Search

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in infancy and childhood. Approximately 20 % of patients with JIA suffer from the polyarticular form of the disease, which causes a substantial disease burden and long-term sequelae. Therapeutic approaches have used steroids and conventional disease modifying antirheumatic drugs (DMARD) but over the last decade new drugs have become available for the treatment of JIA, in particular biologic DMARD. This article summarizes the current therapy options for polyarticular JIA.

Transgenic rats with high expression of HLA-B27 and human β(2) -microglobulin (B27TR) develop a multisystem inflammatory disease resembling human inflammatory bowel disease (IBD) and spondyloarthropaties (SpA). Tumour necrosis factor α (TNF-α) has a crucial role in sustaining chronic inflammation in the gut and joints. The aim of this work was to evaluate whether TNF-α blockade could prevent or reduce the inflammation of peripheral joints in B27TR. A first group of 9-week-old B27TR received an anti-TNF-α monoclonal antibody (mAb) or an isotypic IgG2a,k up to the age of 18 weeks. An untreated group was monitored up to the age of 18 weeks and then randomly assigned to a 9-week treatment with anti-TNF-α mAb or IgG2a,k. Each rat was monitored for clinical IBD and peripheral joint manifestations. After sacrifice the colon and hind paws were examined for macroscopical and microscopical pathological changes. Early TNF-α blockade prevented, and late treatment improved IBD signs in B27TR. Erythema, oedema, inflammatory infiltrate close to the tendons and enthesis, proliferating chondrocyte-like cells, signs of new endochondral bone ossification and bone erosion were observed in peripheral joints of four out of six IgG2a,k-treated B27TR, both at 18 and 27 weeks. Immunopositivity for phosphorylated Smad1/5/8 indicated that the process of joint remodelling was activated in B27TR. Some entheses showed chondroid nodules. Anti-TNF-α treatment reduced inflammation and preserved the enthesis organization in most animals. Occasional and transient erythema and oedema were still present in three of six of the late anti-TNF-α-treated animals. Smad1/5/8 signalling was not inhibited by late anti-TNF-α treatment. In B27TR, articular involvement follows IBD onset and develops at entheses. Early TNF-α blockade prevents the onset of IBD and consequently the development of enthesitis in peripheral joints in the B27TR model of human SpA., (© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

There is increasing appreciation of the important role of B cells in many autoimmune diseases and consequently, increasing interest in treating these disorders through B cell-depletion therapy with rituximab, an anti-CD20 monoclonal antibody. Yet, precisely how this and related drugs exert their therapeutic effects remains controversial. In particular, it is unclear how, in a number of contexts, rituximab can greatly reduce the titer of serum autoantibodies without substantially altering the overall antibody titer. We have studied the action of this drug in the K/BxN mouse model of inflammatory arthritis after first crossing in a human CD20 transgene. Rituximab treatment of these mice led to a decrease in the titer of serum antibodies targeting glucose-6-phosphate isomerase, the relevant autoantigen, but not in the total antibody titer. Glucose-6-phosphate isomerase-specific plasma cells did not reside primarily in the bone marrow as expected but rather in the spleen and lymph nodes, where they had short lives, expressed CD20, and were rapidly depleted by rituximab. These data support a model whereby autoreactive plasma cells (at least certain specificities thereof) are intrinsically different from protective antimicrobial plasma cells in their differentiation, migration, and survival properties. Rituximab targets the former and spares the latter.

Receptor activator of NF-kappaB (RANK) and its ligand (RANKL) are pivotal regulators of osteoclast differentiation. RANK and RANKL also mediate T cell/dendritic cell (DC) interaction. Previous study has shown that RANK/RANKL interaction induces prolonged DC survival and antigen presentation. In the present study, we have newly established a hybridoma which produces neutralizing anti-RANKL monoclonal antibody (IK22-5). By treating collagen-induced arthritis (CIA) mice with IK22-5, we have investigated the role of RANKL in the pathogenesis of CIA. Although IK22-5 had no effect on immune responses or inflammation, it ameliorated bone loss at the site of inflammation. Histological analyses revealed that osteoclast formation was impaired at the site of joint inflammation in IK22-5-treated CIA mice. These results suggest the utility of anti-RANKL mAb for the prevention of osteoporosis associated with joint inflammation in RA.

