Immunotherapy for antineutrophil cytoplasmic antibody–associated vasculitis: challenging the therapeutic status quo?

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dnardestiacidInciousually manifests as a diffuse pulmonary hemorrhage,ReviewANCA are now believed to play a major role in the de-velopment of necrotising vasculitis in these disorders.However, thus far, there are no data showing that ANCACorresponding author: Bosch, X. (xavbosch@clinic.ub.es).* These authors contributed equally to this work.paving the way to new biologicals that are now awaitingtesting.Anti-neutrophil cytoplasmic antibodyassociatedvasculitis: Wegeners granulomatosis, Churg-Strausssyndrome and microscopic polyangiitisAnti-neutrophil cytoplasmic antibodies (ANCA) are IgGantibodies directed against antigenic constituents of neu-trophils contained in the azurophilic granules andmonocytelysosomes. After indirect immunofluorescence of ethanol-fixed neutrophils, two characteristic immunostainingpatterns can be observed: cytoplasmic (C-ANCA) and peri-nuclear (P-ANCA) (Figures 1a and 1b, respectively). Mostcases of C- and P-ANCA are directed against proteinase 3(PR3) and myeloperoxidase (MPO), respectively.Systemic vasculitides are uncommon life-threateningdisorders where vascular inflammation of an autoimmunenature causes occlusion and ischemia of affected tissues.Among these diseases, vasculitis with serum positivity forANCA [ANCA-associated vasculitis (AAV)] is a well-established subgroup of disorder that affects small- (e.g.which commonly leads the patient to respiratory insuffi-ciency. In contrast to MPA, patients with WG and CSSexhibit granulomatous destructive inflammation of therespiratory tract, which in the case of CSS is rich ineosinophils. Early in the course of the disease, CSSpatients present asthma and peripheral blood eosinophi-lia and, subsequently, the lung and the heart may beinfiltrated by eosinophils, producing eosinophilic pneumo-nia and rapid-onset heart failure, respectively. [2] In CSS,vasculitic damage, which appears late in the disease, isusually less severe than in MPA and WG. Other organsthat can be affected in AAV include peripheral nerves,skeletal muscle, skin and joints. [3]Between 80% and 90% of WG and MPA patients haveANCA, mainly directed against PR3 in the case of WG andagainst MPO in the case of MPA [4]. The few WG patientswho are ANCA negative mostly have a granulomatousdisease limited to the respiratory tract, although ANCAoften appear later [5]. ANCA are detected in 40% of CSSpatients, with a predominance of MPO-ANCA [6]. Inaddition to their unquestionable value as disease markers,advances in the knowledge of AAV pathogenesis areprompted interest in biological agents. Continuous features of WG and MPA. In MPA, lung involvementImmunotherapy forcytoplasmic antibovasculitis: challengistatus quo?Xavier Bosch1*, Antonio Guilabert2*, Ger1Department of Internal Medicine, Hospital Clnic, Institut dInvof Barcelona, Barcelona, Spain2Department of Dermatology, Hospital Clnic, Institut dInvestigBarcelona, Barcelona, Spain3Department of Autoimmune Diseases, Hospital Clnic, InstitutUniversity of Barcelona, Barcelona, Spain4Department of Nephrology, Hospital Clnic, Institut dInvestigaBarcelona, Barcelona, SpainAnti-neutrophil cytoplasmic antibodies (ANCA) are IgGantibodies directed against antigenic constituents ofneutrophils contained in the azurophilic granules andmonocyte lysosomes. Systemic vasculitis with ANCA[ANCA-associated vasculitides (AAV)] is a subgroup oflife-threatening inflammatory disorders affecting small-to medium-sized vessels; immunosuppressants and glu-cocorticoids represent the current therapeutic mainstay.Although these agents have improved patients survival,25% present with severe adverse events, and standardtherapy does not sustain remission. Therefore, an unmetneed for safer and more effective therapies has280 1471-4906/$ see front matter 2008 Elantineutrophilyassociatedg the therapeuticEspinosa3 and Eduard Mirapeix4gacions Biome`diques August Pi i Sunyer (IDIBAPS), Universityons Biome`diques August Pi i Sunyer (IDIBAPS), University ofvestigacions Biome`diques August Pi i Sunyer (IDIBAPS),ns Biome`diques August Pi i Sunyer (IDIBAPS), University ofcapillaries) to medium-sized vessels (e.g. renal arteries).Wegeners granulomatosis (WG), microscopic polyangiitis(MPA) and Churg-Strauss syndrome (CSS) are the threeforms of AAV [1]. The incidence of AAV in the developedworld ranges from 2.4 cases permillion (CSS) to 3.6 (MPA)to 8.5 (WG) [2]. AAV are more frequent among whites(90% of cases), and the mean age of presentation is 55years [2]. The clinical manifestations of AAV are diverseand sometimes overlapping. Necrotizing and crescenticglomerulonephritis (NCGN) a severe form of renal vas-cular disorder that produces rapidly progressive renalinsufficiency and pulmonary capillaritis are commonsevier Ltd. All rights reserved. doi:10.1016/j.it.2008.03.001 Available online 24 April 2008Revieware the driving force of granuloma formation in WG andCSS.An unmet need for treatment of AAVCurrently, immunosuppressants (e.g., cyclophosphamideor methotrexate) in combination with glucocorticoids arethe mainstay of AAV treatment [7]. Although dramaticallyimproving