Tolerogenic dendritic cells as a therapy for treating lupus
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(2) 238. C. Llanos et al.. 4. Modulation of DC function in autoimmune diseases . . . . . . . 5. Clinical potential of tolerogenic DCs as an autoimmune treatment. 6. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1. Introduction. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. . . . . . .. 240 242 242 243 243 243. 2. Altered DC-T interactions leading to tolerance loss and autoimmunity in SLE. Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder of unknown etiology that preferentially targets young women and is associated with higher morbidity, disability, and mortality compared to the general population [1]. SLE clinical presentation is diverse, ranging from mild disease to life-threatening symptoms, such as alveolar hemorrhage and neuropsychiatric manifestations (e.g., seizures and psychosis). Although the hallmark of SLE is overproduction of autoantibodies against nuclear constituents, several other components of the innate and adaptive immune responses have been implicated in the development of this disease. Paradoxically, although several mechanisms for SLE pathogenesis have intrigued immunologists for decades, specific and effective therapies have yet to be developed. FDA approval of the first drug treatment for SLE in more than 30 years, Belimumab, was granted last year. In spite of this important breakthrough, all available medications for managing lupus, including Belimumab, work via the same mode of action, namely nonspecific suppression of the immune system. For example, recent progress in using monoclonal antibodies and fusion receptors to block cytokine pathways in rheumatic diseases, such as rheumatoid arthritis and antineutrophil cytoplasm antibody-associated vasculitides, has encouraged lupus researchers to use these same, strategies to treat SLE. Due to the adverse effects associated with these treatments, researchers continue to pursue alternative strategies for treating lupus. Recently, promising new data has emerged revealing the crucial role of the innate immune system, including Toll-like receptors (TLRs), dendritic cells (DCs), and type I interferons (IFNs), in SLE pathogenesis. Such findings have provided scientists and clinicians with new clues to unveiling the complex mechanisms leading to SLE, with the goal of developing novel, specific treatments aimed at restoring tolerance and suppressing the autoreactive immune system. Studies from the past decade have shown that the interaction between DCs and T lymphocytes is essential in maintaining peripheral tolerance to self-constituents. Thus, its role in many inflammatory and autoimmune diseases has been exploited to develop new therapies. DCs have the potential to modulate the effector response of autoreactive T cells by modifying cytokine profiles, thereby ameliorating immune disturbances. In addition, new technical approaches intended to fine-tune the function of immune cells are currently being developed. This review summarizes the most recent research advances in understanding SLE onset and progression, with a special focus on understanding the effects of modulating DCs, which have been revealed to be critical for SLE pathogenesis [2–5].. DCs are the most efficient professional antigen presenting cells (APCs). Nearly ubiquitous in peripheral tissues, DCs capture antigens and direct them to lymphoid organs with the purpose of encountering and activating antigen-specific T cells. Moreover, DCs are supplied with specialized machinery that enables them to process peptide antigens and load them onto antigen presenting molecules, such as MHC-I and MHC-II [6]. DCs also present lipid antigens to T cells through CD1 molecules [7]. DCs express co-stimulatory molecules such as CD80 and CD86 which, together with MHC, provide them with the unique ability to activate naïve T cells [6,8–10]. Besides co-stimulatory molecules, DCs also express inhibitory receptors like PD-L1, which binds PD-1 to inhibit T cells [11]. DCs sense pathogen-associated molecular patterns (PAMPs) through specialized surface receptors known as patternrecognition receptors, which include TLRs and NOD-like receptors. PAMP binding to pattern-recognition receptors promotes a phenotypic change in DCs known as maturation [12–14], which is characterized by the upregulation of surface molecules, such as signal 1 (peptide-MHC complexes) and signal 2 (co-stimulatory molecules), that enable DCs to activate naïve antigen-specific T cells (Fig. 1). A third signal, supplied by DCs already loaded with antigen, involves the release of several cytokines such as IL-12, IL-4, IFN-γ and others that define the nature of the effector response mediated by the activated T cell (Fig. 1) [5,9,10,15]. DCs maintain the balance between antigen-specific immunity and tolerance by integrating activating and inhibitory signals derived from cell surface activating/inhibitory receptor pairs (Fig. 1). A classic prototype of this dual interaction includes the Fcγ receptor family, which recognizes the Fc portion of IgG and is comprised of one inhibitory (FcRγIIB) and three different activating receptors in mice (FcγRI, III, IV) and humans (FcγRIA, IIA, IIIA) [5,10,16–19]. While activating receptors signal through immunoreceptor tyrosinebased activating motifs, inhibitory receptors function through immunoreceptor tyrosine-based inhibitory motifs [5,10,16–19]. Studies have shown that selective engagement of activating Fcγ receptors on the surface of DCs leads to enhanced DC maturation and increased priming efficiency of tumor and pathogen-induced T-cell immunity [20–22]. Accordingly, FcγRIIB knockout mice exhibit exacerbated inflammation, as evidenced by increased susceptibility to experimental autoimmune encephalomyelitis and collagen-induced arthritis (CIA) [22,23]. Furthermore, in certain genetic backgrounds, FcγRIIB deficiency causes spontaneous development of an SLE-like disease characterized by overproduction of anti-DNA. Downloaded from ClinicalKey.com at University of Chile Catholic ALERTA May 09, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved..