The isolation of an anti-C5 single-chain fragment variable (scFv) antibody, TS-A12/22, from a human phage display library, is described. This antibody inhibits the activation of C5 and the assembly of the terminal complement complex implicated in cell and tissue damage. Using antibody-sensitized sheep erythrocytes and rabbit red cells as target cells in hemolytic assays, we found that TS-A12/22 inhibited the activation of C5 by the convertases of both classical and alternative pathways. Western blot analysis and competition experiments with synthetic peptides showed that TS-A12/22 reacted with the alpha chain of C5 and recognized the cleavage site of this complement component by the C5 convertase. As a result, the antibody prevented splitting of C5 and inhibited the generation of C5a and of the terminal complement complex. The identification of the TS-A12/22 recognition site as a conserved sequence in man, mouse, rat and rabbit enabled the demonstration of in vitro inhibition of complement activity in these species. The scFv TS-A12/22 was tested in a rat model of antigen-induced arthritis and proved to be effective in preventing influx of polymorphonuclear cells into the knee joint and C9 deposition on synovial tissue.

Immunization of DBA/1 with 100 microg bovine collagen type II emulsified in Freund's adjuvant, followed by booster injection in incomplete adjuvant at 18 days, leads to development of arthritis in more than 70% of mice by 28 days postinjection. We have previously shown that the novel immunosuppressant molecule CD200Fc (linking an extracellular domain of CD200 with a murine IgG2a Fc region) can suppress induction of disease when given to mice from the time of collagen injection. This occurs in concert with a decrease in the serum levels of anti-collagen IgG ( approximately 50% reduction), with relatively more IgG2b and IgG3, decreased serum levels of TNFalpha and IFN-gamma, and decreased production of those same cytokines after restimulation of lymphocytes in vitro with collagen. Since CD200 induces suppression following engagement of a receptor (CD200R), known to be expressed on, among other cells, macrophages, we investigated whether infusion of anti-CD200R and/or CD200Fc would ameliorate established disease in DBA mice, when injections were begun following collagen immunization. Our data indicate an arrest of disease following either treatment, with modification of a number of immune parameters (serum and lymphocyte cytokine production) consistent with a general role for CD200:CD200R interactions in the regulation of induction and/or expression of autoimmune disorders. When a higher dose (250 microg/mouse) of anti-CD200R was infused into a group of overtly arthritic mice, a significant ( approximately 50%) decrease in arthritic joint score occurred over the 4-week treatment period.

Injection of anti-type II collagen Ab and LPS induces arthritis in mice. The levels of IL-1 beta, IL-6, and chemokines (macrophage inflammatory protein (MIP)-1 alpha, MIP-2, and monocyte chemoattractant protein-1) in the hind paws increased with the onset of arthritis and correlated highly with arthritis scores. The level of TNF-alpha was also elevated, but only transiently. Quantitative real-time PCR analysis revealed increases in cytokine and chemokine mRNA. To elucidate the contribution of inflammatory cytokines and chemokines in arthritis development more directly, recombinant proteins, neutralizing Abs, and knockout mice were used. The injection of rIL-1 beta or TNF-alpha, but not IL-6 or chemokines, induced arthritis when mice were i.v. preinjected with anti-type II collagen Ab. However, a single injection of recombinant cytokines or chemokines into the hind paws did not induce swelling. Arthritis development was inhibited by neutralizing Ab against IL-1 beta, TNF-alpha, or MIP-1 alpha. In contrast, the inhibitory effect by anti-MIP-2 Ab was partial and, surprisingly, Abs to IL-6 and monocyte chemoattractant protein-1 showed no inhibitory effect. Furthermore, arthritis development in IL-1R(-/-) mice and TNFR(-/-) mice was not observed at all, but severe arthritis was developed in IL-6(-/-) mice. These results suggest that IL-1 beta and TNF-alpha play more crucial roles than IL-6 or chemokines in this model. Because arthritis was also developed in SCID mice, the development of arthritis in the Ab-induced mice model is due to a mechanism that does not involve T or B cells.

