complexes into human and rabbit synovial cells. HAP-1 and a non-tissue-specific cationic protein transduction domain, PTD-5, were fused to an antimicrobial peptide, (KLAK) [2], to generate two pro-apoptotic peptides termed DP2 and DP1. Intra-articular injection of these peptides into arthritic rabbit joints induced apoptosis of the hyperplastic synovium, and reduced cellular infiltration and synovitis. These publications and other papers indicate that human and rabbit key mediators of inflammation do share sufficient homology to permit effective testing. Podolin et al. [53] examined the effects of a non-peptide antagonist of human CXCR2 that inhibits human IL-8 binding to, and human IL-8-induced calcium mobilization mediated by, rabbit CXCR2 (but not rabbit CXCR1). They concluded that that the rabbit was an appropriate species to examine the anti-inflammatory effects of human CXCR2-selective antagonists, and investigated anti-arthritic activity using experimental arthritis induced by knee joint injection of human IL-8 or LPS, in addition to the AIA model. The antagonist significantly reduced synovial fluid neutrophils, monocytes, and lymphocytes, and levels of the soluble factors TNF , IL-8, PGE2, leukotriene B4, and leukotriene C4.

Despite the overall promising use of rabbit AIA in recent studies, the model also illustrates some of the difficulties of pre-clinical anti-arthritic drug development. Marcinkiewicz et al. [54] investigated the therapeutic potential of taurolidine in various experimental arthritis models of synovitis. Intraperitoneal treatment with taurolin failed to control the development of CIA in mice with high serum level of IgG anti-CII, but intra-articular application of 2% taurolin resulted in amelioration of AIA in all rabbits with a reduced swelling and SAA levels as compared to the control animals. Histopathologic evaluation revealed extensive necrotic lesions of synovial tissue treated with taurolin, suggesting a synoviorthesis-like effect. This paper demonstrates that not only that the appropriate model selection may be key to the evaluation of an anti-arthritic agent, but also the formulation and delivery can be critical in the trial outcome.

SELECTION OF THE APPROPRIATE ANIMAL MODEL

The majority of potential anti-arthritic therapeutic strategies today are driven by targeted ‘mechanism of action’ approaches at the molecular level. This stands in stark contrast to the methods employed two decades ago, when the majority of arthritis drugs were developed by major pharmaceutical companies using classical medicinal chemistry, biochemistry and animal testing. Rheumatoid arthritis was strictly considered as an autoimmune disease (which it still is), and


immunosuppressive agents were the basic class of compounds for preclinical testing. However, there was a major weakness to this strategy since the majority of the compounds under consideration for development were the byproducts of anti-cancer programs. There has never been sufficient evidence to conclude that dose modification of anti-tumor agents would yield a compound capable of both inducing remission in active rheumatoid arthritis, and then being capable of maintaining remission with a low side-effect profile over years of chronic administration. It could be successfully argued that this strategy did yield methotrextrate as a highly effective ant-arthritic agent, but this drug can hardly be considered as side-effect free with chronic administration, and requires considerable patient management on behalf of the rheumatologist. The MOA approach to drug development is not without problems however, particularly with respect to the complex nature of the human disease. In some respects, the more specific the pathway antagonist leveled at RA, the greater the chance that it will only work in a minority of patients. The history of drug development in the available models may provide useful indications for future drug development.

