REVIEW URRENT C OPINION
Dendritic cells as targets or therapeutics in rheumatic autoimmune disease Ranjeny Thomas
Purpose of review Antigen-specific immunotherapy is a major goal for improvement in the treatment of autoimmune rheumatic disease. Dendritic cells are professional antigen-presenting cells, abundant at mucosal surfaces and in tissues. They also play a critical role in self-tolerance. This review covers recent advances in the field of dendritic cells as targets or therapeutics in rheumatic autoimmune disease. Recent findings Key themes include the phenotypic and functional characterization, lineage relationships and transcription factors involved in the development of the various dendritic cell subsets. Phenotype and function of mouse and human subsets has now been much better mapped. Progress in the elucidation of targeting ligands and routes for induction of antigen-specific tolerance using either antigen-antibody fusion constructs or particulate conjugates is described. Various inflammatory molecules made by dendritic cells, including type I interferon, are important therapeutic targets in autoimmune rheumatic diseases. Approaches to block this and clinical trials in this area are discussed. Summary There are considerable basic science developments in the field of dendritic cells and tolerance that will speed translation to human of the large amount of knowledge generated in mouse in-vivo systems. Various antigen-specific therapy approaches are in the process of translation to the clinic. Keywords antigens, autoimmune disease, dendritic cells, tolerance
INTRODUCTION Antigen-specific immunotherapy is a major goal for improvement in the treatment of autoimmune rheumatic disease (reviewed in [1]). If effective, such strategies promise greater disease specificity, lower toxicity and longer durations of efficacy and thus better patient compliance, as well as potential for disease prevention. Dendritic cells are professional antigen-presenting cells, which are abundant at mucosal surfaces and in tissues. They act as sentinels to sample the environment for antigens. Upon antigen capture, dendritic cells migrate to lymphoid tissues, wherein they present processed antigens to naive T cells [2]. They direct immune responses, including various T-helper responses. They also play an essential role in self-tolerance. For example, constitutive ablation of dendritic cells breaks self-tolerance of CD4þ T cells and results in autoimmune inflammatory disease [3]. Therefore, understanding the biology of dendritic cell antigen presentation as well as the pathology of dendritic cells in autoimmune disease is critical to the development of
effective antigen-specific therapeutic strategies. In this study, I review publications from the last 12–18 months that have advanced knowledge in the field of dendritic cells as targets or therapeutics in rheumatic autoimmune disease. In many cases, authors studied autoimmune models or human diseases other than rheumatic autoimmune disease. However, I have included reference to the broader literature, wherein it has implications for rheumatic disease. For antigen uptake, dendritic cells express a variety of pattern recognition receptors, such as
The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia Correspondence to Ranjeny Thomas, The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia. Tel: +61 7 3443 6960; fax: +61 7 03443 6966; e-mail: [email protected] Curr Opin Rheumatol 2014, 26:211–218 DOI:10.1097/BOR.0000000000000032
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recognition receptors (including some CLR), Fc-g and Fc-e receptors (FcR). Pathogen and damageassociated molecules activate dendritic cells by signalling through these pattern recognition receptors. Dendritic cell ‘maturation’ is exemplified by antigen processing, upregulation of surface expression of MHC and costimulatory molecules (CD80/86) and cytokine production in order to activate T cells [4]. Depending upon the stimuli, activated dendritic cells promote the differentiation of naive T cells into Th1, Th2, Th17 or Treg cells. Maturing dendritic cells also express cytokines that enable the activation of B cells and natural killer (NK) cells. However, specialized subsets of dendritic cells also carry out different functions, including the production of inflammatory or suppressive mediators and promotion of tolerance. Recent studies have identified species-specific phenotypic markers of mouse and human dendritic cell subsets, which have equivalent functional specialization (Fig. 1) [5–7]. Accumulated understanding derived from murine systems is increasingly becoming more translatable to human
KEY POINTS Phenotype and function of equivalent mouse and human subsets have now been mapped, allowing better clinical translation. Antigen-specific tolerance can be achieved in mouse models with targeting ligands using antigen-antibody fusion constructs, particulate conjugates or various types of modified dendritic cells. Various inflammatory molecules made by dendritic cells, including type I interferon, are important therapeutic targets in autoimmune rheumatic diseases. Dendritic cells can be used as carriers of immunomodulatory drugs to block inflammation or affect T cell survival.
Toll-like receptors (TLRs), C type lectin receptors (CLRs), retinoic acid inducible gene I (RIG-I) like receptors, nucleotide-binding oligomerization domain (NOD) like receptor (NLR), apoptotic cell
Origin Monocytes
CDP
Yolk sac IRF8
DC types Inflammatory DCs
Myeloid DCs IRF4 RelB
Human PB
CD1c+ CD14+ CD11b+ CD103-
CD1c+ CD11b+ CD4+
Plasmacytoid DCs
Batf3 IRF8
Langerhans cells
CD141+
BDCA2+CD123+
CD8+ CD103+
PDCA1+
Spleen
VitD RelB
IRF4 RelB
TGFΒ
Human skin
? CD207+
CD1c+ DDCs
CD141+CD14+ DDCs
CD11b+ DDCs
CD207+ CD103+CD205+ DDCs
Skin
CD207+ EpCAM+ CD205+ CD11b+
Function
• IL-23, inflammatory cytokines • Class II-mediated Ag presentation • Endotoxin tolerance
• Cross-presentation • Early IL-2 production • Treg induction
• Type I IFN • CD8 tolerance
• CD4 Tolerance • Epithelial Ag
FIGURE 1. Specialized subsets of dendritic cells and their functions, markers in human and mouse, and transcription factors involved in their development. Precursor cells give rise to specialized subpopulations of dendritic cells and Langerhans cells [5]. Transcription factors IRF4, IRF8, Batf3 and RelB are involved in their development [6,7]. Key phenotypic markers of the mouse and human subpopulations are boxed. Special functions of the subpopulations are shown at the bottom of the figure. CDP, common dendritic cell precursor; DDCs, dermal dendritic cells. 212
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immunology and disease pathology. Dendritic cell subsets in human peripheral blood can be divided into two main branches defined by their lineage markers and function: myeloid and plasmacytoid. Among antigen-presenting cells expressing MHC class II but lacking monocyte or lymphocyte lineage markers, plasmacytoid dendritic cells are CD123þ and myeloid dendritic cells comprise CD1cþ and CD141þsubsets [8,9 ,10]. Both CD1cþ and CD141þ dendritic cells express the myeloid markers CD13 and CD33. &&