(3) Tolerogenic dendritic cells as a therapy for treating lupus. 239. Figure 1 DC and T/B cell interactions in SLE. DCs from lupus patients over-express co-stimulatory molecules and activating Fcγ receptors exhibiting a mature-like phenotype. This altered DCs phenotype would be more immunogenic priming naive T cells and favoring a deregulated Th1/Th17 vs. Th2 profile by secreting proinflammatory cytokines such as IL-1, IL-6, IL-12, IL-23 and TNF-α [4]. DCs from SLE patients could also interact with different B cell populations leading to plasma cell differentiation, antibody class-switching or decreased regulatory B cell function, mechanism thought to be mediated via type I IFNs. Treg function could also be blocked by proinflammatory cytokines derived from mature DCs such as IL-6 and IL-23 [46–49,63–65].. antibodies and development of autoantibody-mediated kidney damage [24]. The many functions of DCs described above are likely carried out by different DC subsets in mice and humans. Discussing every subset is beyond the scope of this review, so we will focus on the two main populations with particular importance in SLE pathogenesis, namely conventional DCs (cDCs) and plasmacytoid DCs (pDCs). Studies have established cDCs as powerful APCs that act as efficient tissue sentinels and preferentially express TLR3, 4, 5, 6, and 8. Engagement of these receptors induces cDCs to produce large amounts of tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-12, and IL-10 upon activation [6,15]. The number of cDCs in the peripheral blood of SLE patients has been shown to be markedly lower, even when compared to control patients afflicted with other autoimmune diseases that have undergone similar pharmacological treatment [3,25]. In addition, cDCs from lupus patients spontaneously overexpress co-stimulatory molecules such as CD86 and CD40 (Fig. 1) [4,26]. Likewise, the expression of activating Fcγ receptors is significantly increased on cDCs from SLE patients compared to those obtained from healthy donors (Fig. 1) [4]. These anomalies suggest that antigens may be presented to T cells in a more immunogenic manner in SLE patients. Increased immunogenicity of cDCs has also been observed in susceptible mouse strains where autologous cDCs loaded with antigens from dying cells break self-tolerance and trigger an autoimmune response characterized by anti-nuclear antibodies, anti-dsDNA antibodies, and renal damage [27,28]. This type of inflammatory response has several features in common with SLE disease in humans. On the other hand, pDCs specialize in the detection of nucleic acids, such as double-stranded RNA and CpG oligodeoxynucleotides, and thus mediate immune responses against this type of PAMP. In humans, TRL7 and TRL9 are. primarily expressed in pDC endosomes, endowing these cells with a high sensitivity to viruses [29–31]. pDCs circulate in the bloodstream and express low levels of MHC-II and CD86 along with undetectable levels of CD80, a phenotype associated with a limited capacity to prime antigen-specific naïve T cells [5,32]. Several studies have established that pDCs release large quantities of typeI IFN following TLR7 and TLR9 ligation to PAMPs such as poly:IC and CpG, respectively, due to their high, constitutive expression of IRF7 [32–34]. Interestingly, reports have demonstrated that, as a result of type I IFN secretion, pDCs can directly induce class switching in antigenspecific B cells [35–37]. This function is particularly notable since one of the main features of SLE pathogenesis is the presence of large amounts of circulating IgG autoantibodies. Although TLRs are usually recognized as receptors of ‘foreign’ antigens, they can also bind self antigens such as self-DNA, heat shock proteins, HMGB1, and fragments of the extracellular matrix [38]. Extracellular self-DNA can be transported into endosomes of pDCs associated with the innate antimicrobial peptide LL-37, a cathelicidin polypeptide, and recognized by TLR9, which leads to IFN-α production [39–41]. This process is critical for disrupting self-DNA tolerance and is associated with the onset of autoimmune conditions such as psoriasis (reviewed in [42]). In fact, patients treated with IFN-α therapy for non-autoimmune diseases, such as hepatitis C virus infection or malignant tumors, develop anti-dsDNA and anti-ANA antibodies along with a lupus-like disease, supporting the idea that pDCs might be involved in the loss of tolerance and subsequent auto-reactive response observed in lupus [43–45]. In addition to their connection to SLE development through potent IFN-α production, activated pDCs decrease regulatory T (Treg) cell function and activate Th17 lymphocytes, thereby producing the exacerbated pro-inflammatory cytokine. Downloaded from ClinicalKey.com at University of Chile Catholic ALERTA May 09, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved..