INFECTIOUS ARTHRITIS AND REACTIVE ARTHRITIS

The selection of an infectious model for preclinical use in RA may imply the belief that RA is an infectious disease, a stance that has been highly controversial for many years [55-58] although recently supported by some DNA analysis studies [59-60]. Further, as Wang et al. [61] observed studies directed at the pathogenesis of infectious disease have twice led to the identification of an endogenous mediator of arthritis. In this paper, they promoted HMGB1 (a 30-kD nuclear and cytoplasmic DNA-binding protein which is a necessary and sufficient mediator of lethal sepsis) as a mediator of arthritis because it is produced at the site of joint inflammation, it causes the development of arthritis when applied to normal joints, and therapies that inhibit HMGB1 prevent the progression of collagen-induced arthritis in rodents. However, the use of infectious models to develop agents for RA is uncommon, although a wide variety of organisms may induce joint disease in a broad range of animal species, including rabbits, dogs, pigs, goats, rats, mice and hamsters. Most models employ intra-articular inoculation to establish disease, although some infectious agents may be administered intravenously or via other extra-articular routes to induce arthritis. The infectious agent may be trophic for the joint due to expression of adhesins or other molecules that promote sequestration within synovial tissues [62], or promote selective migration of T cells to synovial tissue [63]. Staphylococcal species produce a range of receptors for connective tissue components, including collagen and fibronectin. Chronic, persistent infection of the joint can generate excessive local antigenic stimulation, resulting in inflammatory and immune complex-mediated reactions. Bacterial cell wall and mycoplasma membrane components may also provide nonspecific immune activation through mitogenic activity [64, 65], and could provide a useful model for strategies designed to target Toll receptor dependant mechanisms. Viral infection of synovial cells, as seen in the CAEV

model, may elicit novel cell surface antigens or abnormal expression of activation antigens and the overproduction of autoantigens such as Hsps. Viral infection may also disrupt immune regulation, increasing pro-inflammatory cytokines and immune activity against the normally immunologically privileged components of the joint. The histologic and radiologic features of CAEV are characterized by progressive lesions consisting of membrane villus hypertrophy with extensive angiogenesis and mononuclear cell infiltration, and a progression to marked erosive changes. Joint disease is accompanied by an immune response to viral surface and envelope glycoproteins, chronic B cell activation, and the accumulation of activated macrophages and CD8

+ T-cells

within the synovium.

Experimental Staphylococcus aureus (S. aureus) arthritis in mice, rats and rabbits illustrates a number of relevant pathways in joint disease [66]. This organism can induce an exudative arthritis in one or more joints, with extensive destruction of articular cartilage and subchondral bone. The initial features of S. aureus arthritis are synovial infiltration by polymorpho-nuclear leukocytes (PMNs) and endothelial-like cells, followed by extensive synovial hypertrophy with marked proliferation by macrophage and fibroblastic cells and infiltration by B and T-cells. Macrophage production of TNF and IL-6 appear to be critical to the regulation of the cellular influx, due to effects upon adhesion molecules and expression of chemokines [67]. Granulomatous tissue with bacterial foci are frequently present in the joint, and extensive cartilage and bone destruction occurs. S. aureus is usually recovered from the joint, and the virulence factors that mediate arthritis may include the profile of capsular polysaccharides, the production of adhesins and the secretion of endotoxins with superantigenic properties (the capacity to activate a broad range of T-cells by direct binding to the Vß portion of the T-cell receptor rather than by conventional antigen presentation). Superantigen involvement in arthritis is also implicated in mycoplasma (M. arthritidis)-induced arthritis in mice. T cell activation by the mycoplasma superantigen appears crucial to the development of arthritis, and may influence disease through cytokine activation and skewing of the normal TH1/TH2 relationship [50, 68].

Persistence of antigens from micro-organism within the joint appears to be critical for the induction of arthritis, particularly for ‘reactive’ arthritis models. Streptococcal cell wall (SCW) arthritis in rats is induced by an aqueous suspension of cell wall fragments injected intraperitoneally in susceptible rat strains. A chronic, erosive polyarthritis results, with a course of remissions and exacerbations, a feature rarely observed in other animal models [68, 69]. The initial arthritis occurs rapidly, with acute inflammation in rear paws peaking approximately 4 days post-immunization. This inflammation recedes, but chronic arthritis recurs between 2-4 weeks, with synovitis, pannus formation and erosion of cartilage and bone. Cycles of remission and exacerbation may persist over several months and culminate in joint fibrosis and ankylosis. The initial acute arthritis is T-cell independent, but requires an intact alternative complement pathway. In contrast, the chronic phase is complement independent, but mediated by T-cell-dependent mechanisms. Disease exacerbations in SCW arthritis may be provoked by the use of several pro-inflammatory cytokines (IL-1ß, TNF , and -IFN), although IL-2 alone does not mediate a flare reaction. SCW arthritis has been used to test several novel therapeutic approaches,


including a secretory leukocyte protease inhibitor (SLPI) that shares the protease-reactive site found in human SLPI [57], selective inhibitors of p38 MAP kinase [58, 70], and N-butyryl glucosamine [61].