patient survival, they are far from perfect, with25% of patients having treatment-related severe adverseevents (e.g. infections and malignancy) [8]. Furthermore,these drugs do not sustain remission efficaciously (there isa 50% relapse rate [9]), meaning that AAV become chronic,relapsing disorders, with accumulative, irreversible organdamage occurring because of repetitive episodes of diseaseactivity leading to intensification of toxic immunosuppres-sants. Approximately 10% of AAV patients [10] are refrac-tory for the standard immunosuppressant combinationand are at high risk of death [7]. Therefore,more efficaciousand safer alternative treatments are needed to improve theglobal outcome of AAV patients. This, together withgreater insight into AAV pathogenesis, has prompted in-terest in biological agents. A more pathogenesis-orientedtherapeutic approach could overcome the deficiencies ofcurrent therapies by ablating key immune pathways withless toxicity [11]. We will discuss the role of the biologicaltreatments most used in AAV, paying special attention totheir pathogenesis and the immunological rationale ofbiological agents.Figure 1. (a) Characteristic cytoplasmic anti-neutrophil cytoplasmic antibodies (C-ANCA) and (b) perinuclear (P-ANCA) patterns of ANCA binding. Indirectimmunofluorescence of ethanol-fixed neutrophils. Original magnification, 1000(a) and 2500 (b).Pathogenesis of ANCA-associated vasculitisGranuloma formation in WGWG usually starts as a granulomatous disease of therespiratory tract, and in most patients, progresses tosystemic disease with PR3-ANCAassociated vasculitis[12]. This suggests that WG may start with an aberrantcell-mediated immune response to an exogenous orendogenous antigen in the respiratory tract, which resultsin granuloma formation, with humoral autoimmunity toPR3 occurring at a later stage [13]. However, granulomatain WG and their relationship with systemic vasculitis ispoorly understood. No ANCA animal model has yet repro-duced the typical granulomata of WG [14,15].Multiple cell types are present in WG granulomas in-cluding PR3+ cell clusters (neutrophils and monocytes)surrounded by antigen-presenting cells and abundantTh1-type CD4+CD28- effector memory T cells (TEMs).Maturing B and plasma cells are also present, suggestingneoformation of lymphoid like tissue (Figures 2a and 2c)[16].In WG, there is an alteration of T-cell differentiation,with T cells lacking the co-stimulatory molecule CD28being detected early in localized disease with furtherexpansion as WG generalizes [17]. These cells displayfeatures of TEMs with several potent effector functions[18]. Being a major source of Th1-type cytokines [princi-pally tumor necrosis factor a (TNF-a) and interferon g(IFN-g)], CD4+CD28-T cells are thought to be the drivingforce of granuloma formation [19,20]. These cells expressb2-integrin and the Th1-type CC-chemokine receptor 5(CCR5) [21] and also have cytotoxic potential [22]. None-theless, the cause of CD4+CD28 T-cell proliferationremains unclear and might be an antigen (possiblyPR3)-driven process and/or the result of T regulatory celldysfunction in genetically susceptible individuals. In fact,Abdulahad et al. [23] have recently observed that patientswith WG in remission have an expanded number of regu-latory T cells with a defective suppressive function, whichmay be an important factor accounting not only for thedevelopment of WG but also for its relapsing nature.It has recently been postulated that WG granulomamight not be simply a haphazard, deleterious aggregationof immune cells but could also represent a lymphoid struc-ture ultimately responsible for PR3-ANCA production. Forinstance Voswinkel et al. [24] found B lymphocyterichfollicle-like aggregates within the granulomatous lesions ofendonasal specimens ofWG patients in the vicinity of PR3+cells and plasma cells (Figure 2a, c). Analysis of the immu-noglobulin gene repertoire showed autoreactive B cellswith potential affinity for PR3. Chronic secretion ofTNF-a and IFN-g in the granuloma might provide a favor-able proinflammatory environment for the neogenesis ofgerminal centre-like structures, where T and B cellscooperate to break tolerance and maintain antibody pro-duction against PR3. An interesting theory of PR3-directedautoimmunity has recently been proposed. This involvescPR3, the complementary peptide of PR3 encoded by theantisense strand of the PR3 gene [25]. If the immunesystem is exposed to cPR3, antibodies against it canTrends in Immunology Vol.29 No.6appear, which in turn generate anti-idiotype antibodiesthat cross-react with PR3. Accordingly, PR3-encoding gene281Figure 2. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis: pathogenic model and plausible targets for biological therapies. The sites of therapeuticinterventions are indicated with lines in the figure. (a) Granulomatous inflammation in Wegeners granulomatosis (WG). a, Dendritic cells of the lung are exposed to an asyet undefined antigen (possibly PR3). PR3 induces dendritic cell maturation via the protease-activated receptor (PAR)-2 and triggers a Th1-type response. [90]. b, Antigenloaded-dendritic cells travel to draining lymph nodes and present the antigen to nave CD4+ T cells. Dendritic cells produce interleukin 18, among other cytokines, and skewT cells to a Th1 phenotype. c, Activated Th1 effector memory T cells (TEMs) return to the lungs where the antigen persists. TEMs secrete large amounts of interferon g (IFN-g) and tumor necrosis factor a (TNF-a),. which induce macrophage recruitment and maturation with eventual formation of granulomata and tissue destruction. ChronicT-cell activation might promote neogenesis of lymphoid-like tissue where affinity maturation of autoreactive B cells and plasma cells takes place (the latter secreting PR3-ANCA, which, on reaching the bloodstream, cause vasculitis) [24]. (b) ANCA-induced necrotising vasculitis in WG, microscopic polyangiitis (MPA) and Churg-Strausssyndrome (CSS). a, TNF-a induces priming of neutrophils and endothelial cells. b, Cytokine priming triggers neutrophil azurophilic granules containing PR3 and MPO toReview Trends in Immunology Vol.29 No.6282complementary sequences have been identified inmicroorganisms including Staphylococcus aureus, hencesupporting the role of infectious agents as triggering fac-tors of PR3 autoimmunity (molecular mimicry). Chronicand 2d). Noninflammatory physiological mechanisms ofneutrophil clearance also seem to be altered in the pre-sence of ANCA-induced signals. For instance, ANCA bind-ing dysregulates normal neutrophil apoptosis by delayingthe expression of surface phosphatidylserines, which areessential for macrophage-dependent cell removal.Because of this delayed clearance, ANCA-coated neutro-phils undergo secondary necrosis with release ofadditional inflammatory mediators [36]. Moreover,ANCA-opsonized apoptotic neutrophils enhance the rateof uptake by macrophages, which results in them upregu-lating TNF-a [37].In vivo evidence for AAV: humans and animal modelsThe pathogenic role of ANCA in vivo was convincinglydemonstrated in 2002, when Xiao et al. [38] passivelyadministered murine anti-MPO IgG to Rag2/ (recombi-nase activating gene 2) mice (which lack functioning T or BBox 1. Anti-neutrophil cytoplasmic antibodyinducedneutrophil intracellular signallingStudies on neutrophil intracellular signaling pathways that areactivated on anti-neutrophil cytoplasmic antibody (ANCA) bindingces enhanced expression of adhesion molecules (e.g. ICAM-1) by endothelial cells. c,veral effector functions including firm adhesion (and not rolling) of neutrophils to theatory burst and degranulation, which ultimately causes vasculitic damage. ANCA alsoent factors, leading to the recruitment of more inflammatory cells, thus amplifying andReview Trends in Immunology Vol.29 No.6nasal carriage of S. aureus has indeed been related to WG.The vasculitic pole of the spectrum: pathogenic role ofANCAWG, MPA and CSS almost always present necrotisingvasculitis involving different organs. The strong clinicalassociation between MPO-ANCA and PR3-ANCA andAAV, together with compelling evidence from in vitroand animal models, suggests a critical role for these anti-bodies in the pathogenesis of vascular damage in AAV.ANCA antigens are mainly located within the cyto-plasmic granules of resting neutrophils, sheltered fromcirculating ANCA. However, when neutrophils areprimed by TNF-a (and by other cytokines or microbialproducts), MPO and PR3 traffic to the external leaflet ofthe neutrophil plasma membrane, facilitating ANCAbinding [26,27] (Figure 2b, a and b). This preliminarylow-grade inflammation step may occur in vivo as a resultof infection [28]. In 1990, Falk et al. [26] demonstratedthat ANCA binding triggered the release of reactive ox-ygen species and toxic granule enzymes by TNF-aprimed neutrophils. Subsequently, ANCA-activated neu-trophils were found to be able to kill cultured endothelialcells [29,30]. In vitro studies have yielded additionalevidence of an orchestrating role for ANCA in a neutro-phil-mediated vascular injury model. Although themajority of ANCA antigens are located in the cytoplasmof unstimulated neutrophils, a small quantity is presentconstitutively in the plasma membrane. Interestingly, ithas been shown that the baseline level of PR3 surfaceexpression in resting neutrophils varies widely betweenindividuals, and there have been reported higher degreesof PR3 surface expression in WG patients compared withcontrols [31]. One can easily speculate on how a higherconstitutive surface expression of PR3 could increase thelikelihood of PR3-ANCA binding. The neutrophil intra-cellular signaling cascades activated by ANCA bindingare different from those of the normal inflammatoryresponse (Box 1).ANCA are also believed to influence neutrophilendo-thelial interactions. A coated endothelial cell flow modelusing intravital microscopy has shown that primed neu-trophils exposed to ANCA firmly adhere and transmigrateto TNF-aprimed endothelium instead of undergoingrolling adhesion [32]. Calderwood et al. [33] found thatneutrophil adhesion and transmigration ismediated by b2-integrins. Rather than an increase in b2-integrins on theneutrophil surface (which is actually induced by cytokinepriming), ANCA binding promotes a conformationalchange in the CD11b subunit that makes the moleculemore active and enhances ligand binding [32] (Figure 2b,relocate to the cell membrane and allow binding by ANCA. In addition, TNF-a