Rheumatology Advance Access published February 18, 2016

RHEUMATOLOGY

262

Review

doi:10.1093/rheumatology/kew001

The role of toll like receptors in giant cell arteritis Lorraine O’Neill1 and Eamonn S. Molloy1 Abstract

R EV I E W

Key words: giant cell arteritis pathogenesis, toll like receptors, dendritic cells, vascular inflammation.

Rheumatology key messages . .

Toll like receptors are central to the pathogenesis of giant cell arteritis. Toll like receptor inhibition is a potential novel therapeutic strategy in giant cell arteritis.

Introduction

Toll like receptors

GCA is a common systemic vasculitis of unknown aetiology exclusively seen in individuals over the age of 50 [1]. The superficial temporal artery is most classically involved but any medium or large vessel can be affected. GCA occurs more frequently in women and in those of Northern European decent [2]. A wide variety of systemic, neurological and ophthalmic complications can ensue depending on the vascular territory involved. Irreversible visual loss and stroke are the most devastating consequences of this condition occuring in up to 20 and 7% of cases, respectively [3–7]. The pathological hallmark of GCA is of a granulomatous inflammatory infiltrate, composed primarily of T lymphocytes, macrophages and dendritic cells (DCs) together with multinucleated giant cells, necrotic tissue and fibroblasts [8]. Both innate and adaptive immune mechanisms combine to drive local vascular damage as well as intimal hyperplasia, which ultimately leads to luminal stenosis and occlusion [9, 10]. While the pathogenesis of GCA is incompletely understood, evidence suggests that activation of resident DCs in the adventitia via toll like receptors (TLRs) is a critical early step in the development of GCA [11, 12].

TLRs are a family of transmembrane proteins expressed by cells of the immune system and those tissues exposed to the external environment where they act as a first line of defence and provide an important link between innate and adaptive immunity [13]. To date 10 individual TLRs have been found to be expressed in humans [14–27]. TLRs are considered pattern recognition receptors that recognize molecules broadly shared by microorganisms, pathogen-associated molecular patterns, (PAMPs) or dangerassociated molecular patterns (DAMPs) released from damaged tissue [28]. Individual TLRs are differentially distributed within the cell; TLRs 1, 2, 4, 5, 6 and 10 are expressed on the cell surface whereas TLRs 3, 7, 8 and 9 are intracellular and found on intracellular organelles such as endosomes [29].

1 Centre for Arthritis and Rheumatic Diseases, St Vincent’s University Hospital, Dublin Academic Medical Centre, Elm Park, Dublin, 4, Ireland

Submitted 23 June 2015; revised version accepted 7 January 2016 Correspondence to: Eamonn S. Molloy, Department of Rheumatology, St Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. E-mail: [email protected]

TLR signalling Stimulation of TLRs by corresponding PAMPs or DAMPs initiates a complex series of signalling cascades that ultimately leads to the activation of mitogen-activated protein kinases and NF-kB, which direct a variety of cellular responses. PAMPs include components of the bacterial cell wall as well as bacterial and viral DNA, while DAMPs include intracellular proteins such as heat shock proteins. Different TLRs serve as receptors for different ligands, listed in Table 1. The cytoplamic portion of TLRs is similar to the IL-1 receptor family and is hence termed a toll/IL-1 receptor

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GCA is a common primary systemic vasculitis that results in granulomatous inflammation of medium to large arteries. Both innate and adaptive immune mechanisms combine to drive intimal hyperplasia, luminal stenosis and ultimately occlusion. While the pathogenesis of GCA is incompletely understood, the activation of resident adventitial dendritic cells via toll like receptors (TLRs) appears to be a crucial inciting event. Here we explore the role of TLRs in the pathogenesis of GCA, including their effects on dendritic cell and T cell activation and recruitment, putative infectious triggers for GCA and the potential of TLR inhibition as a novel therapeutic strategy in GCA.