MYELOID DENDRITIC CELLS AND THEIR SPECIALIZATION The human peripheral blood CD141þ dendritic cell subset was previously elucidated as the functional equivalent of murine CD8þCD103þCD11b – dendritic cells: both are able to cross-present protein antigen to CD8þ T cells and both express similar genes including the transcription factor BATF3 [11–13]. The CD1cþ peripheral blood dendritic cell subset was recently shown by microarray and functional analysis to be an equivalent human population to the murine CD24þCD11bþ myeloid (possibly monocyte-derived) dendritic cells [9 ]. In mouse intestine, these dendritic cells express CD103 and CD11b [9 ,14]. These myeloid dendritic cells specifically produced interleukin (IL)-23 and IL-6 and induced T helper (Th)-17 cells after fungal infection [9 ,14]. CD1cþCD11cþHLA-DRþCD16 – CD14þ dendritic cells were subsequently identified in human inflammatory fluids, including ascites and rheumatoid arthritis synovial fluid [15 ]. Stimulated ascites fluid CD1cþ dendritic cells also secreted high levels of IL-23 and induced secretion of high levels of T cell IL-17, IFN-g, IL-5 and IL-13 [15 ]. The IRF4 transcription factor expressed by human peripheral blood CD1cþ dendritic cells, inflammatory CD1cþ dendritic cells, monocyte-derived dendritic cells, small intestinal CD103þSIRPahi dendritic cells and murine CD24þCD11bþ myeloid dendritic cells suggests a common developmental pathway for these myeloid dendritic cell populations [9 ,14,15 ]. In contrast, CD103þSIRPaloCD141þ dendritic cells in human small intestine express DNGR1, a marker of Batf3-dependent dendritic cells, that is they bear a developmental relationship with peripheral blood CD141þ dendritic cells [14,16]. In a very interesting study [17], CD141þ dendritic cells isolated from human dermis, which express high levels of CD14 and low levels of CD1c, were found to produce IL-10 and to induce regulatory T cells, which suppressed skin graft inflammation. The authors also found that incubation of CD1cþ peripheral blood dendritic cells or monocyte-derived &&
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dendritic cells with 1a,25-dihydroxy vitamin D3 (active vitamin D) promoted the expression of dermal dendritic cell markers, including CD141, CD14, ILT3, and BATF3 and NECL2 genes. Induced CD141þ dendritic cells also secreted high levels of IL-10 when stimulated by CD154 (CD40-ligand) and suppressed xeno-graft versus host disease (GVHD) in an in-vivo model. Taken together, this group of studies demonstrates that myeloid dendritic cells, including monocyte-derived dendritic cells, in mouse and human appear to have a common lineage-related developmental pathway and can now be identified in blood and mucosal tissues with a set of specific markers. These studies also suggest markers that can be exploited for further characterization of dendritic cells and for their targeting in immunotherapy. Furthermore, they demonstrate the capacity for one subset to differentiate from another. At least in human, a regulatory population of CD141þ dermal dendritic cells could differentiate from two myeloid dendritic cell populations after entering the dermis, an environment rich in the immunosuppressive hormone, vitamin D. Of interest, vitamin D inhibits the RelB subunit of NF-kB, suggesting that RelB influences this differentiation from one myeloid subset to the other [18]. Further evidence for this comes from observations in RelB-deficient mice. Similarly to IRF4-deficient mice, they have greatly reduced proportions of myeloid CD11bþCD4þ dendritic cells but an enrichment in CD8þCD103þ dendritic cells – the CD141þ human dendritic cell equivalent – as well as Foxp3þ Tregs in spleen [19,20]. Although plentiful, these Tregs were unable to suppress the spontaneous autoimmune disease in these mice unless RelBþ dendritic cells were adoptively transferred, providing costimulation for effector T cell and regulatory T cell (Treg) IFN-g production and indoleamine-2,3-dioxygenase expression by host dendritic cells [20]. These data indicate that cooperative cross-talk between dendritic cells, effector and regulatory T cells is required for effective tolerance in autoimmune disease.
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PLASMACYTOID DENDRITIC CELLS AND INTERFERON (AS A TARGET) In mice and humans, plasmacytoid (p) dendritic cells are identifiable by their strong capacity to secrete interferon-a. They have been implicated as major effectors in the pathogenesis of human systemic lupus erythematosus (SLE). A typical ‘signature’ of type I IFN-inducible genes is present in peripheral blood mononuclear cells (PBMCs) of patients with SLE, which is ‘extinguishable’ with systemic steroids. Furthermore, immune complexes of SLE autoantibodies and apoptotic/necrotic
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material, ultraviolet light, neutrophil extracellular traps and platelets are able to stimulate IFNa production by plasmacytoid dendritic cells (pDCs). A number of SLE-associated genes, including IRF5, IRF7, TYK2, TLR7, TLR 8,TLR9, IRAK1, IRF8, TNFAIP3, TNIP1 and STAT4, also implicate the IFN pathway (reviewed in [21]). Exploiting the fact that IRF8-deficient mice lack pDCs, Baccala et al. [22 ] studied the impact of pDCs in the NZB model of SLE. These mice developed no autoantibodies and had reduced renal disease. Furthermore, SLC15A4mutant mice have pDCs but are unable to make type I IFN. Faslpr lupus-prone mice on this mutant background also failed to develop autoantibodies, had reduced lymphadenopathy and prolonged survival [22 ]. These data provide direct evidence for the role of pDCs and their production of IFNa in the pathogenesis of lupus in two mouse models, further cementing type I IFN as a target, and adding IRF8 and SLC15A4 as additional targets in SLE. Notably, a similar type I IFN signature and an increased frequency of peripheral blood pDCs were found in patients with idiopathic thrombocytopenia (ITP). Treatment with intravenous immunoglobulin (IVIG) was shown to extinguish the signature and to reduce the expression of CD16 (FcgRIII) – an activating FcR – by peripheral blood monocytes [23 ]. These results may have broader implications with respect to the mechanism of IVIG in other conditions. Clinical trials of IFNa inhibition in SLE are in progress, and results of phase I and II trials of rontalizumab (humanized anti-IFNa; Genentech) and sifalimumab (anti-IFNa; MedImmune) were reported [24,25]. In both cases, the safety profile was acceptable and there was no excess of viral infections. In the phase II trial of rontalizumab, the primary and secondary outcomes of reduction of disease activity were not met. However, patients with low type I IFN signature at baseline did have significant disease activity responses and capacity to reduce steroid dose. In the phase I trial, there was no impact of sifalimumab on disease activity relative to placebo, unless the results were adjusted for excess pulse steroids. If anything, response was better in those with a high type I IFN signature. IFNa vaccination is another strategy to therapeutically reduce type I IFN levels. Neovacs carried out a proof-ofconcept trial in SLE patients, using a KLH-IFNa conjugate vaccine, which induced anti-IFN antibodies and suppressed IFNa in those immunized [26]. In a phase I/II trial, there was suppression of IFN-regulated genes but no clinical improvement [27]. These results highlight the complexity of the relationship of the type I IFN signature to IFNa pathogenicity, and of trial interpretation in light &&
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of the capacity of steroids to inhibit the same pathway. As antigen-presentation by pDCs has been shown to promote T cell tolerance [28], alternative therapeutic strategies might utilize this property by targeting appropriate antigen to pDCs in vitro or in vivo. Sialic acid binding immunoglobulin-like lectin H (Siglec-H) is a specific marker expressed by pDCs. Loschko et al. found that Ag targeted to Siglec-H using a recombinant antibody–antigen fusion protein induced a state of anergy in T cells in vivo without induction of Treg. They demonstrated proof-of-concept of this strategy by targeting myelin oligodendrocyte glycoprotein antigen to pDCs, which delayed onset and reduced severity of experimental allergic encephalomyelitis (EAE) in mice [29]. There are a variety of other approaches that could be taken to inhibit IFNa production by pDCs, including TLR7 and TLR9 inhibition with CpG oligodinucleotides, deletion using BDCA2 or ILT7 targeting or downstream targets, such as IRAK1/4K and PI3Kd (reviewed in [21]).