induSimultaneous interaction of ANCA with their antigen and Fcg receptor prompts secytokine-primed endothelium. d, Once adhered, ANCA induce the neutrophil respirpromote neutrophil secretion of proinflammatory cytokines and activates complemperpetuating the pathological process. PR3, proteinase 3; MPO, myeloperoxidase;lymphocyteassociated antigen 4-immunoglobulin; TEM, effector memory T cells; ICAMc). ANCA has been shown to induce changes in the neu-trophil actin cytoskeleton resulting in changes in shapeand capillary sequestration, hence favoring adhesion tosmall vessel endothelium [34].Only once adhered to endothelium are ANCA-activatedneutrophils able to release reactive oxygen species andlytic enzymes (including MPO and PR3), damaging vesselwalls [5,27]. Furthermore, ANCA-activated neutrophilsand monocytes also release proinflammatory cytokines[interleukin 1b (IL-1b), IL-6, IL-8, TNF-a, monocyte che-moattractant protein 1 and leukotriene B4], which acti-vate and recruit more inflammatory cells includingmonocytes and T cells (see Box 2), amplifying and perpe-tuating a deleterious immune response [35] (Figures 2bhave focused on the machinery leading to the respiratory burst. Totrigger superoxide generation, a simultaneous engagement ofANCA F(ab)2 (to proteinase 3 or myeloperoxidase) and Fc (to Fc-gIIa and IIIb receptors) is needed, with b2-integrin (CD18/CD11b)intercellular adhesion molecule-1 binding permitting Fc- g receptorto propagate the signal [4]. Each binding activates independent butcomplementary intracellular cascades. The Fc-g receptor bindingleads to the activation of tyrosine kinases (including Src and Syk, clband probably phospholypase C-g) [9193]. ANCA F(ab)2 bindingactivates inhibitory G proteins, phosphatidyl inositol-3 kinase type1-g, protein kinase B and p21ras protein activator [92]. Downstreammediators of both pathways converge on the p21ras, which seemsto be a pivotal mediator controlling the neutrophil respiratory burst[32,92]. With regard to other ANCA-mediated functions, recentinvestigations have revealed that neutrophil cytoskeletal changesrequire Fc-g IIa receptor engagement, tyrosine phosphorylation andcalcium fluxes, whereas the b2 integrindependent pro-adhesivephenotype is mediated mainly by F(ab)2 binding that inducesactivation of diacylglycerol kinase and production of phosphatidicacid. [93]DC, dendritic cell; (PAR)-2, protease activated receptor; CTLA4-Ig, cytotoxic T-1, intercellular adhesion molecule-1.283lymphocytes) and resulted in the development of focalnecrotising, crescentic glomerulonephritis (NCGN) with-out immune deposits (indistinguishable from humanANCA-associated glomerulonephritis), with 15% of glo-meruli suffering damage. The addition of bacterial lipopo-lysaccharide (LPS) increased the number of glomeruliaffected and augmented TNF-a levels [39]. This seemsto confirm in vitro hypotheses underlining the importanceof synergistic TNF-a priming for effective neutrophil acti-vation and how co-infection might exacerbate ANCAeffects. In this regard, the role of toll-like receptors inneutrophil priming may also deserve future investigation.Subsequent mice experiments have demonstrated anessential role for both neutrophils [40] and the alternativepathway (AP) of complement [41,42] in AAV (Table 1). Theactivation of the AP perhaps by ANCA-activated-neu-trophil release of properdin (a positive regulator of AP,which acts by increasing the stability of AP convertases) might create a proinflammatory loop that amplifies vas-cular damage by both recruiting additional neutrophilsand direct cytotoxicity (Figure 2b, d).In 2005, Little et al. [43] developed a Wistar-Kyoto ratmodel in which focal NCGN and pulmonary capillaritiswere induced after immunisation with purifiedhuman MPO. The investigators also explored the effectsof MPO-ANCA on the induction of leucocyteendo-Box 2. Role of effector T cells in vasculitisBesides their role in anti-neutrophil cytoplasmic antibody (ANCA)production (ANCA are high-affinity class-switched antibodies), it isnow suspected that effector T cells can accompany ANCA and thusamplify vascular damage. In fact, T cells are frequently found inbiopsies of vasculitic areas and some T celltargeted therapies havereversed manifestations of vasculitis [23]. Marinaki et al. [94] havefound an association between persistent CD4+ T-cell activation anddisease severity in both Wegeners granulomatosis and microscopicpolyangiitis. In addition, a recent animal model of myeloperoxidase(MPO)-ANCAinduced necrotizing and crescentic glomerulonephri-tis has provided a mechanistic basis for CD4+ T cells in this disease[95]. In light of these results, the authors speculated on the existenceof a synergistic combination of both humoral and cellular auto-immunity to MPO. Initially, ANCA induces glomerular neutrophilinfiltration and degranulation with MPO release. Subsequently,MPO-specific CD4+ T cells are activated, and together with macro-phages, exacerbate pathology (see Table 1).Reviewthelium interactions using intravital microscopy ofmesenteric venules. Administration of CXCL-1 chemo-kine (a rat homolog of IL-8) in the mesenterium of bothimmunised and nave rats (which received purified IgGfrom sera of MPO-immunised rats) led to increasedleucocyte