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Lorraine O’Neill and Eamonn S. Molloy

TABLE 1 Toll like receptors and their ligands Exogenous ligand

TLR 1

Bacterial lipopeptides Mycobacteria Lipopeptides Mycoplasma, Gram+ bacteria Peptidoglycan Gram+ bacteria Zymosan Candida albicans Viral dsRNA Synthetic dsRNA – polyinosinic– polycytidylic Lipopolysaccharide – Gram bacteria

Endogenous ligand Disease

TLR 2

TLR 3

TLR 4

TLR 5 TLR 6 TLR 7

TLR 8

TLR 9

TLR 10

Flagellin – flagellated bacteria Bacterial lipopeptides – Gram+ bacteria ssRNA Synthetic – imiquimod, gardiquimod ssRNA Synthetic – resiquimod CpG DNA bacteria/viruses dsDNA Unknown

Heat shock proteins Serum amyloid A Monosodium urate mRNA

References

RA PsA OA AS Gout SLE Scleroderma Sjo¨gren’s syndrome Myositis Vasculitis

2, 3, 4, 2, 4 1, 2, 3, 2, 4, 5 2, 4 7, 8, 9 2, 4, 7, 2,3,4 2, 4, 9 2, 4, 7,

7, 8 4

8

9

[39–44] [45–48] [49–53] [54–60] [61–63] [64–66] [67–71] [72] [73] [74–80]

Fibrinogen Heat shock proteins Serum amyloid A MSU crystals Unknown Unknown RNA siRNA

The assocation of the TLR TIR domain with MyD88 results in the recruitment of members of the IL-1 receptor-associated kinase family, which in turn activate TNF receptor-associated factor 6 leading to activation of the IkB kinase complex ultimately resulting in translocation of NF-kB to the nucleus, which induces target gene expression of pro-inflammatory cytokines [34–37].

Myosin siRNA aPLs DNA

TLRs play an important role in the pathogenesis of many disease processes including vascular inflammation

High-mobility group box protein Unknown

Increased expression of TLRs has been associated with a number of disease processes including sepsis, immunodeficiency and a number of inflammatory and autoimmune conditions including atherosclerosis and ischaemia–reperfusion injury [38], which share common pathogenic mechanisms with GCA. Known TLR associations with rheumatic diseases are outlined in Table 2. Atherosclerosis is now considered an inflammatory process. Immune cells, particularly DCs, macrophages and T cells, are recruited to the vessel wall. The resulting inflammatory cell infiltrate resident in atherosclerotic plaques produces pro-inflammatory mediators, which cause degradation of the elastic fibres within the vessel wall thereby allowing smooth muscle cells to migrate to the intima. The presence of DCs is associated with plaque destabilization and rupture [81–83]. Many of these pathologic mechanisms are relevant to the pathogenesis of GCA. TLRs are expressed on both immune and resident vascular cells crucial to the development of atherosclerosis. In addition, TLRs 2 and 4 play important roles in the recruitment of monocytes and the formation of foam cells, with TLR 2-dependent signalling playing an important role in the induction of inflammation and matrix degradation in atherosclerotic plaques [84].

TLRs are a family of pattern recognition receptors act as a first line of defence against invading pathogens. TLRs 1, 2, 4, 5, 6 and 10 are expressed on the plasma membrane and detect external antigens while TLRs 3, 7, 8 and 9 are expressed on intracellular compartments such as endosomes and detect internalized ligands. TLRs are activated by PAMPs, from various microorganisms or DAMPs, endogenous ligands released from damaged tissue [40–73]. DAMP: danger-associated molecular patterns; PAMP: pathogenassociated molecular patterns; siRNA: small interfering RNA; ssRNA: single stranded dsDNA; TLR: toll like receptor.