(4) 240. C. Llanos et al.. profile associated with SLE [46–49]. Ouabed and colleagues demonstrated that CpG-activated pDCs but not splenic cDCs impair the suppressive function of Tregs in rats [50]. Moreover, human pDCs stimulated with synthetic (e.g., Imiquimod, also known as R837) or natural (e.g., inactivated influenza A virus or HIV-1 ssRNA) TLR7 ligands release IL-1β and IL-23, which enable allogeneic memory T cells to produce higher levels of pro-inflammatory cytokines (IL-17A, IL-17F, IL-22, IL-26, and CCL20) and RORC, a pattern consistent with a Th17 phenotype [31]. CpG-treated pDCs have also been shown to promote Th17 differentiation in vitro by producing IL-6, TGF-β, and TNF-α, which improve survival after adoptive transfer and reduce tumors in nude mice [51]. In addition, several lines of evidence suggest that different subsets of DCs are able to induce distinctive T helper responses [15,52]. Interestingly, Kim et al. have shown that DCs from female mice lacking Blimp-1, a crucial regulator of plasma differentiation of B cells, enhance the expansion of T Follicular Helper (TFH) through IL-6 production [53]. These alterations in T cell differentiation result in the hyper-production of autoantibodies and a lupus-like phenotype. Several studies have highlighted the contribution of immune complexes to the immune activation and tissue injury observed during SLE pathogenesis. These structures consist usually of autoantibodies binding either to RNA, DNA or nuclear proteins and are abundantly present in SLE patients. Increasing evidence reveals that TLRs recognize RNA and DNA when added along with SLE IgG to pDCs in vitro; however, this is not observed for non-SLE IgG after FcγRIIa-dependent IC endocytosis [54–56]. Therefore, pDCs act as a major player involved in the balance between tolerance and disease onset as these cells can promote intense humoral and cellular immune responses in the presence of nucleic acids. Strategies pointing towards modulation of TLR signaling in pDCs could lead to successful development of effective SLE therapies. This notion is reinforced by evidence that hydroxychloroquine, a drug commonly used to treat SLE, decreases IFN-α and TNF-α production in pDCs upon TLR7 and TLR9 ligation [57].. 3. DC-B-cell interactions and their contribution to SLE B lymphocytes are mostly recognized for their role as antibody-secreting cells. Consequently, due to the presence of autoantibodies, lupus has been traditionally identified as a disease of B cells. In addition to its role in DCs, the inhibitory receptor FcγRIIb exerts several important functions on B cells, including regulation of B-cell activation and maintenance of peripheral B-cell tolerance [24,58]. Once activated by specific antigens, B cells synthesize cytokines and function as APCs, processing and presenting specific antigens on MHC-II molecules to CD4 + T lymphocytes [59,60]. In this context, B cells could be considered relevant players in the APC–T-cell interaction in SLE since they could present autoantigens to T cells. Alternatively, B cells can down regulate T-cell responses via FasL-mediated mechanisms [61,62]. Tian, et al. showed that activated B cells that express FasL and TGF-βinduce Th1 cell apoptosis, thereby suppressing autoimmune diabetes in NOD mice [61]. Anomalies in B-cell regulation could play a role in the development of exacerbated inflammatory responses, such as in autoimmune disorders. involving T-cell priming and DC modulation. In fact, studies have shown that CD19 +CD24 highCD38 high B cells from SLE patients exhibit impaired suppressive activity towards CD4 + T-cell cytokine production [62]. There is mounting evidence that the crosstalk between DCs and B-lymphocytes may also be pertinent to SLE pathogenesis. Wan, et al. showed that activated DCs in lupus-prone mice can induce B-cell proliferation and enhance antibody production [63]. In fact, studies have established that pDCs can induce plasma cell differentiation and promote antibody secretion through type 1 IFN production and CD70 expression [64]. More recently, using a lupus-prone mouse model where cDCs and pDCs are constitutively deleted, Teichmann and coworkers showed that these cells are necessary for plasmablast generation and antibody class-switching [65]. Surprisingly, in these mice, autoantibody serum levels but not total immunoglobulin concentration were lower. Furthermore, this DC-deficient lupus-prone mouse strain displayed markedly less proteinuria and a milder form of renal damage compared to MRL.Fas lpr mice with a normal number of DCs. These data suggest that DCs are crucial for lupus development and could be