adherence and transmigration with microvas-culature focal haemorrhage at chemokine applicationsites. This experiment (despite reinforcing the patho-genic effect of ANCA) confirmed previous in vitro flowmodels showing that ANCA (in collaboration with asynergistic proinflammatory stimulus) promote neutro-phil adhesion to endothelium in vivo. In contrast toaccumulated evidence from MPO-ANCA animal models,there is no convincing in vivo evidence of PR3-ANCApathogenicity.The clearest evidence for the pathogenicity of ANCA inhumans is the reported case of a newborn (whose motherpresented active MPO-ANCA MPA at delivery) who devel-284oped pulmonary haemorrhage and glomerulonephritis48 h after birth. Cordal blood was positive for MPO-ANCAat similar levels to that of the maternal serum. Treatmentof the newborn led to vasculitis resolution and negativisa-tion of serum ANCA [44,45].Rationale and clinical efficacy of biologicals in ANCA-associated vasculitisTNF-a blockers: infliximab and etanerceptThere is compelling in vitro and in vivo evidence for acentral role of TNF-a in AAV pathogenesis. TNF-a med-iates granuloma formation (and maybe lymphoid-like tis-sue neogenesis) in WG and is necessary for endothelialactivation and neutrophil priming in ANCA-mediated vas-cular damage. TNF-a is increased in serum and vasculiticfoci in active disease, with a return to normal levels duringremission [46,47]. Furthermore, anti-TNF-a antibodieshave been shown to prevent [39] and even strongly attenu-ate [43] ANCA-induced NCGN in two animal models.These findings strongly suggest that inhibition of TNF-acould be beneficial in different stages of AAV.Infliximab is a high-affinity chimeric monoclonal anti-TNF-a antibody that blocks cytokine receptor ligation andneutralizes biological activity [48]. It can bind to two TNF-a molecules, and up to three antibodies can bind to onetrimeric TNF-a molecule, thus blocking all the TNF-abinding sites. Infliximab can also bind monomeric TNF-a, preventing formation of the trimer [49]. Four open-labeltrials of infliximab including 51 patients with AAV havebeen performed [8,5052]. Most patients had refractorydisease and were taking corticosteroids and at least one ortwo immunosuppressant drugs at infliximab introduction.In all but one trial [51], patients continued with immuno-suppressants while on infliximab. This, together with thevariable treatment and follow-up times and the varyingdefinitions of remission and relapse between studies, makedefinitive conclusions difficult. However, infliximabachieved a remission rate of up to 80% with only 14% ofrelapses [49]. Clinical responses were observed within 2weeks to 2months, and the reduction inmeanBirminghamVasculitis Activity Score (BVAS) a consensus activityindex was significant and clinically relevant in all stu-dies. In general, infliximab was well tolerated, with infec-tions occurring in six cases.Etanercept is a fusion protein composed of two extra-cellular p75 TNF-a human receptor domains linked to theFc portion of human IgG1. It forms a one-to-one bond withthe active trimeric soluble TNF-a molecule, leaving onebinding site free [49]. In 2001, one open-label trial foundetanercept to be effective in WG [53], and a larger random-ized, placebo-controlled trial (WGET trial) [54] wasdesigned to evaluate the efficacy of etanercept in inducingand maintaining remission in 180 WG patients. Etaner-cept or placebo was added to standard therapies at eachclinical stage. The trial demonstrated no additional effectof etanercept because there were no significant differencesbetween groups in the time to or duration of remission [54].There was a significantly higher incidence of cancer inpatients treated with etanercept [55]. All etanercept-trea-Trends in Immunology Vol.29 No.6ted patients who developed solid-organ tumors alsoreceived cyclophosphamide during the trial. However,ultsmicimmrulilopm-ANof gTable 1. Animal models of AAVHypothesis tested Experimental model Main resMPO-ANCA arepathogenicPassive administration of anti-MPO IgG to Rag2/ and wild-type B6 miceRag 2/withoutof glomePR3-ANCA arepathogenicPassive transfer of PR3-ANCAcontaining IgG to wild-type micein the presence of LPSNo devefeaturesA proinflammatorystimulus of infectiousWild-type B6 mice were transferredwith IgG MPO-ANCA and alsoIgG MPOincreaseReviewthere were no differences between groups in the amount ofcyclophosphamide received during or before the trial. It istherefore possible that the combination of etanercept andcyclophosphamide may heighten the risk of cancer beyondthat observed with cyclophosphamide alone.Uncontrolled studies have shown that patients withrefractory disease achieve sustained remission with inflix-imab. Conversely, the results of the WGET study suggestetanercept cannot be advised for either the induction ormaintenance of remission in AAV. Similar resultsorigin would aggravateMPO-ANCAdependentdamagetreated with bacterial LPSNeutrophils are key-effector cells in thepathogenesis of MPO-ANCAinduced NCGNIgG MPO-ANCA was transferred towild-type B6Neutrophil dANCA IgG-reMice neutrophils were depletedusing rat anti-neutrophilmonoclonal antibodiesComplement plays arole in AAVpathogenesisWild-type B6 mice wereadministered with IgG MPO-ANCAand