We investigated a role for interleukin-4 (IL-4) in suppression of T-cell-mediated antigen-induced arthritis (AIA) in mice by oral administration of the inducing antigen. For this investigation, a monoclonal antibody (11B11 mAb) that specifically neutralizes IL-4 was employed. AIA was induced by immunization with methylated bovine serum albumin (mBSA) (day 0) followed by intraarticular injection of mBSA into the ankle joint. To induce oral tolerance, mBSA was administered orally once a day from day-5 to-1. The 11B11 mAB was injected i.p.. 30 min before each oral administration of mBSA. Oral administration of mBSA resulted in marked suppression of AIA. Suppression of the joint inflammation of the oral antigen was significantly diminished by treatment with 11B11 mAb. The mAb treatment was also followed by blockade of suppression of proliferative responses of lymphoid cells to mBSA by oral antigen. Furthermore, secretion of IL-4 was significantly increased following oral administration of mBSA and the increased IL-4 secretion was markedly reduced by treatment with 11B11 mAb. There was a decrease in production of IFN-gamma in orally tolerized mice that was blocked by the IL-4-neutralizing mAb. Thus, treatment with an anti-IL-4-mAb appears to be effective in blocking suppression of AIA by oral administration of the inducing antigen. The results also suggest that IL-4 may play a role in down-regulation of T-cell-mediated inflammation by feeding pathogenic antigens.

Oral administration of type II collagen (CII) has been shown to suppress collagen-induced arthritis (CIA) in experimental animals. However, the exact mechanism by which CIA is suppressed following administration of CII remains to be investigated, although it was demonstrated that active suppression by regulatory T cells might be involved in the suppression. Therefore, we have examined whether the inhibitory cytokine IL-4 plays a role in the suppression of CIA, by using an anti-IL-4 mAb (11B11 mAb). Mice were fed daily with CII over a period of 10 days before immunization with CII. 11B11 mAb was i.p. injected 30 min before each oral administration of CII. The results showed that treatment with 11B11 mAb markedly blocked suppression of CIA by the oral Ag. The blockade of suppression of CIA by the anti-IL-4 mAb was associated with the blockade of augmentation of IL-4 secretion in CII-fed mice. The treatment with 11B11 mAb also resulted in the prevention of decreases in anti-CII IgG2a Ab production, DTH responses to CII, proliferation of lymphoid cells to CII, and IFN-gamma secretion in mice given CII orally. Thus, the neutralization of IL-4 by an anti-IL-4 Ab appears to be effective in blocking suppression of CIA by oral administration of CII, suggesting that IL-4 may be critically involved in its suppression.

Mercuric chloride (HgCl2) induces a T cell-dependent autoimmune syndrome in Brown-Norway (BN) rats characterized by a humoral response, tissue injury with an accumulation of CD8+ and CD4+ T cells, and an increase in tissue IL-4 mRNA and serum IgE suggesting Th2 cell activation. In other models of autoimmune disease, CD8+ cells act in both anti- and pro-inflammatory capacities, suggesting that functionally distinct CD8+ populations exist in vivo. The effect of treatment with OX8, a depleting anti-CD8 MoAb, on the initiation of HgCl2-induced autoimmunity was assessed in two experiments in a total of 20 BN rats, and compared with 20 animals treated with a control MoAb or PBS. OX8 significantly depleted peripheral blood CD8+ lymphocytes, had no effect on HgCl2-induced anti-collagen or myeloperoxidase antibodies, nor on the incidence or severity of caecal vasculitis. The severity of HgCl2-induced arthritis was significantly reduced in OX8-treated animals; median peak score reduced from 7.5 to 3.0 (experiment 1) and from 7.0 to 4 (experiment 2) (P = 0.009, Mann-Whitney U-test). OX8 treatment also exacerbated the early rise in HgCl2-induced IgE and induced a significant rise in plasma interferon-gamma (IFN-gamma), suggesting that CD8+ cells may have a regulatory influence on Th cell populations. These data provide direct evidence that CD8+ cells may act in a proinflammatory capacity in both this model of autoimmunity and the pathogenesis of inflammatory arthritis.