(TIR) domain [30]. Recognition of PAMPs/DAMPs by TLRs promotes the recruitment of a number of intracellular TIR domain-containing adaptor proteins, namely myeloid differentiation factor 88 (MyD88), MyD88-adaptor-like/TIRassociated protein (MAL/TIRAP), toll receptor-associated activator of interferon (TRIF) and toll receptor-associated molecules (TRAM) that transduce signals from the TIR domains [31, 32]. TLR signalling consists of at least two distinct pathways, a MyD88-dependent pathway that leads to production of pro-inflammatory cytokines and a MyD88-independent pathway associated with the production of IFN-b and maturation of DCs. The majority of TLRs use the MyD88 pathway, with the exception of TLR 3, which only uses the MyD88-independent pathway. TLR 4 uses both pathways [33].

2

TLR association

b-Defensin

Activation of DCs by TLRs is critical to the pathogenesis of GCA DCs are specialized antigen presenting cells, armed with pathogen recognition receptors particularly TLRs, which

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TLR

TABLE 2 Toll like receptor associations with rheumatic disease

Toll like receptors in giant cell arteritis

FIG. 1 Activation of toll like receptors is critical to the pathogenesis of GCA

act as potent T cell activators thereby directing the immune response against invading pathogens [85, 86]. A resident population of myeloid DCs can be found in the adventitia of all medium and large arteries [86]. In noninflamed arteries, adventitial DCs are immature and quiescent and are not recognized by alloreactive T cells. However, triggering by TLRs breaks this self tolerance and induces DC activation (as evidenced by CD83 expression) with subsequent recruitment, activation and retention of T cells within the vessel wall [87]. In this section, the role of DC activation in GCA pathogenesis is discussed. This is supported by the observation that the administration of anti-CD83 antibodies effectively suppresses vascular inflammation in GCA. Temporal artery severe combined immunodeficient (SCID) mouse chimeras when treated with anti-CD83 antibodies have a marked reduction in the inflammatory infiltrate present within the vessel wall and significantly decreased production of INF-g and IL-1b [87]. In GCA, a 5- to 10-fold increase in the number of adventitial DCs is seen. These DCs acquire the CD83

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activation marker and in addition to their presence in the adventitia, these activated chemokine-producing DCs also migrate into the media and form part of the granulomatous inflammatory infiltrate [87, 88] (Fig. 1). TLRs possess the ability to activate DCs and sequences for TLR 2 and TLR 4 have been found on a number of medium and large vessels, including the temporal artery [89]. In a SCID mouse chimera model, Ma Krupa et al. [87] engrafted normal human temporal arteries onto SCID mice and exposed the mice to a number of mediators known to activate DCs. Stimulation with lipopolysaccharide (LPS) (a TLR 4 ligand) and complete Freund’s adjuvant (a TLR 2 ligand) induced DC differentiation and maturation. Maximum DC activation was seen following administration of LPS, resulting in production of chemokine (C–C motif) ligand (CCL) 21, CCL 19, CCL 18 and IL-18 [87]. These DCs were strongly positive for the activation marker CD83. Both CD83 and CD86 promote T cell recruitment via IL-18, a pro-inflammatory cytokine from the IL-1 family that mediates both Th1 and Th2 responses [90] and that in combination with IL-12 has been shown to induce IFN-g

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The adventitia–media border of all medium to large vessels contains a resident population of dendritic cells (DCs), which express a family of pathogen recognition receptors known as toll like receptors (TLRs). Binding of endogenous or exogenous ligands (P) results in DC activation, maturation and migration to the media where DCs produce chemokines and promote T cell activation and recruitment. Once matured, DCs are now trapped in the granulomatous lesions in GCA where they continue to provide stimulatory signals to T cells via the CD86 co-stimulatory molecule, further propagating vascular inflammation.

