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The diverging roles of dendritic cells in kidney allotransplantation
Transplantation Reviews xxx (2015) xxx–xxx
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The diverging roles of dendritic cells in kidney allotransplantation☆ Manuel Alfredo Podestà ⁎, David Cucchiari, Claudio Ponticelli Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano – Milano, Italy
a b s t r a c t Dendritic cells (DCs) are a family of antigen presenting cells that play a paramount role in bridging innate and adaptive immunity. In murine models several subtypes of DCs have been identified, including classical DCs, monocyte-derived DCs, and plasmacytoid DCs. Quiescent, immature DCs and some subtypes of plasmacytoid cells favor the expression of regulatory T cells, but in an inflammatory milieu DCs become mature and after intercepting the antigen migrate to lymphatic system where they present the antigen to naïve T cells. Transplant rejection largely depends on the phenotype and maturation of DCs. The ischemia–reperfusion injury causes the release of endogenous molecules that are recognized as danger signals by the pattern recognition receptor of the innate immunity with subsequent activation of inflammatory cells and mediators. In this environment DCs become mature and migrate to lymphonodes where they present the alloantigen to T cells and direct their differentiation towards Th1 and Th17 effector cells. On the other hand, manipulation of DCs may favor T cell differentiation towards tolerant Th2 and T regulators (Treg). Experimental studies in murine models showed the possibility of inducing an operational tolerance by injecting immature tolerogenic DCs. Recently, such a possibility has been also confirmed in primates. Although manipulation of DCs may represent an important step ahead in kidney transplantation, a number of technical and ethical issues should be solved before its clinical application. © 2015 Elsevier Inc. All rights reserved.
1. Introduction In 1868 Paul Langherans, still a student, first described branched cells resembling neurons in the skin [1]. For many years the function of these cells remained an enigma, although their frequent presence in inflammatory granulomas led to hypothesize a possible protective role of these cells against infection. In 1973 Ralph Steinman and Zanvil Cohn, by using phase-contrast light microscopy, identified a novel type of cells in adherent cell populations prepared from mouse peripheral lymphoid organs. These cells represented only 0.1–1.6% of the total nucleated cells and had strange morphological features. The nucleus was large, retractile, contorted in shape, with two or more small nucleoli. The abundant cytoplasm contained many large spherical mitochondria. The cells had characteristic movements and showed branched projections. The authors proposed the term dendritic cells (DCs) for this novel cell type [2,3] and demonstrated their importance in stimulating the leukocyte reaction [4]. Since then, further studies elucidated the origin of DCs and their central role in immune regulation. 2. Ontogenesis and functions of DCs DCs are a family of professional antigen-presenting cells (APCs). DCs can be found in the skin and mucosal tissues (Langerhans cells), in ☆ Funding: No support has been provided for this paper. ⁎ Corresponding author at: Istituto Clinico Humanitas IRCCS, Via Manzoni 56, 20089 Rozzano – Milano, Italy. Tel.: +39 3420036285. E-mail address: [email protected] (M.A. Podestà).
parenchymal organs and gastrointestinal apparatus, in thymus, lymph nodes and in blood. Anatomically-wise, DCs may be divided in “resident” lymphoid tissue and “migratory” non-lymphoid tissue DCs. Although the ontogenesis of human DCs is still poorly defined, murine models provided great insight on their different roles. Multiple subsets of DCs have been identified in mouse (Table 1). They could be roughly divided in classical DCs (cDCs), monocyte-derived DCs (moDCs) and plasmacytoid DCs (pDCs) (Fig. 1). The term “myeloid” is often used to distinguish all types of DCs from pDCs, which were originally described as lymphoid. Classical DCs can be further divided into two subsets characterized by either CD8α/CD103 (cDC type 2) or CD11b (cDC type 1) expression. + (found in lymphoid tissues) and CD103 + (found in nonCD8α lymphoid tissues) cDCs are the best characterized murine DCs subset and seem to play a major role in antigen presentation to CD8 + T-cells through MHC-I. CD11b + DCs in contrast are more ill-defined and show superior induction of CD4+ T-cell proliferation [5]. cDCs may originate from both myeloid and lymphoid precursor, but are more frequently derived from a common monocyte-DC precursors in the bone marrow [6]. However, the fact that DCs acquire the expression of the marker CD8α only after their maturation may suggest that some DCs come from lymphoid cells that acquire the CD8 + phenotype on CD40CD40L engagement [7]. Monocyte-derived DCs, also known as inflammatory DCs, are a heterogeneous group of cells that are originated from phlogistic monocitic infiltrates, as supported by their expression of CD64/FcγRI [8,9] in addition to CD11c, CD11b and Ly6C [10]. These cells produce TNFα and iNOS and were shown to favor Th17 polarization [11].