OTHER DENDRITIC CELL TARGETING AND DELIVERY STRATEGIES A number of strategies to target dendritic cells in vivo for immunomodulation in autoimmune disease applications have been reported. Recombinant antibody–antigen fusion proteins have been well described for the application of antigen-specific tolerance. To understand the mechanisms and relative advantages of targeting different dendritic cell subsets in skin, myelin oligodendrocyte glycoprotein antigen-fusion proteins were constructed with antiDEC205 (CD205) or anti-langerin (CD207) to target skin migratory CD103þ dendritic cells and Langerhans cells, or with anti-Treml4 and anti-DCIR2 to target CD8þ and CD8 – lymphoid-resident dendritic cells, respectively. The authors noted that antiDEC205 was fairly nonselective, as labelled antibodies were taken up by both migratory CD103þ DCs and CD8þ lymphoid-resident dendritic cells after subcutaneous injection. Interestingly, when targeting migratory CD103þ dermal dendritic cells and Langerhans cells, Foxp3þ Treg were induced in draining lymph nodes, and EAE was suppressed. Thus, targeting of Langerin and DEC-205 induced Treg and suppressed EAE most effectively after subcutaneous injection [30]. These results confirm previous evidence that skin Langerhans cells constitutively provide low level signal for proliferation and induce tolerance in vivo, and that migratory rather than lymphoid-resident dendritic cells induce Treg conversion in lymph nodes [5,31]. Figure 1 summarizes dendritic cell subsets in mouse Volume 26 Number 2 March 2014
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and human peripheral blood, spleen and skin, transcription factors involved in their differentiation and functional specialisations. Note that all subsets are involved in tolerance involving different aspects of immunity. Alternative approaches to dendritic cell targeting employed dendritic cell ligands conjugated to nano or microparticles for delivery of antigens and other actives to dendritic cells. For example, multivalent glycopeptide dendrimers conjugated to glycan-based compounds (such as DC-SIGN) were shown to target dendritic cells, and to be internalized, to enter the lysosomes and to deliver their conjugated antigen in vivo. Ex-vivo stimulation with lipopolysaccharide induced secretion of IL-10 [32]. Poly (d lactide co-glycolide) nanoparticles were shown to target dendritic cells without inducing activation. Targeting was improved when a ligand such as anti-DEC-205 was conjugated to the particles [33]. CLEC9aþ dendritic cells were targeted for cross-presentation of protein after intravenous (i.v.) delivery of a nanoemulsion, wherein antiCLEC9a was conjugated to biosurfactant protein DAMP4 [34]. Delivery of PLGA-antigen particles intranasally induced Foxp3þ Treg in the nasopharynx and suppressed delayed-type hypersensitivity in an antigen-specific manner [35]. Li et al. reported that coimmunization of sequence-matched DNA and protein antigen induced CD11cþCD40loIL-10þ DCs (so-called ‘DC-regs’) and antigen-specific Treg. The immunogens were taken up by caveolae-mediated endocytosis and blocked caveolin-1 phosphorylation, thus increasing Tollip expression. This led to feedback induction of SOCS1 and suppression of NF-kB and STAT1a [36]. A fusion protein of cholera toxin B with glutamic acid decarboxylase antigen suppressed dendritic cell IL-12 production and increased IL-10 [37]. These studies indicate that a variety of dendritic cell targeting approaches can be used in mouse models to induce antigen-specific tolerance or to modulate dendritic cell function. Dendritic cells can also be targeted for antiinflammatory effects. Mycophenolate nanogels (without antigen) were shown to target dendritic cells in vivo and to suppress inflammatory cytokine in the NZB/W F1 model of SLE [38]. Such delivery strategies promise improved bioavailability and fewer off-target effects than systemic dosing of the drug. In an interesting variation on this theme, dendritic cells loaded with the immunosuppressive drug, FK-506 and antigen were shown to kill T cells in an antigen-specific manner. The mechanism was unusual in that dendritic cells loaded with FK-506 did not take on a regulatory phenotype but rather delivered the drug to T cells during antigen presentation, thus preventing upregulation of T cell
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bclXL and survival [39 ]. Intravenous HIV-based lentiviral vectors were reported as another antiinflammatory strategy. They preferentially transduced F4/80þLy6cþ splenic inflammatory macrophages/dendritic cells and reduced production of pro-inflammatory cytokines including IL-6 and IL-23 and reduced T cell IL-17 production [40].
NOVEL INFLAMMATORY MOLECULE AND RECEPTOR TARGETS SPECIFIC TO DENDRITIC CELLS Dendritic cells are important cells of both adaptive and innate immune system. As described above for pDCs, there are many receptors and inflammatory molecules expressed by dendritic cells, which are potentially useful targets in rheumatic or autoimmune inflammatory diseases. Dendritic cells were shown to express cannabinoid receptor 2 (CBR2). CBR2 agonists decrease autoimmune inflammation and dendritic cell production of pro-inflamamtory cytokines and capacity to stimulate CD4þ T cells. CBR2 agonists were found to inhibit dendritic cell migration from peripheral tissues by blocking MMP9 expression, which is required for dendritic cells to break down extracellular matrix and enter lymphatic vessels [10]. Similarly, oral fumarates are used for the treatment of multiple sclerosis and psoriasis. Ghoreschi found that they promote ‘type II’ dendritic cells, which produce IL-10 rather than IL-23/IL-12, and which induce Th2 T cells in vivo. Fumarate depletes glutathione and increases reactive oxygen species and heme-oxgenase-1, thereby reducing STAT-1 phosphorylation in dendritic cells. The latter prevents IL-12 and IL-23 production [41]. The ataxia telangiectasia mutated (ATM) pathway was also shown to regulate IL-23 expression by dendritic cells. Incubation of human monocytederived dendritic cells with a selective ATM antagonist increased IL-23 while low-dose ionizing radiation induced ATM phosphorylation and reduced IL-23 expression. Repression of endoplasmic reticulum stress by ATM was responsible for this effect [42]. These pathways are of direct relevance to the spondyloarthropathies. The frequency of dendritic cells in lymphoid organs is regulated in parallel with that of Treg in a flt3-dependent pathway [43]. A novel approach to suppression of autoimmune disease was taken by Billiard et al. [44 ] who blocked delta-like ligand 4-Notch signalling with nocastrin. This promoted the accumulation of thymic dendritic cells and Foxp3þ Tregs in the thymic cortex, by converting T cell progenitors to immature dendritic cells, and these in turn promoted Treg conversion. In mice, nocastrin prevented development of type 1 diabetes
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in a Treg-dependent manner, and a single treatment reversed established diabetes [44 ]. This strategy may be particularly useful in autoimmune diseases of childhood, in which the thymus would be responsive to such immunomodulation. &&