Rag2/ mice received anti-MPO splenocytes. All micedeveloped NCGNComplemenNCGN in allComplement was depleted usingcobra venom factorIgG MPO-ANwild-type B6C5/ and fainvolvementalternative pC5, C4 and factor B knockoutmice were also administeredIgG MPO-ANCAC5 is critical for MPO-ANCArelated damageWild-type B6 mice were injectedwith IgG ANCA MPO, LPS and anti-murine C5 monoclonal antibodyBB5.1Anti-C5 pretNCGN inducLPSAnti-C5 treaNCGN inducLPSMPO-ANCA are able topromote leukocyteendotheliuminteractions in vivoWistar Kyoto rats were immunizedwith human MPO and developedhuman anti-MPO that cross-reacted with murine MPORats immundeveloped NIgG from immunized rats waspassively transferred tononimmunized ratsLeukocyte atransmigratifocal haemointravital miimmunized aplaces wherCXCL-1 was applied to themesenterium of ratsBoth anti-MPO-CD4+ Tcells (cellular response)and MPO-ANCA(humoral response)play a role in NCGNWild-type B6 mice, MPO/ andmMT/ (mice lacking matureB cells) were immunized withhuman MPO (hMPO) anddeveloped both humoral (exceptmMT/ mice) and cellularautoimmunity to mice MPO(mMPO)Immunized wpresented acneutrophils,and crescenof anti-GBMSheep anti-mouse glomerularbasement membrane antibodieswere used to induce neutrophilrecruitment to the glomeruliAdministratito immunizeprevented dextracapillarrecruitmentleukocytes bAnti-CD4+ monoclonal antibodieswere used to neutralize CD4+ TcellsAbbreviations: AAV, anti-neutrophil cytoplasmic antibodyassociated vasculitis; MPO, mand crescentic glomerulonephritis; PR3, proteinase 3; LPS, lipopolysaccharide; TNF-a,Comments Refs.e developed focal NCGNune deposits with 15%suffering damageWild-type B6 mice developed inaddition cutaneous vasculitis andpulmonary capillaritis[38]ent of human AAV When TNF-a was locally injected,there was aggravation ofpanniculitis[14]CA dose-dependentlomerular damageLPS increased TNF-a levels [39]Pretreatment with monoclonalTrends in Immunology Vol.29 No.6were observed in Crohns disease (a granulomatousinflammatory bowel disease), where infliximab inducedeffective remission but etanercept did not [56,57]. Thismight be explained by the differences in the TNF-a bindingcharacteristics of infliximab and etanercept. Unlike inflix-imab, etanercept binding is restricted to the trimeric formof soluble TNF-a. Moreover, etanercept complex bondsare less stable, resulting in release of dissociated bioactiveTNF-a [49]. Finally, infliximab ligates transmembraneTNF-a with greater avidity than etanercept, which mayantibodies against TNF-a partlyattenuated the NCGNepletion prevented MPO-lated NCGNImmunohistological staining ofkidney specimens demonstratedthat induction of NCGN by anti-MPO IgG was accompaniedbyglomerular influx of neutrophils[40]t depletion totally blockedmiceIncubation of human neutrophilswith PR3 or MPO-ANCA isolatedfrom AAV patients resulted inrelease of factors that activatedcomplement[41]CA caused disease inand C4/ mice but not inctor B/ mice, suggestingof the complementathwayreatment preventeded by Ig ANCA-MPO and[42]tment strongly attenuateded by Ig ANCA-MPO andized with human MPOCGN and capillaritisThe rate of leukocytetransmigration was half reduced,and renal damage was almostreversed when rats were treatedwith anti-TNF-a monoclonalantibodies[43]dherence andon with microvasculaturerrhage was observed (bycroscopy) in bothnd nonimmunized rats ine CXCL-1 was appliedild-type B6 micecumulation ofCD4+ cells, macrophagest formation after injectionantibodiesImmunized MPO/ with hMPOneither recruited effector cells norpresented crescent formation,suggesting that mMPO acts as aplanted autoantigen in theglomeruli[95]on of anti-CD4 antibodiesd wild-type miceeleterious glomerulary proliferation andof macrophages andut not neutrophilsImmunized mMT/ mice did notdeveloped MPO-ANCA butpresented glomerular findingssimilar to that of wild-type miceInjection of LPS and sera fromimmunized MPO/ mice inducedrapid influx of neutrophils to theglomeruli (measured by intravitalmicroscopy) with MPO depositionyeloperoxidase; ANCA, anti-neutrophil cytoplasmic antibody; NCGN, necrotizingtumor necrosis factor a.285induce apoptosis or lysis of membrane TNF-aexpressingimmune effector cells [5860].B-cell depletion with rituximabRituximab is a chimeric monoclonal anti-CD20 antibodythat induces both complement and antibody-dependentdestruction of all B-lineage cells with the exception ofplasma and pre-B cells, which do not express surfaceCD20. Four weekly infusions of rituximab deplete periph-eral B cells for 612 months. Rituximab has shown verypromising effectiveness in non-Hodgkin B cell lymphoma,rheumatoid arthritis and systemic lupus erythematosus[61]. The rationale for rituximab use in AAV rests on theassumption that elimination of immediate precursors ofCD20 plasma cells could interfere with their replacement,leading to transient pathogenic antibody removal andhealing of vasculitis. This presupposes that ANCA areproduced by short- and not long-lived plasma cells [62].In addition, rituximab might block B celldependent auto-immune arms unrelated to autoantibody production suchas cytokine secretion, antigen presentation and inter-actions with T cells and other antigen presenting cells,thus hypothetically producing widespread