http://dx.doi.org/10.1016/j.trre.2015.04.001 0955-470X/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Podestà MA, et al, The diverging roles of dendritic cells in kidney allotransplantation, Transplant Rev (2015), http:// dx.doi.org/10.1016/j.trre.2015.04.001
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Table 1 Characterization of murine and human DCs subsets identified by the most commonly employed cellular markers. Localization
Origin
DC subset
Markers (mouse)
Markers (human)
Proposed function
Lymphoid tissue
Myeloid
cDC type 1
CD1c (BDCA-1) [11]
Induction of CD4+ T-cell proliferation
Myeloid
cDC type 2
CD141 (BDCA-3) [11]
Antigen presentation to CD8+ T-cells
Myeloid
moDC
CD11c, CD14 [11,22]
Inflammation, tissue repair
Plasmacytoid
pDC
cDC type 1
CD303 (BDCA-2), CD304(BDCA-4), CD123 (IL-3R) [21] CD1c (BDCA-1) [24]
Interferon production, tolerance (?)
Myeloid
Myeloid Myeloid
cDC type 2 moDC
CD11b, CD11c [5,13] CD8α, CD11c [5,13] CD11c, CD11b, Ly6C, CD64 [9,10] mPDCA1, CD4, CD45RA [13,14] CD11b, CX3CR1, F4/80, SIRPα [17] CD103 [17]
Antigen presentation to CD8+ T-cells Inflammation, tissue repair
Plasmacytoid
pDC
CD141 (BDCA-3) [26] CD209 (DC-SIGN) CD1c (BDCA-1) CD68 [24] CD303 (BDCA-2) CD123 (IL-3R) [24]
Kidney
Plasmacytoid DCs are circulating dendritic cells mainly found in lymphoid organs and characterized by a well developed secretory apparatus that produces high doses of type I interferon upon viral infections [12]. pDCs express high levels of mPDCA1, but display a rather low expression of CD11c or CD14, which distinguishes them from cDCs or monocytes, respectively [13,14]. While it is relatively simple to purify DCs from lymphoid organs, consistent efforts were required to identify and characterize non-
Induction of CD4+ T-cell proliferation
Interferon production, tolerance (?)
lymphoid tissue DCs. Renal resident DCs have been localized in close proximity to peritubular capillaries in mice by identification of CD11c through immunohistochemistry [15]. These cDCs are originated from bone marrow progenitors, but a derivation from circulating Ly6C + monocytes, which infiltrate the kidney upon inflammation, has also been considered [16]. CD11c + renal cDCs can be further divided in two different subsets, based on the expression of either CD103 or CD11b, CX3CR1 and F40/80 [17].
Fig. 1. Schematic representation of DCs subsets and their main functions. cDCs are originated from a common monocyte-DC precursor, and can be further divided in two subsets in mice + /CD103+ type 2 and CD11b+ type 1) that share common features with human BDCA-3+ and BDCA-1+ DCs respectively. Type 1 cDCs show superior induction of CD4+ T-cell pro(CD8α liferation, while type 2 cDCs play a major role in antigen presentation to CD8+ T-cells. moDCs are originated from inflammatory monocitic infiltrates and favor Th17 polarization. pDCs are circulating DCs that produce high doses of type I interferon upon viral infections.