IMMUNOSUPPRESSIVE AND TOLEROGENIC DENDRITIC CELLS AND MEDIATORS OF SUPPRESSION IL-27, produced by dendritic cells stimulated by IFN-b, is a critical inducer of IL-10þ T regulatorytype 1 (Tr1) cells. In a study of mechanism, the effects of IL-27 were shown to be mediated in part by induction of the regulatory molecule CD39 in dendritic cells. CD39 reduced extracellular ATP and activation of the inflammasome [45 ]. Inflammatory myeloid Ly6chi dendritic cells/monocytes became suppressive when stimulated by IFN-g, granulocyte-macrophage colony stimulating factor (GM-CSF), tumour necrosis factor (TNF) and CD40ligand. Nitric oxide production was responsible for T cell suppression. The authors proposed that this is a natural feedback mechanism to curb inflammatory dendritic cells [46]. Low-dose GM-CSF itself can prevent the development of various autoimmune diseases in mice, through induction of tolerogenic CD8 – myeloid dendritic cells from bone marrow precursors and expansion of Foxp3þ Tregs. The Treg expansion was shown to be mediated through Jagged1 and OX40L signalling of T cell Notch3 and OX40 receptors, respectively [47]. Finally, Chen et al. [54] found that mesenchymal stem cells (MSCs)-conditioned medium drove monocytederived dendritic cells towards a myeloid-derived suppressor cell phenotype, mediated by the chemokine GRO-g [48]. Although MSC show much promise for tolerance, advances in the understanding of their mechanisms are welcome additions to the literature. Various immunomodulators alter the differentiation and function of dendritic cells such that they induce antigen-specific tolerance when exposed to antigen and injected (’tolerogenic dendritic cells’). A number of such strategies are now in clinical trials, including dendritic cells modified with the NF-kB inhibitor Bay11-7082, and dendritic cells modified with vitamin D3, dexamethasone and monophosphoryl lipid A (reviewed by [49]). Volchenkov et al. [50] generated dendritic cells modified with vitamin D3, dexamethasone and lipopolysaccharide (LPS) from primary systemic sclerosis patients. The dendritic cells suppressed T cell activation and induced a Treg population in vitro, but without antigenspecificity. Suppression was associated with high IL-8 secretion [50]. Carbon monoxide is an alternative strategy to modify dendritic cell function. &
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Endogenous carbon monoxide is released during oxidative degradation of heme proteins, by heme oxygenases, for example HO-1. The carbon monoxide releasing molecule (CORM) was found to promote tolerance independently of IL-10 and CD4þ T cells. These dendritic cells inhibited development of type 1 diabetes in mice in a CD8þ T celldependent manner [51]. Similarly, carbon monoxide could be administered to FcgRIIb-deficient lupus-prone mice either using a carbon monoxide chamber or by administration of cobalt or tin pyrophosphate. Treated mice had lower expansion of CD11bþ inflammatory dendritic cells, resulting in less renal damage and lower titres of antihistone antibodies [52]. With the aim of translation to the clinic, others are searching for molecules that can modify dendritic cells towards a tolerogenic phenotype. Matsumoto et al. [53] screened libraries of bioactive inhibitors for molecules reducing CD80, CD86 and increasing IL-10 and found a protein kinase C inhibitor with these properties. The dendritic cells generated were immunosuppressive in vitro and in vivo [53]. Dendritic cells with similar properties were induced with secretory IgA though reduction of expression of SIGNR1 [54].
CONCLUSION Much progress has been made over the last 5–10 years in the discovery of immunomodulators of monocyte-derived dendritic cell function and their development and implementation for translation to trials in autoimmune disease. Further publication of trials is anticipated. In the last 12 months, big strides have been made in the phenotypic and functional characterization, lineage relationships and transcription factors involved in the development of the various dendritic cell subsets. Several key publications have been able to link phenotype and function of mouse and human subsets, which will speed translation to human of the large amount of knowledge generated in mouse in-vivo systems. Furthermore, considerable progress has been made in the elucidation of targeting ligands and routes for induction of antigen-specific tolerance using either antigen–antibody fusion constructs or particulate conjugates. Figure 2 shows the principle behind this approach, using langerinþ skin dendritic cells as an example [30]. What is needed now is to integrate this with understanding of human disease genetics and immunopathology to determine whether antigen targeting to dendritic cells will have the predicted tolerogenic effects in the clinic. The targeting of drugs to dendritic cells for anti-inflammatory effects or for delivery to T cells is an interesting Volume 26 Number 2 March 2014
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AutoAg-anti-langerin construct or conjugate
Langerin+ DC
Skin
Ag presentation by MHC molecules
Joint Inflamed mΦ, DC, effector T cells Ag-specific regulation
RA joint
Blood Foxp3+ Agspecific induced Treg
Draining lymph node
Draining lymph node
FIGURE 2. Principle of targeting tolerogenic dendritic cell populations in vivo for antigen-specific immunotherapy. An antibody specific for a tolerogenic dendritic cell population (exemplified here by Langerhans cells) is either conjugated or engineered to include arthritogenic antigen. After injection, the complex is taken up and processed by the DC and the antigen presented in the context of MHC class II. Induced antigen-specific Treg exert antigen-specific suppression in inflamed joints. Adapted from [1].
new emerging theme. Dendritic cells remain very exciting targets and therapeutics for autoimmune rheumatic disease. Acknowledgements The author is supported by a Future Fellowship from the Australian Research Council and by Arthritis Queensland. I thank Amelie Casgrain for editorial assistance. Conflicts of interest The author has filed provisional patents surrounding technology for targeting dendritic cells for antigenspecific tolerance and is a director of a spin-off company, which is commercializing vaccines that target dendritic cells to suppress autoimmune diseases.
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J Immunol 2011; 187:4018–4030. 21. Kirou KA, Gkrouzman E. Antiinterferon alpha treatment in SLE. Clin Immunol 2013; 148:303–312. 22. Baccala R, Gonzalez-Quintial R, Blasius AL, et al. Essential requirement for && IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus. Proc Natl Acad Sci U S A 2013; 110:2940–2945. Mouse models demonstrating an essential role for plasmacytoid dendritic cells and their production of interferon-a in lupus. 23. Sehgal K, Guo X, Koduru S, et al. Plasmacytoid dendritic cells, interferon & signaling, and FcgammaR contribute to pathogenesis and therapeutic response in childhood immune thrombocytopenia. Sci Transl Med 2013; 5:193ra189. Demonstration of a type 1 interferon signature in childhood immune thrombocytopenia, and the mechanism by which IVIG suppresses the signature. 24. McBride JM, Jiang J, Abbas AR, et al. Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: results of a phase I, placebo-controlled, double-blind, dose-escalation study. Arthritis Rheum 2012; 64:3666–3676. 25. Petri M, Wallace DJ, Spindler A, et al. Sifalimumab, a human antiinterferonalpha monoclonal antibody, in systemic lupus erythematosus: a phase I randomized, controlled, dose-escalation study. Arthritis Rheum 2013; 65:1011–1021. 26. Mathian A, Amoura Z, Adam E, et al. Active immunisation of human interferon alpha transgenic mice with a human interferon alpha Kinoid induces antibodies that neutralise interferon alpha in sera from patients with systemic lupus erythematosus. Ann Rheum Dis 2011; 70:1138–1143. 27. Lauwerys BR, Hachulla E, Spertini F, et al. Down-regulation of interferon signature in systemic lupus erythematosus patients by active immunization with interferon alpha-kinoid. Arthritis Rheum 2013; 65:447–456. 28. Gilliet M, Liu YJ. Generation of human CD8 T regulatory cells by CD40 ligandactivated plasmacytoid dendritic cells. J Exp Med 2002; 195:695–704. 29. Loschko J, Heink S, Hackl D, et al. Antigen targeting to plasmacytoid dendritic cells via Siglec-H inhibits Th cell-dependent autoimmunity. J Immunol 2011; 187:6346–6356. 30. Idoyaga J, Fiorese C, Zbytnuik L, et al. Specialized role of migratory dendritic cells in peripheral tolerance induction. J Clin Invest 2013; 123:844–854. 31. Shklovskaya E, O’Sullivan BJ, Ng LG, et al. Langerhans cells are precommitted to immune tolerance induction. Proc Natl Acad Sci 2011; 108:18049–18054.