Lorraine O’Neill and Eamonn S. Molloy

Different TLR ligands induce distinct patterns of vascular inflammation Deng et al. [94] investigated the role of TLRs in vascular inflammation by stimulating temporal arteries in organ culture with a panel of TLR ligands. Marked upregulation of CD83 was observed following stimulation with LPS (TLR 4 ligand) and flagellin (TLR 5 ligand). Agonism of TLRs 3 and 9 failed to elicit a temporal artery response. Lipoteichoic acid, a TLR 2/6 agonist, did increase DC activation, but much less so than LPS or flagellin. However, it has been noted in other settings that lipoteichoic acid differs from other TLR2 agonists in the kinetics of TLR2 pathway activation with a reduced ability to recruit leucocytes in vivo [95]. The responses to LPS and flagellin were further explored by Deng et al. [94]. The exposure of temporal arteries to LPS and flagellin in both organ culture and in the SCID mouse chimera model, where temporal artery sections from a single donor were engrafted onto multiple SCID mice with subsequent adoptive transfer of allogenic CD4 T cells, resulted in significant T cell recruitment and in situ activation. Both LPS and flagellin were equally effective in stimulating T cells. However, flagellin stimulation resulted in T cell accumulation in the adventitia causing a perivascular inflammatory infiltrate while LPS produced a transmural pattern of inflammation [94]. These data suggest that, in addition to triggering the inflammatory cascade, pathogens may potentially direct the adaptive immune response and induce distinct patterns of vasculitis via TLR activation. Different patterns of vascular inflammation have been reported in temporal artery biopsy specimens from GCA patients, even within the same artery [96] and adventitial inflammatory infiltrates have been reported in patients with PMR without clinical evidence of GCA [97]. It is conceivable, therefore, that differential TLR activation may influence the progression from PMR to GCA and the variable histological patterns observed in GCA patients.

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A number of infectious agents have been associated with GCA Involvement of a variety of infectious agents as potential triggers has been frequently proposed in the pathogenesis of GCA. The increased prevalence in Northern Europe together with both seasonal and cyclical variations in incidence patterns observed in some cohorts is suggestive of an environmental trigger. The key role of TLR-mediated DC activation in establishing vascular inflammation in GCA, as discussed above, generates the obvious hypothesis that PAMPs derived from one (or more) infectious agents may initiate TLR activation and thereby trigger the onset of GCA. Resident DCs may respond to a wide array of infectious stimuli depending on their TLR profile. However, to date no definite causative organism has been found [2, 4, 98, 99]. Distinct peak incidences of GCA and PMR in a Danish cohort were associated with epidemics of Mycoplasma pneumoniae (a TLR 1/2/6 ligand [100]) infection [99]. Wagner et al. [101] in 2000 identified Chlamydia pneumoniae (a TLR 2/4 ligand), via PCR and/or immunohistochemistry in the temporal arteries of eight patients in a cohort of nine with biopsy-proven GCA. None of their nine control patients tested positive. Chlamydia pneumoniae was identified in the adventitia and in 95% of cases was found to co-localize with DCs [102]. A number of subsequent larger studies, however, failed to demonstrate C. pneumoniae in temporal artery specimens of patients with GCA [103–105]. Varicella-Zoster virus (VZV) (a TLR 2/ 9 ligand) [106, 107] remains of interest in GCA both as a potential trigger and as a mimic with VZV-induced vasculopathy presenting in a similar fashion to GCA [108]. The search for VZV in the temporal arteries of patients with GCA has also yielded conflicting results. The majority of studies have failed to identify VZV in temporal arteries of patients with GCA or have identified VZV in low quantities in a minority of patients [103, 109–114]. However, a recently published study detected VZV antigen in 61/82 patients (74%) with biopsy confirmed GCA, with VZV detectable in only 1/13 (8%) normal temporal arteries. VZV antigen was mostly found in the adventitia followed by the media and intima [115]. It is also conceivable that in the pathogenesis of GCA, TLRs are activated by endogenous rather than exogenous ligands. We have recently reported that acute-phase serum amyloid A, an endogenous TLR2 ligand, has proinflammatory and pro-angiogenic effects in an ex vivo temporal artery culture model [116]. Further research is underway to establish whether these effects are mediated via TLR2 activation.