Please cite this article as: Podestà MA, et al, The diverging roles of dendritic cells in kidney allotransplantation, Transplant Rev (2015), http:// dx.doi.org/10.1016/j.trre.2015.04.001
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Mouse and human DCs system share some similarities; however murine markers such as CD8α and CD11b are not expressed on human cDCs. Consistent efforts have been directed towards the creation of a unified classification (Table 1). For instance, based on transcriptomic and functional studies, human CD1c +/BDCA1 + lymphoid tissueresident and human CD207 − CD14 + non-lymphoid cDCs have been grouped as CD11b +-like cDCs, while it was demonstrated that CD141/ + cDCs BDCA3 + shares a distinct gene signature with mouse CD8α [18–20]. pDCs in humans are characterized by the expression of CD123/IL-3R, CD303/BDCA-2 and CD304/BDCA-4, and by the absence of the common myeloid markers [21]. Human moDCs have been only recently identified in psoriatic skin and malignant ascites, but their full characterization remains somewhat controversial [22,23]. Woltman et al. reported the first detailed analysis of DC subsets in the human kidney. They described two different subsets of myeloid DCs in donor pre-transplant biopsies, defined by either positive staining for BDCA-1+, CD68+ and DC-SIGN+ (moDCs) or single positive staining for BDCA-1+ (cDCs type 1) [24,25]. In addition, the authors also detected a minor population of BDCA-2+ plasmacytoid DCs in tubulointerstitial areas. Interestingly, none of these cellular subsets were positive for DC-LAMP, thus indicating that renal DCs are immature [24]. BDCA-3 + cDCs were identified in kidney biopsies from patients with active lupus nephritis, although they were not present in normal kidneys [26]. 3. DCs as regulators of the immune response The ability of DCs to regulate immunity is dependent on their maturation in an inflammatory milieu. Pathogen associated molecular patterns (PAMPs) and danger associated molecular patterns (DAMPs) are recognized by Toll-like receptors (TLRs) and other receptors of the innate immunity, such as NOD-like and RIG-I receptors. TLRs activate a number of adapter proteins (i.e. MyD88, IRAK, TRAM, TRAF, TRIF) that mediate specific protein–protein interactions eventually leading to the formation of transcription factors—nuclear factor kinase B, interferon regulator3, mitogen-activated protein3—which induce or inhibit the genes that organize the inflammatory response [27]. A variety of factors favoring an inflammatory environment can induce maturation of DCs, including bacterial-derived antigens, viral products, inflammatory cytokines, CD40/CD40L engagement. Mature DCs exert three distinctive
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functions: (i) a sentinel role in which antigens are captured and presented, (ii) a migratory function, in which DCs move to the T-dependent areas of lymphoid organs and bind antigen-specific T cells, (iii) an activation role, in which T-cell growth and effector function are induced (Fig. 2). Interestingly, DCs may present captured antigen on both MHC-I and MHC-II class molecules. The former mechanism, which relies on endocytosis and proteasome processing, leads to CD8 + T-cell activation through a process termed cross-presentation, which enables immune response against intracellular pathogens. In contrast, MHC-II molecules assembly is attained through lysosome breakdown of endocytic vesicles, which results in antigen presentation and activation of CD4 + T-cells. This function is tightly controlled by a number of factors leading to DCs maturation, such as Toll-like receptor (TLR) signaling and exposure to inflammatory cytokines [28]. On the other hand, immature DCs may induce tolerance by immune response down-regulation. When antigens are experimentally delivered to DCs without maturation stimuli, MHC–peptide complexes are formed in the steady state. Naïve T cells, after recognizing their ligands on these DCs, divide repeatedly but are then deleted [29] and favor the generation of Foxp3+ T regulators (Tregs), which can be specific for either self- or non-self antigens [30]. Furthemore, thymoid DCs present self-antigens to naïve T-cells, inducing the process of clonal deletion and positively selecting natural Tregs [31]. Thus, DCs can no longer be considered as a homogeneous cell type performing a single function of defense against pathogens and foreign antigens. Their phenotype and function depend on white cell lineages and maturation stimuli that can activate divergent arms of the immune system. Further studies will be required to fully elucidate the role of human subsets of DCs. 4. Innate immunity in allotransplant Innate immunity plays a pivotal role in initiating an autoimmune response and in defending against oncogenic events [32,33]. In allotransplantation, innate immunity can be triggered in the donor even before the transplant. In the case of deceased donor the sympathetic system hyperactivity, associated with brain death, causes a generalized ischemia aggravated by the use of vasoconstrictor agents, which are necessary to sustain the circulation. After clamping the kidney vessels, the
Fig. 2. Maturation and migration of DCs: from a tolerant to an immunogenic phenotype. In a quiescent environment DCs release cytokines that can favor the development of immunological tolerance. However, in presence of pathogen aggression or release of endogenous substances by stressed cells, the molecular patterns of PAMPs or DAMPs are recognized by TLRs and other receptors of the innate immune recognition system. These receptors recruit adapter proteins which activate several kinases that amplify the signal, leading to activation of nuclear factor kB and interferon regulator 3. These transcription factors can induce genes that orchestrate the immune and inflammatory response. In an inflammatory environment, DCs become mature and migrate to lymphonodes where they present the antigen to the T cells so allowing the activation of the adaptive immunity.