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Immunopathogenesis and treatment of autoimmune diseases 32. Garcia-Vallejo JJ, Ambrosini M, Overbeek A, et al. Multivalent glycopeptide dendrimers for the targeted delivery of antigens to dendritic cells. Mol Immunol 2013; 53:387–397. 33. Lewis JS, Zaveri TD, Crooks CP2nd, et al. Microparticle surface modifications targeting dendritic cells for nonactivating applications. Biomaterials 2012; 33:7221–7232. 34. Zeng BJ, Chuan YP, O’Sullivan B, et al. Receptor-specific delivery of protein antigen to dendritic cells by a nanoemulsion formed using top-down noncovalent click self-assembly. Small 2013; 9:3736–3742. 35. Keijzer C, Slutter B, van der Zee R, et al. PLGA, PLGA-TMC and TMC-TPP nanoparticles differentially modulate the outcome of nasal vaccination by inducing tolerance or enhancing humoral immunity. PLoS One 2011; 6:e26684. 36. Li J, Geng S, Xie X, et al. Caveolin-1-mediated negative signaling plays a critical role in the induction of regulatory dendritic cells by DNA and protein coimmunization. J Immunol 2012; 189:2852–2859. 37. Odumosu O, Nicholas D, Payne K, et al. Cholera toxin B subunit linked to glutamic acid decarboxylase suppresses dendritic cell maturation and function. Vaccine 2011; 29:8451–8458. 38. Look M, Stern E, Wang QA, et al. Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice. J Clin Invest 2013; 123:1741–1749. 39. Orange DE, Blachere NE, Fak J, et al. Dendritic cells loaded with FK506 kill T & cells in an antigen-specific manner and prevent autoimmunity in vivo. Elife 2013; 2:e00105. A novel mechanism of drug delivery to kill T cells through contact with dendritic cells. 40. van den Brand BT, Vermeij EA, Waterborg CE, et al. Intravenous delivery of HIV-based lentiviral vectors preferentially transduces F4/80þ and Ly-6Cþ cells in spleen, important target cells in autoimmune arthritis. PLoS One 2013; 8:e55356. 41. Ghoreschi K, Bruck J, Kellerer C, et al. Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med 2011; 208:2291–2303. 42. Wang Q, Franks HA, Lax SJ, et al. The ataxia telangiectasia mutated kinase pathway regulates IL-23 expression by human dendritic cells. J Immunol 2013; 190:3246–3255.
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Dendritic cells as targets or therapeutics in rheumatic autoimmune disease Ranjeny Thomas
Purpose of review Antigen-specific immunotherapy is a major goal for improvement in the treatment of autoimmune rheumatic disease. Dendritic cells are professional antigen-presenting cells, abundant at mucosal surfaces and in tissues. They also play a critical role in self-tolerance. This review covers recent advances in the field of dendritic cells as targets or therapeutics in rheumatic autoimmune disease. Recent findings Key themes include the phenotypic and functional characterization, lineage relationships and transcription factors involved in the development of the various dendritic cell subsets. Phenotype and function of mouse and human subsets has now been much better mapped. Progress in the elucidation of targeting ligands and routes for induction of antigen-specific tolerance using either antigen-antibody fusion constructs or particulate conjugates is described. Various inflammatory molecules made by dendritic cells, including type I interferon, are important therapeutic targets in autoimmune rheumatic diseases. Approaches to block this and clinical trials in this area are discussed. Summary There are considerable basic science developments in the field of dendritic cells and tolerance that will speed translation to human of the large amount of knowledge generated in mouse in-vivo systems. Various antigen-specific therapy approaches are in the process of translation to the clinic. Keywords antigens, autoimmune disease, dendritic cells, tolerance
INTRODUCTION Antigen-specific immunotherapy is a major goal for improvement in the treatment of autoimmune rheumatic disease (reviewed in [1]). If effective, such strategies promise greater disease specificity, lower toxicity and longer durations of efficacy and thus better patient compliance, as well as potential for disease prevention. Dendritic cells are professional antigen-presenting cells, which are abundant at mucosal surfaces and in tissues. They act as sentinels to sample the environment for antigens. Upon antigen capture, dendritic cells migrate to lymphoid tissues, wherein they present processed antigens to naive T cells [2]. They direct immune responses, including various T-helper responses. They also play an essential role in self-tolerance. For example, constitutive ablation of dendritic cells breaks self-tolerance of CD4þ T cells and results in autoimmune inflammatory disease [3]. Therefore, understanding the biology of dendritic cell antigen presentation as well as the pathology of dendritic cells in autoimmune disease is critical to the development of
effective antigen-specific therapeutic strategies. In this study, I review publications from the last 12–18 months that have advanced knowledge in the field of dendritic cells as targets or therapeutics in rheumatic autoimmune disease. In many cases, authors studied autoimmune models or human diseases other than rheumatic autoimmune disease. However, I have included reference to the broader literature, wherein it has implications for rheumatic disease. For antigen uptake, dendritic cells express a variety of pattern recognition receptors, such as
The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia Correspondence to Ranjeny Thomas, The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia. Tel: +61 7 3443 6960; fax: +61 7 03443 6966; e-mail: [email protected] Curr Opin Rheumatol 2014, 26:211–218 DOI:10.1097/BOR.0000000000000032
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recognition receptors (including some CLR), Fc-g and Fc-e receptors (FcR). Pathogen and damageassociated molecules activate dendritic cells by signalling through these pattern recognition receptors. Dendritic cell ‘maturation’ is exemplified by antigen processing, upregulation of surface expression of MHC and costimulatory molecules (CD80/86) and cytokine production in order to activate T cells [4]. Depending upon the stimuli, activated dendritic cells promote the differentiation of naive T cells into Th1, Th2, Th17 or Treg cells. Maturing dendritic cells also express cytokines that enable the activation of B cells and natural killer (NK) cells. However, specialized subsets of dendritic cells also carry out different functions, including the production of inflammatory or suppressive mediators and promotion of tolerance. Recent studies have identified species-specific phenotypic markers of mouse and human dendritic cell subsets, which have equivalent functional specialization (Fig. 1) [5–7]. Accumulated understanding derived from murine systems is increasingly becoming more translatable to human
KEY POINTS Phenotype and function of equivalent mouse and human subsets have now been mapped, allowing better clinical translation. Antigen-specific tolerance can be achieved in mouse models with targeting ligands using antigen-antibody fusion constructs, particulate conjugates or various types of modified dendritic cells. Various inflammatory molecules made by dendritic cells, including type I interferon, are important therapeutic targets in autoimmune rheumatic diseases. Dendritic cells can be used as carriers of immunomodulatory drugs to block inflammation or affect T cell survival.