TLR 4 polymorphisms and GCA In addition to environmental triggers, various genetic factors have been associated with GCA. Given the potential role of TLR4 in the pathogenesis of GCA, a number of studies have addressed the possibilty of an association between TLR4 polymorphisms and GCA susceptibility. Palomino-Morales and colleagues [117] obtained blood

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production in Th 1 cells [91]. CCL 19 and CCL 21 are important factors in the maturation of DCs and indirectly induce T cell responses [92]. CCL 18 in particular is thought to contribute to the recruitment of naive T cells [88]. In another model of GCA, bioartificial arteries were engineered by embedding human vascular smooth muscle cells into type 1 collagen matrix. The resulting three dimensional tubular constructs were incubated with immature DCs, which migrated into the tubes but took up residence in the outer vascular smooth muscle cell layer, only thereby mimicking the in vivo environment. Stimulation with LPS doubled the fraction of activated CD83 + DCs present [93]. In a human artery in vitro culture model, stimulation with LPS for 24 h resulted in upregulation of DC activation markers, CD83 and CD86. Denudation of luminal endothelial cells in this model had no effect on TLR 4-induced DC activation, whereas removal of the adventitia and its resident DC population abrogated the effects of TLR 4 stimulation [89].

Toll like receptors in giant cell arteritis

from 210 patients with biopsy-proven GCA and 678 matched controls. Samples were genotyped for the TLR4-(+896 A/G) (rs4986790) gene polymorphism by PCR and the TLR4-(+896 A/G) allele was found to be significantly increased in the biopsy-positive patients vs controls [117]. Two subsequent studies did not demonstrate a significant difference in genotype or allele frequencies between patients and controls [118, 119] and a cumulative meta-analysis of these three studies failed to demonstrate an association of TLR4-(+896 A/G) gene polymorphism with susceptibility to GCA [120]. The lack of an association between TLR4 gene polymorphisms and GCA has in addition been confirmed in a non-European cohort [121].

Activated DCs are essential for the activation of naive T cells. Mature DCs express a number of chemokines including CCL 18, CCL 19 and CCL 21. Using the severe combined immunodeficiency (SCID) mouse chimera model, normal temporal arteries were engrafted onto SCID mice and the mice injected with LPS. T cell clones were subsequently adoptively transferred into the chimeras, which infiltrated the temporal artery grafts and accumulated at the adventitia–media border. Transfer of human T cell clones without prior LPS stimulation did not result in accumulation of T cells within the vessel wall [87]. DCs of patients with PMR are activated, express CD83 and produce chemokines including CCL 19 and CCL 21 in the absence of an inflammatory infiltrate. In HLA-DR4matched temporal arteries from patients with GCA, PMR and controls without vasculitis that were co-implanted onto SCID mice, activated T cells present in the inflamed temporal arteries of patients with GCA migrated into the non-inflamed PMR arteries but avoided the control arteries, highlighting the importance of activated DCs in T cell recruitment in GCA [87]. These recruited T cells undergo activation, and initiate production of IFN-g, a key driver of vascular inflammation in GCA. In the bioartificial artery model, stimulation with LPS did increase the number of T cells recruited into the DC free constructs; however, optimal T cell recruitment was seen in the tubes populated with DCs and stimulated with LPS [93]. DCs are co-localized with activated CD4+ T cells in granulomatous lesions in GCA [122]. These activated DCs express the CD86 co-stimulatory molecule giving them the means to provide stimulatory signals to the activated T cells [88]. DCs generally migrate to adjacent lymphoid tissue unless they have reached a certain stage of maturity. DCs in granulomatous lesions in GCA have reached full maturity and therefore have lost their ability to migrate. Instead they remain at the site of inflammation within the vessel wall, produce chemokines and continue to stimulate T cells [88]. Further evidence of the importance of activated DCs in T cell activation and recruitment comes from the observation that temporal artery SCID mouse chimeras treated with anti-CD83 antibodies have a marked reduction in the inflammatory