CARTILAGE AUTOIMMUNITY MODELS

Collagen-induced arthritis has essentially become the standard pre-clinical development model for anti-arthritic therapies during the last fifteen years. The MHC restricted reaction to the major joint protein resulting in autoimmune joint disease is intellectually attractive, and closely resembles many aspects of RA. T cell directed immunothe-rapy was initiated when cyclosporin was shown to prevent the onset of arthritis and slow the progression of established disease [71]. Targeting specific T cell subsets, based upon observations of skewing of T cell poplations in affected joints [72] has produced inconsistent findings. Immunization agaist Vß peptides using BUB mice elicited antibodies reactive with the self-TCR and prevented the induction of collagen-induced arthritis by eliminating or downregulating pathogenic T cells [73], and antibodies to specific Vß subsets have also been successful in CIA [74, 75], although this finding is not universal [76, 77]. However, CIA was critical for the development of cytokine inhibitors for clinical use in RA. Inhiibtion of IL-1ß using IL-1 receptor antagonist protein (IRAP or IL-1ra) [78] or antibodies to IL-1ß [79] was successful in collagen-induced arthritis, and inhibition of TNF using soluble TNF receptor, recombinant TNF receptor: human Fc fusion protein, or antibodies to TNF all yielded suppression of the clinical aspects of CIA [80-82]. These preclinical findings contributed to the successful development of anti-cytokine therapy for RA [83-85], which has now become the accepted standard of care. Since the delivery of most cytokine inhibitors raises several practical problems and site injection complications, gene therapy is commonly evaluated in CIA [86]. Systemic delivery of a TNF R gene via adenoviral vectors was shown to reduct the severity of collagen-arthritis in rats, but was limited in intra-articular use due to the pro-inflammatory nature of the vector [87]. Systemic delivery of chimeric human p55 TNFR-IgG fusion protein via adenovirus vector to mouse CIA had a short-term beneicial effect [88], and again may have been limited by vector related issues. Recent approaches using the electrotransfer of plasmids encoding cytokine inhibitors [56, 59] and intranasal delivery delivery [89] have circumvented many of the inflammation-promoting properties of the early vectors. It is surprising how readily accomplished nasal delivery was in mice, who appear to instinctively inhale small volumes of fluid placed on the entrance to the nasal cavity. This tendency, and the lack of a gag reflex to expel drugs delivered by oral gavage, are highly useful when considering the appropriate method of drug delivery. There have been several reports of anti-arthtic effects in CIA using gene therapy to deliver IL-4 [90-92], and this strategy may have promise for the treatment of RA. The injection of viral IL-10 via an adenoviral vector carrying the IL-10 gene into paw suppressed the development of collagen arthritis and reduced the progression of disease to non-injected paws. Anti-heterologous CII antibodies were unaffected, but IL-10 suppressed autoantibodies to murine type II collagen

[93]. Vectors containing the murine IL-18 binding protein isoform c gene [94], IL-10 [95], and IL-1ra [96] have been demonstrated to be effective following intra-articular injection using CIA. Gene therapy has extended beyond cytokine inhibition in the CIA model to address specific T cell based therapy. Antigen-specific T cell mediated gene therapy [97] using T-cell hybridomas specific for type II collagen and transduced to express an IL-12 antagonist were tested in collagen immunized DBA/1 mice. The cell transfer was without effect on systemic T and B cells responses to CII, although antigen-elicited IFN production was decreased while IL-4 responses in vitro were augmented. Collagen reactive T cells migrated to inflammed joints, with a subsequent reduction or blockade of arthritis. Recently, TCR / genes from an arthritic paw resident T cell clone autoreactive (but not specific for type II collagen) were tested for therapeutic effects. TCR genes from transduced T cells accumulated in the inflamed paw, and injection of cells cotransduced with the TCR / genes and soluble TNFR-Ig genes resulted in a significant suppression of CIA with reductions in TNF , IL-17, and IL-1ß expression [98]. Thus, it appears that CIA still repesents an excellent overall model for new drug development.