Toll-like receptors (TLRs), C type lectin receptors (CLRs), retinoic acid inducible gene I (RIG-I) like receptors, nucleotide-binding oligomerization domain (NOD) like receptor (NLR), apoptotic cell
Origin Monocytes
CDP
Yolk sac IRF8
DC types Inflammatory DCs
Myeloid DCs IRF4 RelB
Human PB
CD1c+ CD14+ CD11b+ CD103-
CD1c+ CD11b+ CD4+
Plasmacytoid DCs
Batf3 IRF8
Langerhans cells
CD141+
BDCA2+CD123+
CD8+ CD103+
PDCA1+
Spleen
VitD RelB
IRF4 RelB
TGFΒ
Human skin
? CD207+
CD1c+ DDCs
CD141+CD14+ DDCs
CD11b+ DDCs
CD207+ CD103+CD205+ DDCs
Skin
CD207+ EpCAM+ CD205+ CD11b+
Function
• IL-23, inflammatory cytokines • Class II-mediated Ag presentation • Endotoxin tolerance
• Cross-presentation • Early IL-2 production • Treg induction
• Type I IFN • CD8 tolerance
• CD4 Tolerance • Epithelial Ag
FIGURE 1. Specialized subsets of dendritic cells and their functions, markers in human and mouse, and transcription factors involved in their development. Precursor cells give rise to specialized subpopulations of dendritic cells and Langerhans cells [5]. Transcription factors IRF4, IRF8, Batf3 and RelB are involved in their development [6,7]. Key phenotypic markers of the mouse and human subpopulations are boxed. Special functions of the subpopulations are shown at the bottom of the figure. CDP, common dendritic cell precursor; DDCs, dermal dendritic cells. 212
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immunology and disease pathology. Dendritic cell subsets in human peripheral blood can be divided into two main branches defined by their lineage markers and function: myeloid and plasmacytoid. Among antigen-presenting cells expressing MHC class II but lacking monocyte or lymphocyte lineage markers, plasmacytoid dendritic cells are CD123þ and myeloid dendritic cells comprise CD1cþ and CD141þsubsets [8,9 ,10]. Both CD1cþ and CD141þ dendritic cells express the myeloid markers CD13 and CD33. &&
MYELOID DENDRITIC CELLS AND THEIR SPECIALIZATION The human peripheral blood CD141þ dendritic cell subset was previously elucidated as the functional equivalent of murine CD8þCD103þCD11b – dendritic cells: both are able to cross-present protein antigen to CD8þ T cells and both express similar genes including the transcription factor BATF3 [11–13]. The CD1cþ peripheral blood dendritic cell subset was recently shown by microarray and functional analysis to be an equivalent human population to the murine CD24þCD11bþ myeloid (possibly monocyte-derived) dendritic cells [9 ]. In mouse intestine, these dendritic cells express CD103 and CD11b [9 ,14]. These myeloid dendritic cells specifically produced interleukin (IL)-23 and IL-6 and induced T helper (Th)-17 cells after fungal infection [9 ,14]. CD1cþCD11cþHLA-DRþCD16 – CD14þ dendritic cells were subsequently identified in human inflammatory fluids, including ascites and rheumatoid arthritis synovial fluid [15 ]. Stimulated ascites fluid CD1cþ dendritic cells also secreted high levels of IL-23 and induced secretion of high levels of T cell IL-17, IFN-g, IL-5 and IL-13 [15 ]. The IRF4 transcription factor expressed by human peripheral blood CD1cþ dendritic cells, inflammatory CD1cþ dendritic cells, monocyte-derived dendritic cells, small intestinal CD103þSIRPahi dendritic cells and murine CD24þCD11bþ myeloid dendritic cells suggests a common developmental pathway for these myeloid dendritic cell populations [9 ,14,15 ]. In contrast, CD103þSIRPaloCD141þ dendritic cells in human small intestine express DNGR1, a marker of Batf3-dependent dendritic cells, that is they bear a developmental relationship with peripheral blood CD141þ dendritic cells [14,16]. In a very interesting study [17], CD141þ dendritic cells isolated from human dermis, which express high levels of CD14 and low levels of CD1c, were found to produce IL-10 and to induce regulatory T cells, which suppressed skin graft inflammation. The authors also found that incubation of CD1cþ peripheral blood dendritic cells or monocyte-derived &&
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dendritic cells with 1a,25-dihydroxy vitamin D3 (active vitamin D) promoted the expression of dermal dendritic cell markers, including CD141, CD14, ILT3, and BATF3 and NECL2 genes. Induced CD141þ dendritic cells also secreted high levels of IL-10 when stimulated by CD154 (CD40-ligand) and suppressed xeno-graft versus host disease (GVHD) in an in-vivo model. Taken together, this group of studies demonstrates that myeloid dendritic cells, including monocyte-derived dendritic cells, in mouse and human appear to have a common lineage-related developmental pathway and can now be identified in blood and mucosal tissues with a set of specific markers. These studies also suggest markers that can be exploited for further characterization of dendritic cells and for their targeting in immunotherapy. Furthermore, they demonstrate the capacity for one subset to differentiate from another. At least in human, a regulatory population of CD141þ dermal dendritic cells could differentiate from two myeloid dendritic cell populations after entering the dermis, an environment rich in the immunosuppressive hormone, vitamin D. Of interest, vitamin D inhibits the RelB subunit of NF-kB, suggesting that RelB influences this differentiation from one myeloid subset to the other [18]. Further evidence for this comes from observations in RelB-deficient mice. Similarly to IRF4-deficient mice, they have greatly reduced proportions of myeloid CD11bþCD4þ dendritic cells but an enrichment in CD8þCD103þ dendritic cells – the CD141þ human dendritic cell equivalent – as well as Foxp3þ Tregs in spleen [19,20]. Although plentiful, these Tregs were unable to suppress the spontaneous autoimmune disease in these mice unless RelBþ dendritic cells were adoptively transferred, providing costimulation for effector T cell and regulatory T cell (Treg) IFN-g production and indoleamine-2,3-dioxygenase expression by host dendritic cells [20]. These data indicate that cooperative cross-talk between dendritic cells, effector and regulatory T cells is required for effective tolerance in autoimmune disease.