a potential therapeutic target for treating SLE [65]. Reports also indicate that a novel subset of regulatory DCs induce B lymphocytes to differentiate into regulatory B cells capable of exerting regulatory functions in vitro and in vivo through IL-10 secretion [66]. Interestingly, although lupus patients display a similar number of regulatory B cells compared to healthy controls, they produce less IL-10 and are unable to suppress cytokine production by CD4 + T cells [62]. A better understanding of the B-cell regulatory network could provide new therapeutic tools for developing efficient autoimmune therapies targeted against DCs.. 4. Modulation of DC function in autoimmune diseases Immature or tolerogenic DCs express low levels of surface MHC molecules, possess a lower co-stimulatory to inhibitory signal ratio, and exhibit reduced pro-inflammatory cytokine production (Fig. 2) [15,67]. The ability of this specific DC subset to either induce Treg expansion and/or render T lymphocytes anergic makes them especially attractive as targets for cell-based therapies for treating autoimmune diseases (Fig. 2). Furthermore, it is currently possible to expand and modulate DCs in vitro to generate cells with tolerogenic capacity. Several methods are available to generate tolerogenic DCs. Maturation can be pharmacologically inhibited in vitro to obtain cells that are unresponsive to danger and pro-inflammatory signals that may be present in the cellular environment of patients receiving the treatment. In an effort to generate tolerogenic DCs that retain this phenotype in vivo, DCs have been manipulated with several anti-inflammatory and immunosuppressive drugs that interfere with various checkpoints of DC differentiation, maturation, and expansion (e.g., VitaminD3, aspirin, rapamycin and rosiglitazone, HO-1 inducers, spironolactone and andrographolide; (Fig. 2) [68–74]. Our group has shown that inhibition of nuclear factor kappa B (NFκB) in DCs promotes an immature phenotype that renders them unresponsive to inflammatory stimuli and unable to. Downloaded from ClinicalKey.com at University of Chile Catholic ALERTA May 09, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved..
(5) Tolerogenic dendritic cells as a therapy for treating lupus. 241. Figure 2 Pharmacologic modulation of DCs. Anti-inflammatory and immunosuppressive drugs act via multiple mechanisms mainly affecting different checkpoints of DC maturation, co-stimulation, proinflammatory cytokines production and T cell priming. Vitamin-D3 exerts its function binding to its receptor and initiating genomic responses [69]; aspirin inhibits COX1/2 (cyclooxygenase) [72]; rapamycin inhibits mTOR activity [73,74]; rosiglitazone binds to PPARs and initiates genomic responses [75,76]; Cobalt Protoporphyrin, an HO-1 inducer, binds to HO-1 promoter and initiates its transcription [95]; spironolactone blocks the binding of aldosterone with mineralocorticoid receptor [96]; and andrographolide blocks signaling pathways of NFkB activation [71,76].. activate T cells [9,71,75,76]. More recently, other modulation strategies, such as gene-based therapy and the use of helminth-derived extracts, have also been explored. Silencing of the IL-12 p35 gene using siRNA has also been tested in CIA. The treated DCs were less able to induce allogeneic T-cell proliferation and displayed a Th2 phenotype, which was advantageous in changing the cytokine balance of a Th1/ Th17-mediated disease such as CIA [77]. A similar rationale was adopted by Carranza and coworkers when Fasciola hepatica total extracts were used to modulate DCs treated with CpG and pulsed with bovine collagen II. These cells produced higher levels of IL-10 and TGF-β relative to controls and lower levels of pro-inflammatory cytokines, such as IL-12p70, TNF, IL-6, and IL-23, than cells treated with CpG alone [78]. Moreover, when CIA mice were treated with these cells, the inflammatory symptoms were ameliorated [78]. Regarding the mechanisms underlying DC-induced tolerance, results from DC and Treg crosstalk studies have suggested that inhibition of pro-inflammatory cytokines may be crucial for promoting peripheral tolerance. Tregs are critical for maintaining peripheral T-cell tolerance because their depletion leads to autoimmunity [79,80]. In addition, it has been reported that in vitro DC maturation impairs Treg function [81]. DCs stimulated with TLR ligands, such as LPS and CpG, interfere with Treg cell-mediated suppression through. the production of IL-6 and other as-yet unidentified cytokines in a process that is independent of cell surface co-stimulatory receptor expression on DCs [81,82]. IL-6 