Please cite this article as: Podestà MA, et al, The diverging roles of dendritic cells in kidney allotransplantation, Transplant Rev (2015), http:// dx.doi.org/10.1016/j.trre.2015.04.001
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short warm ischemia and the longer cold ischemia further reduce the oxygen and energetic supply leading to generation of reactive oxygen species, intra-cellular acidosis caused by the increased production of lactic acid from anaerobic glycolysis, and cell swelling caused by the impaired function of ATP-dependent sodium–potassium pumps [34]. These changes can cause damage to all cellular components that may ultimately result in cell cycle arrest and even cell death. The reperfusion of an ischemic kidney may result in further inflammation and oxidative damage, a paradoxical phenomenon termed ischemia–reperfusion injury (IRI). The microvascular injury caused by ischemia enhances fluid filtration and leukocyte plugging in capillaries and in postcapillary venules. After reperfusion, damaged endothelial cells secrete additional reactive oxygen species and favor the release of inflammatory mediators and proteolytic enzymes. Among them, caspases can mediate apoptosis in a significant number of sub-lethally injured cells. In addition to endothelial cells, proximal tubular epithelial cells are particularly vulnerable to the toxic effects of reperfusion and tend to undergo more necrosis in comparison with the less sensitive segments, because they have higher metabolic demands [35,36]. The dying cells release in the extra-cellular space endogenous molecules that are recognized as DAMPs from the pattern recognition receptors of the innate immunity.
deletion of the T clone or generation of Tregs. Nevertheless, mature DCs can transfer these molecules to other immune cells (i.e. B-cells and monocytes) that can operate as APCs [48,49]. The antigen may be presented to T cells by the donor DCs (direct pathway), by the recipient DCs in case of donor DCs depletion (indirect pathway) or by a passage of alloantigen from donor to recipient DCs (semidirect pathays). T cell polarization is of paramount importance in determining the effect of the immune response on the allograft. Differentiation towards the pro-inflammatory Th1 and Th17 phenotypes has a pivotal role in rejection, whereas Th2 and Treg polarization results in a protective effect on the transplanted organ. This polarization is guided by DCs and is controlled by cytokines, transcription factors and environmental factors. Aside from TCR and B7-group signaling, other DCs receptors seem to greatly influence microenvironment and skew T-cell polarization. Sphingosine-1 phosphate (S1P), a sphingolipid produced by phosphorilation of sphngosine, is the natural ligand for a family of five G-protein coupled receptors. The absence of S1P3 on DCs prevents their maturation and skews T-cell polarization towards a Th2 phenotype, thus attenuating IRI [50]. These findings suggest the importance of DCs S1P3 in modulating T cell function and support the development of S1P3 antagonist in tolerance induction in organ transplantation. 6. The dual role of DCs in rejection
5. DCs as the bridge between innate and adaptive immunity IRI and inflammation are the essential steps that lead to maturation of DCs in kidney transplant. Even before undergoing necrosis, damaged cells release several DAMPs, among which the best studied are HighMobility Group Box 1 Protein (HMGB1) and heat-shock proteins (HSPs), such as HSP72. Generation of reactive oxygen species (ROS) can moreover damage extra-cellular proteins, creating fragments of hyaluronan, fibronectin and heparan sulfate that can elicit TLRsmediated DCs activation [37]. Upon receptor engagement with these DAMPs, DCs modify their phenotype, increasing expression of MHCrelated proteins, which are essential to intercept the antigen. In addition, upon challenge with DAMPs, DCs express chemokine receptors that lead them to the T-dependent zone of secondary lymphoid organs, where the interaction between innate and adaptive immunity finally occurs. Their capacity to migrate, their constitutive expression MHC-I and MHC-II, as well as co-stimulatory and adhesion molecules, make DCs ideal cells for the activation of naïve T cells [38]. An important role is played by interleukin 12 [39] and chemokine receptors that help DCs to migrate into the T-cell zone of lymphoid organs [40]. Complement can