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PLASMACYTOID DENDRITIC CELLS AND INTERFERON (AS A TARGET) In mice and humans, plasmacytoid (p) dendritic cells are identifiable by their strong capacity to secrete interferon-a. They have been implicated as major effectors in the pathogenesis of human systemic lupus erythematosus (SLE). A typical ‘signature’ of type I IFN-inducible genes is present in peripheral blood mononuclear cells (PBMCs) of patients with SLE, which is ‘extinguishable’ with systemic steroids. Furthermore, immune complexes of SLE autoantibodies and apoptotic/necrotic
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material, ultraviolet light, neutrophil extracellular traps and platelets are able to stimulate IFNa production by plasmacytoid dendritic cells (pDCs). A number of SLE-associated genes, including IRF5, IRF7, TYK2, TLR7, TLR 8,TLR9, IRAK1, IRF8, TNFAIP3, TNIP1 and STAT4, also implicate the IFN pathway (reviewed in [21]). Exploiting the fact that IRF8-deficient mice lack pDCs, Baccala et al. [22 ] studied the impact of pDCs in the NZB model of SLE. These mice developed no autoantibodies and had reduced renal disease. Furthermore, SLC15A4mutant mice have pDCs but are unable to make type I IFN. Faslpr lupus-prone mice on this mutant background also failed to develop autoantibodies, had reduced lymphadenopathy and prolonged survival [22 ]. These data provide direct evidence for the role of pDCs and their production of IFNa in the pathogenesis of lupus in two mouse models, further cementing type I IFN as a target, and adding IRF8 and SLC15A4 as additional targets in SLE. Notably, a similar type I IFN signature and an increased frequency of peripheral blood pDCs were found in patients with idiopathic thrombocytopenia (ITP). Treatment with intravenous immunoglobulin (IVIG) was shown to extinguish the signature and to reduce the expression of CD16 (FcgRIII) – an activating FcR – by peripheral blood monocytes [23 ]. These results may have broader implications with respect to the mechanism of IVIG in other conditions. Clinical trials of IFNa inhibition in SLE are in progress, and results of phase I and II trials of rontalizumab (humanized anti-IFNa; Genentech) and sifalimumab (anti-IFNa; MedImmune) were reported [24,25]. In both cases, the safety profile was acceptable and there was no excess of viral infections. In the phase II trial of rontalizumab, the primary and secondary outcomes of reduction of disease activity were not met. However, patients with low type I IFN signature at baseline did have significant disease activity responses and capacity to reduce steroid dose. In the phase I trial, there was no impact of sifalimumab on disease activity relative to placebo, unless the results were adjusted for excess pulse steroids. If anything, response was better in those with a high type I IFN signature. IFNa vaccination is another strategy to therapeutically reduce type I IFN levels. Neovacs carried out a proof-ofconcept trial in SLE patients, using a KLH-IFNa conjugate vaccine, which induced anti-IFN antibodies and suppressed IFNa in those immunized [26]. In a phase I/II trial, there was suppression of IFN-regulated genes but no clinical improvement [27]. These results highlight the complexity of the relationship of the type I IFN signature to IFNa pathogenicity, and of trial interpretation in light &&
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of the capacity of steroids to inhibit the same pathway. As antigen-presentation by pDCs has been shown to promote T cell tolerance [28], alternative therapeutic strategies might utilize this property by targeting appropriate antigen to pDCs in vitro or in vivo. Sialic acid binding immunoglobulin-like lectin H (Siglec-H) is a specific marker expressed by pDCs. Loschko et al. found that Ag targeted to Siglec-H using a recombinant antibody–antigen fusion protein induced a state of anergy in T cells in vivo without induction of Treg. They demonstrated proof-of-concept of this strategy by targeting myelin oligodendrocyte glycoprotein antigen to pDCs, which delayed onset and reduced severity of experimental allergic encephalomyelitis (EAE) in mice [29]. There are a variety of other approaches that could be taken to inhibit IFNa production by pDCs, including TLR7 and TLR9 inhibition with CpG oligodinucleotides, deletion using BDCA2 or ILT7 targeting or downstream targets, such as IRAK1/4K and PI3Kd (reviewed in [21]).
OTHER DENDRITIC CELL TARGETING AND DELIVERY STRATEGIES A number of strategies to target dendritic cells in vivo for immunomodulation in autoimmune disease applications have been reported. Recombinant antibody–antigen fusion proteins have been well described for the application of antigen-specific tolerance. To understand the mechanisms and relative advantages of targeting different dendritic cell subsets in skin, myelin oligodendrocyte glycoprotein antigen-fusion proteins were constructed with antiDEC205 (CD205) or anti-langerin (CD207) to target skin migratory CD103þ dendritic cells and Langerhans cells, or with anti-Treml4 and anti-DCIR2 to target CD8þ and CD8 – lymphoid-resident dendritic cells, respectively. The authors noted that antiDEC205 was fairly nonselective, as labelled antibodies were taken up by both migratory CD103þ DCs and CD8þ lymphoid-resident dendritic cells after subcutaneous injection. Interestingly, when targeting migratory CD103þ dermal dendritic cells and Langerhans cells, Foxp3þ Treg were induced in draining lymph nodes, and EAE was suppressed. Thus, targeting of Langerin and DEC-205 induced Treg and suppressed EAE most effectively after subcutaneous injection [30]. These results confirm previous evidence that skin Langerhans cells constitutively provide low level signal for proliferation and induce tolerance in vivo, and that migratory rather than lymphoid-resident dendritic cells induce Treg conversion in lymph nodes [5,31]. Figure 1 summarizes dendritic cell subsets in mouse Volume 26 Number 2 March 2014
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and human peripheral blood, spleen and skin, transcription factors involved in their differentiation and functional specialisations. Note that all subsets are involved in tolerance involving different aspects of immunity. Alternative approaches to dendritic cell targeting employed dendritic cell ligands conjugated to nano or microparticles for delivery of antigens and other actives to dendritic cells. For example, multivalent glycopeptide dendrimers conjugated to glycan-based compounds (such as DC-SIGN) were shown to target dendritic cells, and to be internalized, to enter the lysosomes and to deliver their conjugated antigen in vivo. Ex-vivo stimulation with lipopolysaccharide induced secretion of IL-10 [32]. Poly (d lactide co-glycolide) nanoparticles were shown to target dendritic cells without inducing activation. Targeting was improved when a ligand such as anti-DEC-205 was conjugated to the particles [33]. CLEC9aþ dendritic cells were targeted for cross-presentation of protein after intravenous (i.v.) delivery of a nanoemulsion, wherein antiCLEC9a was conjugated to biosurfactant protein DAMP4 [34]. Delivery of PLGA-antigen particles intranasally induced Foxp3þ Treg in the nasopharynx and suppressed delayed-type hypersensitivity in an antigen-specific manner [35]. Li et al. reported that coimmunization of sequence-matched DNA and protein antigen induced CD11cþCD40loIL-10þ DCs (so-called ‘DC-regs’) and antigen-specific Treg. The immunogens were taken up by caveolae-mediated endocytosis and blocked caveolin-1 phosphorylation, thus increasing Tollip expression. This led to feedback induction of SOCS1 and suppression of NF-kB and STAT1a [36]. A fusion protein of cholera toxin B with glutamic acid decarboxylase antigen suppressed dendritic cell IL-12 production and increased IL-10 [37]. These studies indicate that a variety of dendritic cell targeting approaches can be used in mouse models to induce antigen-specific tolerance or to modulate dendritic cell function. Dendritic cells can also be targeted for antiinflammatory effects. Mycophenolate nanogels (without antigen) were shown to target dendritic cells in vivo and to suppress inflammatory cytokine in the NZB/W F1 model of SLE [38]. Such delivery strategies promise improved bioavailability and fewer off-target effects than systemic dosing of the drug. In an interesting variation on this theme, dendritic cells loaded with the immunosuppressive drug, FK-506 and antigen were shown to kill T cells in an antigen-specific manner. The mechanism was unusual in that dendritic cells loaded with FK-506 did not take on a regulatory phenotype but rather delivered the drug to T cells during antigen presentation, thus preventing upregulation of T cell
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bclXL and survival [39 ]. Intravenous HIV-based lentiviral vectors were reported as another antiinflammatory strategy. They preferentially transduced F4/80þLy6cþ splenic inflammatory macrophages/dendritic cells and reduced production of pro-inflammatory cytokines including IL-6 and IL-23 and reduced T cell IL-17 production [40].