may play a major role in T-cell activation due to its ability to overcome Tregmediated suppression. Treg inhibition by DCs could be especially important in SLE patients where IL-6, among other cytokines, is increased [83,84]. In a triple SLE–congenic lupus-prone mouse, IL-6 overproduction by DCs resulted in inhibition of Treg activity [82]. Lack of a well-defined autoantigen is a major hindrance in the use of tolerogenic DCs for SLE treatment. However, the possibility of modulating DCs as a treatment strategy has been explored. Using mice that spontaneously develop SLE as a result of genetic deletion of FcγRIIb, our laboratory investigated the ability of NFκB inhibitors, such as andrographolide and rosiglitazone, to prevent disease onset [85]. Mice treated with these inhibitors showed reduced immune complex deposition in the glomeruli, leading to protection from inflammation in the kidney and prevention of proteinuria [85]. These treatments also reduced circulating autoantibody levels significantly [85]. Furthermore, splenic DCs from mice treated with the NFκB inhibitors exhibited a reduction in maturation marker expression (e.g., CD40 and CD86) compared to control mice [85]. Collectively, these data suggest that the essential underlying mechanism for SLE disease amelioration involved the. Downloaded from ClinicalKey.com at University of Chile Catholic ALERTA May 09, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved..
(6) 242. C. Llanos et al.. generation of immature DCs after NFκB inhibition [85]. In other studies, lupus-prone mice were treated with subnanomolar concentrations of a nucleosomal histone peptide. Tolerogenic DCs were purified from peptide-treated animals and adoptively transferred into non-treated lupus-prone mice. Interestingly, the treated animals showed a decrease in both circulating ANAs and renal damage [86]. Similarly, when lupus mice were administered a peptide derived from the complementarity-determining region-1 (hCDR1) of an anti-DNA antibody, SLE was ameliorated [87]. Moreover, DCs from the immunized animals expressed lower levels of MHC-II, CD80, and CD86, which is consistent with an immature/tolerogenic phenotype [87]. Although numerous strategies have been described for inducing tolerogenic DCs, comparative studies evaluating the effectiveness of these tolerogenic strategies are still required to develop an adequate suppressive therapy.. 5. Clinical potential of tolerogenic DCs as an autoimmune treatment Based on the general mechanisms underlying autoimmune diseases, the most logical goal of any treatment would be to restore immune tolerance to self antigens without compromising the ability of the immune system to efficiently respond to foreign threats. In systemic autoimmune diseases such as lupus, the breakdown in tolerance is widespread and involves autoantigens that are present in several cell types, making the design of therapies based on antigen-specific tolerance more difficult. DCs can be found in two different functional states, immature/tolerogenic and mature/immunogenic. It is important to note that, due to their capacity to induce antigen-specific tolerance, immune modulation with tolerogenic DCs does not induce general, widespread immunosuppression. Therefore, use of these cells as a treatment would not be associated with an increased susceptibility to pathogens and opportunistic infections, which is one of the most common complications linked to currently available conventional immunosuppressant drugs. Moreover, new biologic agents have been associated with an overall increased risk of adverse events compared to placebo and, although still controversial, have also been reported to elevate the risk of developing solid tumors [88,89]. In this regard, since immature DCs could promote specific tolerance to autoantigens, they should not disrupt the immune system's ability to maintain vigilance against malignancies, thereby conferring an additional benefit to this therapeutic approach. Furthermore, the use of tolerogenic DCs to treat autoimmune diseases has already been explored in type 1 diabetes mellitus. Giannoukakis, et al. conducted a randomized placebo-controlled trial to evaluate the safety of autologous tolerogenic DCs in 10 patients with type 1 diabetes mellitus [90]. Tolerogenic DCs were generated using anti-sense oligonucleotides for CD40, CD80, and CD86 transcripts and administered. The placebo group received autologous unmanipulated DCs. These researchers reported that this therapy was well-tolerated by the diabetes patients, who also did not experience any adverse effects 1 year later [90]. This approach was also successfully