also contribute to the link between innate and adaptive immunity: for instance, the component C3 can modulate cell-mediated response [41]. Moreover, the C3d component binds to the CR2 receptor on the surface of follicular DCs and favors the interaction with the CR2-associated antigen on B cells, triggering antibodymediated response [42]. The C5a component expressed on DCs favors their maturation and their capacity of activate T cells [43]. The terminal components C5b-C9 bind to APC and help them in the direct recognition of the antigen [44]. Thus, DCs are critical early initiators of innate immunity in the kidney and orchestrate inflammation subsequent to IRI. They are capable of inducing sterile inflammation after reperfusion directly through the production of proinflammatory cytokines and other soluble inflammatory mediators or indirectly through activation of effector T lymphocytes and natural killer T cells (NKT), innate-like lymphocytes that bind to glycolipid antigens presented by CD1d [45]. T-cell activation by DCs requires two signals: the first one is provided by the contact between the MHC-mounted antigen and the specific T-cell receptor (TCR). The second signal of co-stimulation is generated by the contact between molecules of the B7 group on the surface of DCs (CD80 and CD86) and adhesion molecules on the surface of the T cell (CD28). The presence of co-stimulatory molecules is a typical prerogative of DCs [46,47] and their absence favors tolerance, leading to
Monocyte–macrophages have been found as the predominant cellular infiltrate in kidney allograft rejection and represent a major outcome indicator [51,52]. Zuidwijk et al. analyzed and quantified DC subsets in a setting of acute rejection, finding an exceptionally high number of mature renal DC-SIGN + myeloid DCs (moDCs), which exceeded the renal BDCA-1 + (type 1) cDCs. The increased moDC/cDC ratio supports the theory of a monocitic infiltration of the kidney in the setting of acute rejection, with subsequent local differentiation to moDCs. The density of both myeloid subsets of mature DCs was associated with high inflammation score of the Banff 07 classification, graft interstitial fibrosis/ tubular atrophy and loss of renal function in the long term [53], showing that both myeloid subsets are involved in acute allograft rejection. Plasmacytoid DCs have been frequently associated to tolerance induction [54,55]. However, pDCs were found to be increased in acute allograft rejection, and their density appeared to correlate with inflammation and chronic injury [53]. Experimental studies suggest that localization of DCs may influence their function: graft-resident DCs and locally recruited systemic DCs may indeed exert different roles that can influence the outcome of the kidney allograft. Studies in rat showed that renal cold IRI caused loss of graft DCs and progressive infiltration of host DC and CD4 + T cells with effector/effector-memory phenotypes. These changes in graft/ host DC populations were associated with development of tubulointerstitial lesions, suggesting that graft–resident DCs might have a protective role while infiltrating host DCs exert deleterious effects on graft function [56]. In addition to origin and localization, also soluble mediators of the microenvironment are likely to influence DCs phenotype and function in the kidney. In conditions of cellular stress such as hypoxia/IRI, adenosine extracellular concentrations increase by enhanced conversion of ATP. Adenosine, acting on several specific receptors (i.e. A1AR, A2AR, A2BR and A3R), mediates adaptation to hypoxia, conferring an antiinflammatory state and a protective effect at cellular level [57]. By contrast, ATP released by apoptotic cells acts as both a DAMP and a chemoattractant for neutrophils and monocytes [58]. The enzymatic conversion steps from ATP to adenosine are regulated by two enzymes, CD39 and CD73 [59]. Activation of A2AR expressed on DCs and T cells suppresses the immune response in allograft rejection [60]. Consistent with this finding, the expression of human CD39 in transgenic mice enhances the conversion of extracellular ATP to adenosine, and was shown to be protective in a murine renal transplant model characterized by prolonged cold
Please cite this article as: Podestà MA, et al, The diverging roles of dendritic cells in kidney allotransplantation, Transplant Rev (2015), http:// dx.doi.org/10.1016/j.trre.2015.04.001