NOVEL INFLAMMATORY MOLECULE AND RECEPTOR TARGETS SPECIFIC TO DENDRITIC CELLS Dendritic cells are important cells of both adaptive and innate immune system. As described above for pDCs, there are many receptors and inflammatory molecules expressed by dendritic cells, which are potentially useful targets in rheumatic or autoimmune inflammatory diseases. Dendritic cells were shown to express cannabinoid receptor 2 (CBR2). CBR2 agonists decrease autoimmune inflammation and dendritic cell production of pro-inflamamtory cytokines and capacity to stimulate CD4þ T cells. CBR2 agonists were found to inhibit dendritic cell migration from peripheral tissues by blocking MMP9 expression, which is required for dendritic cells to break down extracellular matrix and enter lymphatic vessels [10]. Similarly, oral fumarates are used for the treatment of multiple sclerosis and psoriasis. Ghoreschi found that they promote ‘type II’ dendritic cells, which produce IL-10 rather than IL-23/IL-12, and which induce Th2 T cells in vivo. Fumarate depletes glutathione and increases reactive oxygen species and heme-oxgenase-1, thereby reducing STAT-1 phosphorylation in dendritic cells. The latter prevents IL-12 and IL-23 production [41]. The ataxia telangiectasia mutated (ATM) pathway was also shown to regulate IL-23 expression by dendritic cells. Incubation of human monocytederived dendritic cells with a selective ATM antagonist increased IL-23 while low-dose ionizing radiation induced ATM phosphorylation and reduced IL-23 expression. Repression of endoplasmic reticulum stress by ATM was responsible for this effect [42]. These pathways are of direct relevance to the spondyloarthropathies. The frequency of dendritic cells in lymphoid organs is regulated in parallel with that of Treg in a flt3-dependent pathway [43]. A novel approach to suppression of autoimmune disease was taken by Billiard et al. [44 ] who blocked delta-like ligand 4-Notch signalling with nocastrin. This promoted the accumulation of thymic dendritic cells and Foxp3þ Tregs in the thymic cortex, by converting T cell progenitors to immature dendritic cells, and these in turn promoted Treg conversion. In mice, nocastrin prevented development of type 1 diabetes
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in a Treg-dependent manner, and a single treatment reversed established diabetes [44 ]. This strategy may be particularly useful in autoimmune diseases of childhood, in which the thymus would be responsive to such immunomodulation. &&
IMMUNOSUPPRESSIVE AND TOLEROGENIC DENDRITIC CELLS AND MEDIATORS OF SUPPRESSION IL-27, produced by dendritic cells stimulated by IFN-b, is a critical inducer of IL-10þ T regulatorytype 1 (Tr1) cells. In a study of mechanism, the effects of IL-27 were shown to be mediated in part by induction of the regulatory molecule CD39 in dendritic cells. CD39 reduced extracellular ATP and activation of the inflammasome [45 ]. Inflammatory myeloid Ly6chi dendritic cells/monocytes became suppressive when stimulated by IFN-g, granulocyte-macrophage colony stimulating factor (GM-CSF), tumour necrosis factor (TNF) and CD40ligand. Nitric oxide production was responsible for T cell suppression. The authors proposed that this is a natural feedback mechanism to curb inflammatory dendritic cells [46]. Low-dose GM-CSF itself can prevent the development of various autoimmune diseases in mice, through induction of tolerogenic CD8 – myeloid dendritic cells from bone marrow precursors and expansion of Foxp3þ Tregs. The Treg expansion was shown to be mediated through Jagged1 and OX40L signalling of T cell Notch3 and OX40 receptors, respectively [47]. Finally, Chen et al. [54] found that mesenchymal stem cells (MSCs)-conditioned medium drove monocytederived dendritic cells towards a myeloid-derived suppressor cell phenotype, mediated by the chemokine GRO-g [48]. Although MSC show much promise for tolerance, advances in the understanding of their mechanisms are welcome additions to the literature. Various immunomodulators alter the differentiation and function of dendritic cells such that they induce antigen-specific tolerance when exposed to antigen and injected (’tolerogenic dendritic cells’). A number of such strategies are now in clinical trials, including dendritic cells modified with the NF-kB inhibitor Bay11-7082, and dendritic cells modified with vitamin D3, dexamethasone and monophosphoryl lipid A (reviewed by [49]). Volchenkov et al. [50] generated dendritic cells modified with vitamin D3, dexamethasone and lipopolysaccharide (LPS) from primary systemic sclerosis patients. The dendritic cells suppressed T cell activation and induced a Treg population in vitro, but without antigenspecificity. Suppression was associated with high IL-8 secretion [50]. Carbon monoxide is an alternative strategy to modify dendritic cell function. &
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Endogenous carbon monoxide is released during oxidative degradation of heme proteins, by heme oxygenases, for example HO-1. The carbon monoxide releasing molecule (CORM) was found to promote tolerance independently of IL-10 and CD4þ T cells. These dendritic cells inhibited development of type 1 diabetes in mice in a CD8þ T celldependent manner [51]. Similarly, carbon monoxide could be administered to FcgRIIb-deficient lupus-prone mice either using a carbon monoxide chamber or by administration of cobalt or tin pyrophosphate. Treated mice had lower expansion of CD11bþ inflammatory dendritic cells, resulting in less renal damage and lower titres of antihistone antibodies [52]. With the aim of translation to the clinic, others are searching for molecules that can modify dendritic cells towards a tolerogenic phenotype. Matsumoto et al. [53] screened libraries of bioactive inhibitors for molecules reducing CD80, CD86 and increasing IL-10 and found a protein kinase C inhibitor with these properties. The dendritic cells generated were immunosuppressive in vitro and in vivo [53]. Dendritic cells with similar properties were induced with secretory IgA though reduction of expression of SIGNR1 [54].
CONCLUSION Much progress has been made over the last 5–10 years in the discovery of immunomodulators of monocyte-derived dendritic cell function and their development and implementation for translation to trials in autoimmune disease. Further publication of trials is anticipated. In the last 12 months, big strides have been made in the phenotypic and functional characterization, lineage relationships and transcription factors involved in the development of the various dendritic cell subsets. Several key publications have been able to link phenotype and function of mouse and human subsets, which will speed translation to human of the large amount of knowledge generated in mouse in-vivo systems. Furthermore, considerable progress has been made in the elucidation of targeting ligands and routes for induction of antigen-specific tolerance using either antigen–antibody fusion constructs or particulate conjugates. Figure 2 shows the principle behind this approach, using langerinþ skin dendritic cells as an example [30]. What is needed now is to integrate this with understanding of human disease genetics and immunopathology to determine whether antigen targeting to dendritic cells will have the predicted tolerogenic effects in the clinic. The targeting of drugs to dendritic cells for anti-inflammatory effects or for delivery to T cells is an interesting Volume 26 Number 2 March 2014
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Dendritic cells as targets in rheumatic autoimmune disease Thomas
AutoAg-anti-langerin construct or conjugate
Langerin+ DC
Skin
Ag presentation by MHC molecules
Joint Inflamed mΦ, DC, effector T cells Ag-specific regulation
RA joint
Blood Foxp3+ Agspecific induced Treg
Draining lymph node
Draining lymph node
FIGURE 2. Principle of targeting tolerogenic dendritic cell populations in vivo for antigen-specific immunotherapy. An antibody specific for a tolerogenic dendritic cell population (exemplified here by Langerhans cells) is either conjugated or engineered to include arthritogenic antigen. After injection, the complex is taken up and processed by the DC and the antigen presented in the context of MHC class II. Induced antigen-specific Treg exert antigen-specific suppression in inflamed joints. Adapted from [1].
new emerging theme. Dendritic cells remain very exciting targets and therapeutics for autoimmune rheumatic disease. Acknowledgements The author is supported by a Future Fellowship from the Australian Research Council and by Arthritis Queensland. I thank Amelie Casgrain for editorial assistance. Conflicts of interest The author has filed provisional patents surrounding technology for targeting dendritic cells for antigenspecific tolerance and is a director of a spin-off company, which is commercializing vaccines that target dendritic cells to suppress autoimmune diseases.
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