immunologiceffects [16]. In AAV patients, the number of activatedcirculating B lymphocytes correlates with disease activityand extent of involvement [63]. Rituximab has mostly beenused to treat refractory disease in small case series and afew uncontrolled studies [6472]. Most patients were tak-ing simultaneous drugs (including initial high-dose gluco-corticoids [67,69,70] and immunosuppressants) at the timeof rituximab introduction. Rituximab addition led toclinical response in 64 of 72 patients, with 83% experien-cing complete remission by 6 months. In addition, ritux-imab favored the tapering (or withdrawal) of concomitantmedication. Of note, nonresponders exhibited mostly gran-ulomatous manifestations (e.g. retroorbital granulomas).Rituximab universally induced total depletion of circulat-ing B cells by 1 month, and ANCA titers generallydecreased, but only 50% of patients achieved negativisa-tion. Some patients experienced complete remission withno significant decrease in ANCA titers or before ANCAdrop [66,68,71]. Approximately one third of patients suf-fered a relapse in the follow-up, and retreatment wasgenerally successful [73]. Relapses were frequently pre-ceded by a rise in ANCA titers and, in all but one case, bycirculating B-cell recovery that occurred within 612months [64,68]. Rituximab was well tolerated, and fewserious infusion reactions or infections were reported. B-cell depletion led to a decrease in IgM levels and a slightreduction in IgG.Although preliminary, these results raise questionsabout AAV pathogenesis. It seems that granulomatousfeatures are resistant to rituximab, which confirms thecurrent concept that B cells and ANCA have a negligiblerole in initiating or sustaining granuloma-dependentdamage [62]. However, rituximab seems to effectively healvasculitis, apparently by preventing generation of ANCA,although some patients respond with B-cell depletion butwithout ANCA clearance. Similarly, rituximab failed toReviewreduce antidoubled-stranded DNA and antiphospholipidantibodies in patients with systemic lupus erythematosus286[11]. This challenges the theory of ANCA production byshort-lived plasma cells. The lack of negativisation in onehalf the cases suggests that a significant proportion ofANCA may be produced by autoreactive long-lived plasmacells. The ANCA isotype (IgG) and the presence of somaticmutations point to long-lived plasma cells as the source ofANCA [62]. Some authors even suggest that the negativi-sation of ANCA and the good clinical response observed insome trials was merely caused by high doses of concomi-tant glucocorticoids [11,62]. Another plausible explanationis that the beneficial effect of rituximab depends more onthe inhibition of B-cell functions other than antibody pro-duction (e.g. the B-cell influence on T-cell functions)[68,74].IFN-a in the treatment of CSSProliferating eosinophils play a pivotal role in the patho-genesis of CSS by infiltrating tissues and causing damagevia release of lytic proteins. CSS patients have been trea-ted with IFN-a since the 1990s because of its capacity tosuppress overreactive Th2-immune responses and itsinhibitory effect on eosinophil effector functions [6]. IFN-a receptors are detectable on both CD4+ T cells and eosi-nophils, and their ligation inhibits eosinophil-activating T-cell cytokine production (including IL-5) and the release ofeffector molecules by eosinophils [75]. To date, the effec-tiveness of IFN-a has not been studied systematically.Short-term benefits have only been reported in smallstudies totaling eight patients [7678]. Furthermore, lo-ng-term use has been associated with leukoencephalopa-thy [16], which, in our opinion, may limit the use of IFN-afor CSS in the future.Conclusions and future directionsAmong available biologicals, only rituximab and infliximabhave been trialed with apparent initial success in theclinic. The high expectations generated by rituximab arebeing tested in two prospective randomized trials (RITUX-VAS and RAVE) designed to confirm the short-term safetyand efficacy in granulomatous and vasculitic disease andclarify the mechanism of action of the drug. This mightprovide more insight into the role of B cells in AAVpathogenesis [73]. Similarly, infliximab may deserve aclinical trial to elucidate whether in contrast to etaner-cept and by virtue of its differences it is a useful agent inany of the disease states of AAV. In the meantime, theseagents should be restricted to patients who prove refrac-tory to standard immunosuppressants or patients includedin clinical trials.The need for better drugs, and the continuous advancesin the knowledge of the pathogenesis of AAV, is fuellingimmunotherapy research in this group of autoimmunediseases. Some novel agents are awaiting testing in AAVpilot studies. Agents containing cytotoxic T lymphocyteassociated antigen 4-immunoglobulin (CTLA4) haveachieved good results in rheumatoid arthritis [79], psor-iasis [80] and renal transplantation patients [81]. Abata-cept and belatacept are fusion proteins (combining theIgG1 Fc fragment with the extracellular domain of humanTrends in Immunology Vol.29 No.6CTLA4) that bind to CD80 and CD86 (with higher avidityin the case of belatacept) and prevent these co-stimulatorymolecules from