ARTHRITIS MODELS PROVOKED BY NON-SPECIFIC INFLAMMATORY STIMULANTS AND

IMMUNE REACTIONS

Although adjuvant arthritis is usually associated with the development of COX inhibitors, it remains a viable model for novel anti-arthritic therapy [99]. In particular, AA serves as a model for the role of heat shock proteins (HSP) in autoimmune arthritis. HSPs are potential targets for regulatory T cells due to over-expression in inflamed joints, and immunization against hsp affords protection against the induction of AA [100]. Cross-reactivity to microbial HSP has been promulgated in the pathology of RA, and an association between increased expression of HSP and susceptibility to AA has been demonstrated [101]. The injection of anti-CD134 liposomes (directed against T cells that responded to the disease-associated epitope of mycobacterial heat shock protein 60) subcutaneously in the hind paws of AA rats targeted CD4

+CD134

+ T-cells in the popliteal lymph nodes and resulted

in the amelioration of the experimental arthritis. It would therefore appear that AA represents the ideal model to address pre-clinical strategies directed towards hsp based therapies, including such approaches as DNA vaccines [102]. Several other approaches have been recently evaluated in AA, including autologous stem cell transplantation [103], gene therapy based upon artificial chromosome vector systems [104], CCR-5 antagonists [105] and Treg cells (CD4

+CD25

+ T-

cells). Overall, although AA is a somewhat ‘old fashioned’ model of RA, it possesses several autoimmune pathways that are current for drug development. Pristane-induced arthritis, despite its unique autoimmune profile elicited by a non-specific entity, MHC associated susceptibility and excellent pathology, remains somewhat underused in pre-clinical development. This is probably due to the long latency period for arthritis development, although it could be argued that this drawback accurately resembles rheumatoid disease. Despite the lack of popularity compared with CIA, PIA has been successfully used to evaluate anti-arthritis strategies. These include antibodies to CD4 and CD8 [106], anti-TNF [107],


immunization of mice with an immunodominant epitope from heat-shock protein 65 (hsp 65) [108], antibo-dies to Oncostatin M [109] and an extensive evaluation of prednisolone, methotrexate, three nonsteroidal antiinfla-mmatory drugs (celecoxib, diclofenac, and indomethacin), a p38 MAPK inhibitor, SB242235, and human soluble TNF receptor (sTNFR; etanercept) and murine sTNFR fusion proteins [110].

As discussed in the previous section, AIA remains a useful model that can be controlled from the standpoint of joint selection, which can afford some advantages. A recent study [111] has investigated the influence of the phosphodiesterase (PDE) IV inhibitor rolipram, which resulted in the inhibition of early AIA with downregulation of OVA-specific splenocyte proliferation and decreased IFN-gamma release, but no effects on IL-10, or levels of anti-OVA IgG, IgG2a, and IgG1. Other investigations have examined the effects of chondromodulin [112], the natural weak androgen dehydroepiandrosterone [113], and human anti-C5 single-chain Fv (scFv) [114].

ARTHRITIS MODELS FROM TRANSGENIC MANIPULATION OF GENES RELEVANT TO INFLAMMATORY AND IMMUNE RESPONSES

The capability of gene knockout (or positive deregulation) to evaluate the effects of a specific pathway on the susceptibility or resistance to arthritis is a useful tool for evaluating potential pathway specific inhibitors for arthritis. A number of transgenic mouse lines sponta-neously develop arthritis, including mice transgenic for the env-pX region of the human T-cell leukemia virus (HTLV) type 1 genome, which develop a spontaneous chronic arthritis due to T cell responses to the expression of the tax gene [115, 116], knock-in mice (gp130DeltaSTAT/ DeltaSTAT), in which all STAT-binding sites were deleted from their gene encoding gp130 but binding sites for both Janus kinases (JAKs) and for the protein tyrosine phosphatase-2 (SHP-2) were preserved [117], and mice in which the src homology 2 domain-bearing protein tyrosine phosphatase binding site of gp130, tyrosine 759, was mutated to phenylalanine [118]. These models have not been widely disseminated for use in drug development. There are two major tactics that have been employed using transgenic mice:

1) Examination of the transgene effect on collagen-induced arthritis, including the engineering of hybrid mice that express human MHC antigens [119] and, 2) investigation of arthritis in an established transgenic line using passively transferred arthritis. For the latter approach, the development of an effective antibody for the elicitation of arthritis [120] was a byproduct of a serendipitous experiment that yielded an interesting murine model of RA. The K/BxN T cell receptor mouse model appeared when the KRN TCR trangenic mouse was crossed with the NOD (non-obese diabetes) mouse [121]. The progeny from this cross developed a spontaneous, symmetrical arthritis in peripheral joints with a pathology closely resembling RA. Histological features include synovial inflitration, pannus formation, erosive disease and bone remodeling. The critical autoimmune reactivity resides in the specificity of the KRN Vß6 T cell receptor.

Although initially characterized as reactive with a bovine ribonuclease peptide in context of the MHC antigen I-A

k, the

KRN TCR responds to glucose-6-phosphate isomerase (G6PI) in context of the NOD-derived I-A

g7 class II MHC molecule.

This immune recognition gives rise to anti-G6PI autoanti-bodies, which appear to be key in the development of joint disease, since the passive transfer of these antibodies can result in joint disease. The K/BxN model has be used directly for therapeutic development, as illustrated by successful treatment with an angiogenesis inhibitor [122]. However, the use of K/BxN serum to passively transfer arthritis has been used to investigate the effects of other transgenes, and Choe et al. [123] reported that neither IL-1R nor MyD88-deficient mice developed detectable arthritis after transfer of K/BxN sera, and that serum transferred arthritis was not sustained in TLR-4 mutant mice.

The generation of transgenics on a CIA susceptible background requires considerably more time and effort, but has the advantage of examining the entire profile of the arthritogenic response. B10.Q.IL-10(-/-) mice were shown to have increased CIA incidence and more severe arthritis than B10.Q.IL-10 (+/-) littermates [124], suggesting that IL-10 may exert an anti-arthritic effect. Using a similar approach, transgenic mice that harbored the tumor necrosis factor-stimulated gene 6 (TSG-6) under the control of the T cell-specific lck promoter were shown to exhibit reduced susceptibility to CIA [125], mice over-expressing intracellular interleukin-1 receptor antagonist (icIL-1Ra1) or secreted interleukin-1 receptor antagonist (sIL-1Ra) were resistant to CIA induction [126], and DBA/1J mice with mutations of the Perforin (pfp) molecule (DBA/1J-pfp-/-) were less susceptible to CIA [127].

Although not strictly a transgenic model, the SKG mutant strain [128] has recently emerged as a potential model for novel therapeutic strategies. Joint disease occurs due to a spontaneous point mutation of the gene encoding an SH2 domain of the signal transduction molecule ZAP-70 in T cells. The mutation results in changes in the threshold of thymic selection, permitting the survival of autoimmune T cells. Erosive arthritis and joint infiltration occurs after 8-12 months, and is predominantly mediated by CD4

+ T cells. The

autoimmune profile includes production of rheumatoid factors, antibodies to type II collagen, hypergammaglobulinemia, and antibody to hsp-70. Disease may be adoptively transferred by T cells (but not antibody), and there appears to be an environmental factor as gnotobiotic mice do not develop arthritis [129]. Overall, the representation of the broad aspects of RA by a point mutation appears to represent a powerful tool for the analysis of RA, and although cytokines appear to contribute to the pathology [130], no therapeutic studies have been published in this model to date.

However, transgenic mice can also illustrate some of the paradoxes of the etiology of arthritis. Amano et al. [131] demonstrated that mice overexpressing an E3 ubiquitin ligase (Synoviolin/Hrd1) developed a spontaneous arthropathy, but synoviolin/hrd1 (+/-) mice were resistant to collagen-induced arthritis. The authors suggest that this paradox is explained by the enhanced apoptosis of synovial cells, but there is a danger in the over-reliance on transgenic mice to accurately depict the total effects of the gene product under investigation. Despite that cautionary note, it appears that transgenic models provide


a novel means to address the specific mechanism of action of a potential anti-arthritic strategy, and could eventually lead to the ‘best’ model for rheumatoid arthritis.

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Received: December 14, 2007 Revised: January 23, 2008 Accepted: February 22, 2008

animal model-ra therpy

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