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ischemia [61]. Recent experimental data also showed that DCs tolerized with an A2AR agonist suppress NKT cell activation in vivo, attenuating IRI [62]. These studies demonstrated that renal interstitial DCs phenotype is determined at least in part by the expression of A2AR. In summary, in organ transplantation DCs have a central role in initiating alloantigen-specific immunity, but they may also favor an operational tolerance. These contrasting effects of DCs depend on their origin and state of quiescence or maturation as well as by their location and the chemical composition of the surrounding microenvironment. 7. Manipulation of DCs in allotransplant recipients Tolerogenic DCs with immunoregulatory functions have been considered as a possible target to induce and maintain immune tolerance. In murine models, adoptive transfusions of tolerogenic DCs could obtain an expansion of Tregs and reduced allotransplant sensitization in different types of transplants [63–65]. Other approaches explored in animal models comprised the inhibition of DCs maturation with agents such as vascular–endothelial growth factor [66], IL-10 [67], laquinimoid [68], shikonin [69], honokiol [70], immunoglobulins [71] and phosphodiesterase inhibitors [72]. Alternatively, drugs favoring the production of Tregs have been employed. A promising class of drugs is represented by mTOR inhibitors [73,74]. A combination therapy has been recently used to obtain an operational tolerance in primates: in Rhesus macaque, pre-transplant intravenous infusion of tolerogenic DCs, together with mTOR inhibitor rapamycin and the B7-CD28 co-stimulation blocking agent CTLA4-Igcould significantly prolong kidney allograft survival in comparison with control monkeys not receiving DCs [75]. In the clinical setting, a French multicenter study is evaluating the potential role of 1,25-α-dihydroxyvitamin D in renal transplantation, which may interfere with DCs maturation and T cell differentiation [76]. There are some encouraging data on mTOR inhibitors clinical application. Rapamycin administration to dialysis patients waiting for transplantation was able to expand the production of Tregs [77]. In addition, the conversion from cyclosporine to rapamycin increased the number of tolerogenic DCs and Tregs in renal transplant recipients [78]. Increasing attention has been paid to pDCs: as already stated, even though their capacity to prime T cell responses after infection or immunization has been well demonstrated, these DCs may also exert an opposite tolerogenic role in different systems. Plasmacytoid DCs that migrate to the thymus upon the influence of CCR9 and in the absence of TLR signaling can drive CD4+CD25 +FoxP3+ Treg development [55,79]. Some data speak in favor of a tolerogenic effect of pDCs. Among pediatric liver-transplant recipients with rejection, the number of pDCs was significantly lower and the ratio cDCs/pDCs was significantly higher than the ones in non rejecting patients [80]. Conversely, precursor pDC was significantly higher in operationally tolerant pediatric liver transplant recipients than in those with maintenance immunosuppression and correlated with the Treg frequency [81]. Pallotta et al. found that indoleamine 2,3-dioxygenase (IDO) was involved in intracellular signaling events responsible for the self-amplification and maintenance of a stably regulatory phenotype in pDCs and showed that IDO has a tonic, non-enzymatic function that contributes to TGF-β-driven tolerance in non-inflammatory contexts [82]. Although a broad definition of steady-state pDCs as tolerogenic is premature [83], these cells seem to exert better tolerogenic effect in comparison with cDCs and may represent possible targets for obtaining an operational tolerance in organ transplantation [84]. Despite this favorable data, ex vivo manipulation of DCs is limited by some factors, such as the high cost and the long time needed to handle in laboratory. Moreover, before assessing their role in clinical trials a number of problems should be better clarified including cell isolation and purification techniques, source, timing, route, frequency and dose of administration [85]. Some possible adverse events should be taken into account. Maturation of tolerogenic DCs after in vivo injection or the presence of a contaminant cell product could lead to the