interacting with CD28 for full T-cellantigenmediated activation and clonal expansion [79](Figure 2a, b). A diminished frequency of homozygosityfor the shortest allele of the CTLA4 microsatellite poly-morphism (AT)n (a crucial allele formaintenance of normallevels of CTLA4 expression and balance between T-cellactivation and inhibition) has been reported in WG [82],making co-stimulatory signals an attractive target fornovel therapeutics.Agents intended to neutralise IL-18 might also have arole in AAV, because several pathogenic steps can betargeted at once. IL-18 induces Th1 responses andenhances IFN-g production (Figure 2a, b) and, morespecifically, IL-18 is upregulated in renal biopsies ofpatients with active disease. Furthermore, in vitro studieshave found that IL-18 can prime neutrophils (via themitogen-activated protein kinase p38) for ANCA-mediatedsuperoxide burst in a manner similar to TNF-a [83].IL-5 is known to be the most relevant Th2-cytokineinvolved in eosinophil proliferation, maturation and fullactivation of eosinophils and levels of this cytokine runparallel to disease severity [84]. Similarly, activation of Tcells from CSS patients induces the production of higheramounts of IL-5 compared with healthy controls [85].Therefore, the neutralization of IL-5 with mepoluzimab(a monoclonal antibody against IL-5) could be beneficial inCSS.With regard to B-cell therapies, ocrelizumab, ofatumu-mab (both humanised anti-CD20 antibodies) and epratu-zumab (humanised anti-CD22 antibody, a surface receptorspecifically expressed on B cells) could provide more effec-tive and long-lasting B-cell depletion without the devel-opment by the patient of neutralizing anti-chimericantibodies [73,86]. B-cell activating factor belonging tothe TNF family (BAFF) B-cell activating factor (a T-cellcytokine critically involved in B-cell maturation and sur-vival) is increased in patients with active WG [87]. There-fore, anti-BAFF antibodies (belimumab) could subtlymodulate T- and B-cell interaction in AAV without B-celldepletion (Figure 2a, c). BAFF levels are elevated withrituximab therapy, suggesting that the addition of belimu-mab could enhance B cell suppression [73].In 2007, Huugen et al. [42] proved that monoclonalantibodies against the complement component C5 cansignificantly attenuate MPO-ANCA NCGN, probably byinhibiting neutrophil recruitment, paving the way for itsuse in AAV. Inhibition of C5 cleavage with eculizumab (ahumanised monoclonal antibody) or pexelizumab (itssingle chain version) has produced clinical benefit in par-oxysmal nocturnal haemoglobinuria and ischaemia-reper-fusion injury, respectively, with good adverse-eventprofiles [88].ANCA-mediated leucocyteendothelium interactionsrepresent an exciting area to explore. Neutrophil fixedadhesion via b2-integrin intercellular adhesion mol-ecule-1 (ICAM-1) binding is a prerequisite for the neutro-phil respiratory burst. Therefore, monoclonal antibodiesagainst CD11b and/or ICAM-1 would prevent neutrophil-related primary endothelial damage. (Figure 2b, c). Sim-Reviewilarly, peptides (cyclic hexapeptides) can be designed toselectively bind and inactivate crucial adhesion molecules[89]. Interfering with the specific neutrophil signallingcascades induced by ANCA is another promising strategy.Blockade of the crucial downstreammediator p21ras by itsselective inhibitor farnesylthiosalicylic acid might neutral-ise noxious superoxide production and vascular necrosis.Gene therapy might be the last frontier in the treatment ofAAV. Gene transfer (using viral vectors or transfectedinflammatory cells) would allow the delivery of a steadynontoxic concentration of a desired factor (cytokine naturalinhibitors or even enzymes catalysing a therapeutic pro-duct) specifically at the disease site.AcknowledgementsWe thank Monica Perez-Poquet and Jose Manuel Mascaro, Jr. fortechnical support in the development of manuscript figures.References1 Jennette, J.C. et al. (1994) Nomenclature of systemic vasculitides.Proposal of an international consensus conference. Arthritis Rheum.37, 1871922 Seo, P. and Stone, J.H. (2004) The antineutrophil cytoplasmicantibody-associated vasculitides. Am. J. 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Transplant. 21, 1825183295 Ruth, A.J. et al. (2006) Anti-neutrophil cytoplasmic antibodies andeffector CD4+ cells play nonredundant roles in anti-myeloperoxidaseReview Trends in Immunology Vol.29 No.669, 605615 crescentic glomerulonephritis. J. Am. Soc. Nephrol. 17, 19401949289Immunotherapy for antineutrophil cytoplasmic antibody-associated vasculitis: challenging the therapeutic status quo?Anti-neutrophil cytoplasmic antibody-associated vasculitis: Wegener's granulomatosis, Churg-Strauss syndrome and microscopic polyangiitisAn unmet need for treatment of AAVPathogenesis of ANCA-associated vasculitisGranuloma formation in WGThe vasculitic pole of the spectrum: pathogenic role of ANCAIn vivo evidence for AAV: humans and animal modelsRationale and clinical efficacy of biologicals in ANCA-associated vasculitisTNF- blockers: infliximab and etanerceptB-cell depletion with rituximabIFN- in the treatment of CSSConclusions and future directionsAcknowledgementsReferences

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