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TLR signalling may also play an important role in driving angiogenesis and vascular remodelling in GCAs In our previously described ex vivo temporal artery culture model [116], stimulation of temporal artery explants from patients with GCA with Pam3Csk4, a TLR2 agonist, resulted in significantly increased expression of proinflammatory cytokines IL-6, IL-8 and the pro-angiogenic mediator angiopoietin-2. Differential effects for MMP2/9 expression were observed on zymography following TLR2 stimulation. In addition, Pam3Csk4 induced endothelial cell tube formation and myofibroblast outgrowths, highlighting the potential of TLR2 to promote angiogenesis as well as vascular inflammation and remodelling in GCA [123].

TLRs are variably expressed both in peripheral blood mononuclear cells of patients with GCA and throughout the macrovasculature There are no reliable biomarkers to assess patients with GCA. Changes in the traditional inflammatory markers (CRP and ESR) do not consistently reflect disease activity [124]. Aberant expression of TLRs has been demonstrated in peripheral blood mononuclear cells (PBMCs) of patients with GCA [125], which in addition to providing clues to the pathogenesis may prove useful as potential biomarkers. Increased expression of TLR7 has been shown on PBMCs in both patients with PMR and patients with GCA [125]. Increased expression of TLR9 has been demonstrated on B cells of patients with GCA who have active disease. TLR3 is overexpressed on both T and B cells in patients with active GCA. No differences were found for expression of TLRs 2, 4, 5, 6 and 8 in PBMCs in GCA. Despite increased expression of TLR7, circulating monocytes from patients with PMR and GCA show reduced in vitro responses following stimulation with TLR7 agonists when compared with healthy controls. Response to TLR7 agonism returns to normal in patients with GCA in remission [125]. However, further studies are needed to understand the potential role of PBMCexpressed TLRs in the assessment of patients with GCA. Pryshchep and colleagues [89] have profiled the expression of TLRs 1–9 within the temporal, carotid, subclavian, mesenteric and iliac arteries as well as the thoracic aorta. Expression of the various TLRs differed significantly between vascular territories. TLR2 and TLR4 were ubiquitously expressed. Temporal arteries demonstrated high expression of TLR 2, 4 and 8 with intermediate results for TLR 1, 5 and 6. All arteries contained the DC activation marker CD11c with highest transcripts found in the aorta, carotid and iliac arteries. Similar to previous studies, these CD11c-positive cells were found at the adventitia–media border [89].

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T cell activation in GCA is dependent on DCs and mediated by TLRs

infiltrate present within the vessel wall and significantly decreased production of INF-g and IL-1b [87].

Lorraine O’Neill and Eamonn S. Molloy

TLR inhibition may be an effective therapeutic strategy in GCA

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Summary GCA is the most common primary systemic vasculitis in adults, affecting medium and large arteries. Its pathological hallmark is of a granulomatous inflammatory infiltrate [8], which is dependent on recruitment of T cells by activated DCs. DCs are antigen presenting cells indigenous to the media–adventitial junction of all medium and large arteries where they exert a gatekeeper function and provide an important link between innate and adaptive immunity. In non-inflamed arteries DCs are immature, quiescent and primarily tolerogenic, protecting the artery from inflammation [12, 87]. TLRs are a family of pattern recognition receptors which are expressed on DCs [13]. TLRs 2 and 4 are ubiquitously expressed throughout the macrovasculature, are highly expressed in temporal arteries and act as potent stimulants of DC activation and maturation [89]. Once activated, DCs drive activation, differentiation and recruitment of T cells, which produce IFN-g, a key driver of vascular inflammation in GCA (Fig. 1). Different TLR ligands are thought to induce distinct patterns of vasculitis [94] and TLR 2 agonism has been shown to increase expression of pro-inflammatory cytokines, angiogenic factors and MMPs, and stimulate myofibroblast outgrowths and endothelial cell tube formation, all of which may contribute to vascular inflammation and remodelling in GCA [116]. The potential role of TLRs in initiating the cascade of events that culminates in the transmural inflammation typical of GCA is consistent with the hypothesis that one or more infectious agents trigger the onset of GCA. However, to date, no such organism has been definitively implicated [2]. Alternatively, endogenous TLR ligands may conceivably play a role in the initiation of GCA. Given the urgent unmet need for safe and effective therapies in GCA, TLR inhibition is a potential novel therapeutic strategy that merits further investigation. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest.