Autoimmune MRL/lpr mice were treated for 12-14 weeks with anti-CD4 monoclonal antibody to define the role of CD4+ T cells in the pathogenesis of the inflammatory central nervous system (CNS) lesions, arthritis and sialadenitis characteristic of the strain. Anti-CD4 therapy effectively prevented the development of CNS lesions and arthropathic changes. Marked depletion of CD4+ T cells was documented in the mononuclear cells infiltrating the major salivary glands but the severity of sialadenitis was significantly increased by chronic anti-CD4 immunotherapy. This dissociation between beneficial and harmful effects of anti-CD4 treatment in the MRL/lpr mouse suggests that the net regulatory effect of CD4+ T cells on the underlying autoimmune-mediated inflammatory process may be positive or negative depending on the organ system involved. The pathogenetic mechanisms of inflammation and tissue destruction in this model of systemic autoimmune disease are in some instances target organ-specific.

Collagen induced arthritis (CIA) is an animal model of inflammatory polyarthritis. Type II collagen is the major matrix protein of hyaline cartilage. Susceptibility to CIA is linked to the Major Histocompatibility Complex Class II genes but the presence of T cells expressing specific variable beta (V beta) chain of their T cell receptor (TCR) is also required. Pretreatment with the monoclonal antibody H57-597 directed against the TCR alpha beta framework prevented the onset of arthritis in the majority of animals. The depletion of the T cell population did not lead to any apparent health problems. These experiments demonstrate the important role of the alpha/beta T cell and its receptors in the CIA model. Further, anti-TCR alpha beta antibodies may be of value in the therapy of autoreactive disorders.

Rats treated with an mAb (R73) against the TCR-alpha beta failed to develop chronic persistent arthritis after injection of streptococcal cell walls. Histologically, R73 mAb-treated rats had mild hyperplasia of synovial lining cells and minimal destruction of cartilage. In contrast, control-treated animals developed marked pannus formation, with pronounced infiltration of mononuclear cells and severe destruction of cartilage and subchondral bone. The preventive effect of R73 mAb on streptococcal cell wall-induced arthritis was associated with the marked depletion of alpha beta + T cells by R73 mAb. These results indicate that T cells play a crucial role in chronic erosive streptococcal cell wall-induced arthritis.

Activation of T cells is critical for the development of type II collagen (CII)-induced arthritis (CIA). However, the relative importance of T cells in their delivery of help to B cells, promoting autoantibody formation or acting as inflammatory initiating cells, is unclear. The effect of a monoclonal antibody directed to the alpha/beta T cell receptor (TcR) on the development of autologous CIA was studied. Two weeks after immunization with autologous CII the onset of severe arthritis occurred, followed by a chronic arthritis activity in the peripheral joints. Anti-TcR treatment before immunization suppressed the incidence of arthritis and the autoantibody response to CII. Treatment given immediately before the expected onset delayed the appearance of arthritis. Treatment given to already arthritic rats reduced the severity. In the latter two groups the serum levels of anti-CII autoantibodies were not affected. The duration of the ameliorating effect was limited and with the return of arthritis a concomitant antibody response towards the injected mouse anti-TcR antibody was observed. These results show that the role of T cells in both the induction and perpetuation of CIA is essential and not limited to the triggering of production of pathogenic anti-CII autoantibodies.

Monoclonal anti-idiotypic antibodies previously shown to react with a cross-reactive idiotope of anti-collagen II auto-antibodies were used for in vivo treatment of DBA/1 mice receiving immunization with arthritogenic native rat collagen type II. Injection of 100 micrograms of the anti-idiotypic antibody 3 weeks before the collagen immunization resulted in a significant suppression of collagen arthritis, compared with mice treated with a monoclonal control antibody. The treatment with anti-idiotypic antibody 3 weeks before collagen immunization could also cause a marked down-regulation of the total serum levels of anti-collagen II antibodies. When the anti-idiotypic antibodies were administered near the time for induction of arthritis (2 days after collagen immunization) a significant effect was seen on the collagen arthritis, but not on the levels of anti-collagen antibody. As collagen-induced arthritis is a disease where both T- and B-cell mediated immunity are believed to play critical roles, the present effects of the in vivo anti-idiotype treatment on arthritis development could provide an interesting system for the study of idiotype regulation on both B- and T-cell arthritis-associated autoimmunity.