evaluated as a treatment for rheumatoid arthritis (RA). Tolerogenic DCs derived from peripheral monocytes of RA patients were. generated using NFκB inhibitors and pulsed with citrullinated peptides known to be potential relevant antigens in RA. A single dose of these tolerogenic DCs was administered to 29 RA patients. Only mild adverse effects were reported and activity scores of the disease were consistent with a decrease in inflammatory parameters [91]. The use of ex vivo-generated tolerogenic DCs pulsed with a restricted mix of SLE-associated antigens (e.g., nucleosomes, Ro, La, Sm, and, histone 2a) would be a potential experimental approach to reestablishing peripheral tolerance towards antigen-specific CD4 + T cells and (indirectly) B cells [92–94]. Interestingly, Crispin et al. isolated monocytes from lupus patients and generated DCs in vitro using IL-4 and GM-CSF. Surprisingly, the responses to stimuli such as TNF-α and LPS were abnormal in DCs from these SLE patients, showing reduced upregulation of co-stimulatory molecules and surface maturation markers relative to healthy controls. Nonetheless, the researchers evaluated the ability of these cells to induce tolerance using an allogeneic recall assay. Interestingly, IL10-treated DCs maintained their ability to induce tolerance, as evidenced by a lower proliferation index of allogeneic primed T cells. These data highlight the promising nature of this therapeutic strategy as an effective therapy. However, one potential problem with a therapy based on autologous DCs could be the difficulty in tracking these cells once they are infused in a patient. Monitoring the administered DCs would allow us to evaluate their lifespan and homing, which would provide valuable information for establishing suitable dosages and confirming that the cells actually reached the target tissue [92]. Patient response to the therapy and dosage should be addressed using clinical endpoints and safety parameters. Alternatively, the effectiveness of this treatment can be assessed by evaluating changes in the number of circulating Tregs or the expression of appropriate biomarkers affected by tolerogenic DCs in vivo.. 6. Concluding remarks This review highlights the most relevant work pertaining to understanding the involvement of DCs in SLE onset and progression. The data support a critical role for the DC–T-cell interaction in the loss of tolerance and maintenance of autoimmunity in this disease. Most importantly, recent research suggests that modulation of DCs could be an effective, promising new strategy for treating SLE. Additional research is required to elucidate the relevant antigens to use and the mechanisms involved. Nevertheless, DC modulation as a therapeutic approach provides several advantages, including increased safety and specificity, as well as potentially lower cost and financial burden to health care systems and patients. Although we believe that current data support the rationale behind the use of tolerogenic DC as a therapeutic strategy for treating lupus, several relevant issues remain to be defined to continue the progress in this area. Questions, such as which tolerogenic DC and autoantigen to use for therapy, the route of administration, the characteristics of the patients and when to administer the treatment during the disease course, need to be addressed. A better understanding of the DC role in SLE pathogenesis would definitely provide some of the answers needed and may increase the possibilities of using DCs as a therapy for SLE and other autoimmune diseases.. Downloaded from ClinicalKey.com at University of Chile Catholic ALERTA May 09, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved..
(7) Tolerogenic dendritic cells as a therapy for treating lupus. Conflict of interest statement The author(s) declare that there are no conflicts of interest.. Acknowledgments The authors are supported by grants FONDECYT no. 1110518, FONDECYT no. 1070352, FONDECYT no. 1085281, FONDECYT no. 1100926, FONDECYT no. 3070018, FONDECYT no. 3100090, FONDECYT no. 11075060, FONDECYT no. 1100926, and FONDECYT no. 1110397. CONICYT Capital Humano Avanzado en Academia no. 791100015 and Millennium Institute on Immunology and Immunotherapy (no. P09/016-F). AMK is a Chaire De La Région Pays De La Loire De Chercheur Étranger D'excellence and a CDD-DR INSERM.. References [1] S. Bernatsky, et al., Mortality in systemic lupus erythematosus, Arthritis Rheum. 54 (8) (2006) 2550–2557. [2] P. Blanco, et al., Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus, Science 294 (5546) (2001) 1540–1543. [3] P. 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