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Given the pivotal role of TLRs in directing the immune response and their pathogenic role in the evolution of many inflammatory and autoimmune conditions, it is not surprising that therapeutic targeting of TLRs and TLR signalling is gaining interest. Current strategies include inhibition of individual TLRs or components of their signalling pathways using mAb or small molecule inhibitors with a view to modulating the innate immune response, thereby ameliorating TLR induced inflammatory cascades. As previously mentioned, GCA and other vascular inflammatory conditions such as atherosclerosis and ischaemia–reperfusion injury share many common pathogenic mechanisms. TLRs 2 and 4 in particular have been established as central to the pathogenesis of ischaemia–reperfusion injury in a number of organ systems [126]. Attention has therefore focused on TLR inhibition as a potential treatment strategy with to date beneficial effects of inhibition of both TLR 2 and 4 demonstrated in a number of animal models of both renal and cardiac ischaemia–reperfusion injury [127–130]. OPN-305 is a humanized IgG4 mAb directed against TLR 2 and its safety and efficacy in preventing delayed graft function is currently being investigated [131]. OPN-305 was well-tolerated in a phase 1, randomized, doubleblind, placebo-controlled, dose-escalating study in healthy subjects. Treatment related adverse effects were similar in both active drug and placebo arms and included headache, nasopharyngitis, abdominal pain and dizziness. No serious or fatal adverse events were reported in the treatment group. No clinically significant differences were observed with regard to total white cell count or other haematological or biochemical parameters or ECG findings [132]. TLR 4 inhibition has shown promise in the treatment of RA. Chaperonin 10, a heat shock protein with antiinflammatory effects due to TLR 4 inhibition, has been evaluated in a phase II, randomized, double blind multicentre study of 23 patients with moderate–severe, active RA. Patients received IV chaperonin 10 twice weekly for 12 weeks and were randomly assigned to one of three dosing arms—5, 7.5 or 10 mg. At the end of the study period, 12 patients had at least an ACR 20 response, with clinical remission achieved in 3/23. Chaperonin 10 was generally well tolerated, but adverse events included disease flare and upper respiratory tract infection [133]. More recently, NI-0101, a humanized monoclonal antiTLR 4 antibody, has demonstrated therapeutic potential. In a synovial explant culture model, NI-0101 inhibited both TNF-a and IL-6 production and in a murine model of inflammatory arthritis halted disease progression [134]. In a phase 1 study, NI-0101 effectively inhibited LPSinduced cytokine release as well as preventing a CRP rise and flu-like symptoms in the LPS-treated patients. NI-0101 appeared to be well tolerated and no safety signals of concern were identified [135]. To date, no data exist on the effects of TLR inhibition in the context of GCA. An urgent unmet need exists in GCA

for alternative, selective treatment strategies given the significant burden of steroid toxicity in this elderly population [39] and the dearth of proven alternative immunosuppressive therapies. Given that TLRs, particularly TLRs 2, 4 and 5, are implicated in GCA pathogenesis, TLR inhibition merits exploration as a potential therapeutic strategy for GCA.

Toll like receptors in giant cell arteritis

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