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The diverging roles of dendritic cells in kidney allotransplantation☆ Manuel Alfredo Podestà ⁎, David Cucchiari, Claudio Ponticelli Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano – Milano, Italy
a b s t r a c t Dendritic cells (DCs) are a family of antigen presenting cells that play a paramount role in bridging innate and adaptive immunity. In murine models several subtypes of DCs have been identified, including classical DCs, monocyte-derived DCs, and plasmacytoid DCs. Quiescent, immature DCs and some subtypes of plasmacytoid cells favor the expression of regulatory T cells, but in an inflammatory milieu DCs become mature and after intercepting the antigen migrate to lymphatic system where they present the antigen to naïve T cells. Transplant rejection largely depends on the phenotype and maturation of DCs. The ischemia–reperfusion injury causes the release of endogenous molecules that are recognized as danger signals by the pattern recognition receptor of the innate immunity with subsequent activation of inflammatory cells and mediators. In this environment DCs become mature and migrate to lymphonodes where they present the alloantigen to T cells and direct their differentiation towards Th1 and Th17 effector cells. On the other hand, manipulation of DCs may favor T cell differentiation towards tolerant Th2 and T regulators (Treg). Experimental studies in murine models showed the possibility of inducing an operational tolerance by injecting immature tolerogenic DCs. Recently, such a possibility has been also confirmed in primates. Although manipulation of DCs may represent an important step ahead in kidney transplantation, a number of technical and ethical issues should be solved before its clinical application. © 2015 Elsevier Inc. All rights reserved.
1. Introduction In 1868 Paul Langherans, still a student, first described branched cells resembling neurons in the skin [1]. For many years the function of these cells remained an enigma, although their frequent presence in inflammatory granulomas led to hypothesize a possible protective role of these cells against infection. In 1973 Ralph Steinman and Zanvil Cohn, by using phase-contrast light microscopy, identified a novel type of cells in adherent cell populations prepared from mouse peripheral lymphoid organs. These cells represented only 0.1–1.6% of the total nucleated cells and had strange morphological features. The nucleus was large, retractile, contorted in shape, with two or more small nucleoli. The abundant cytoplasm contained many large spherical mitochondria. The cells had characteristic movements and showed branched projections. The authors proposed the term dendritic cells (DCs) for this novel cell type [2,3] and demonstrated their importance in stimulating the leukocyte reaction [4]. Since then, further studies elucidated the origin of DCs and their central role in immune regulation. 2. Ontogenesis and functions of DCs DCs are a family of professional antigen-presenting cells (APCs). DCs can be found in the skin and mucosal tissues (Langerhans cells), in ☆ Funding: No support has been provided for this paper. ⁎ Corresponding author at: Istituto Clinico Humanitas IRCCS, Via Manzoni 56, 20089 Rozzano – Milano, Italy. Tel.: +39 3420036285. E-mail address: [email protected] (M.A. Podestà).
parenchymal organs and gastrointestinal apparatus, in thymus, lymph nodes and in blood. Anatomically-wise, DCs may be divided in “resident” lymphoid tissue and “migratory” non-lymphoid tissue DCs. Although the ontogenesis of human DCs is still poorly defined, murine models provided great insight on their different roles. Multiple subsets of DCs have been identified in mouse (Table 1). They could be roughly divided in classical DCs (cDCs), monocyte-derived DCs (moDCs) and plasmacytoid DCs (pDCs) (Fig. 1). The term “myeloid” is often used to distinguish all types of DCs from pDCs, which were originally described as lymphoid. Classical DCs can be further divided into two subsets characterized by either CD8α/CD103 (cDC type 2) or CD11b (cDC type 1) expression. + (found in lymphoid tissues) and CD103 + (found in nonCD8α lymphoid tissues) cDCs are the best characterized murine DCs subset and seem to play a major role in antigen presentation to CD8 + T-cells through MHC-I. CD11b + DCs in contrast are more ill-defined and show superior induction of CD4+ T-cell proliferation [5]. cDCs may originate from both myeloid and lymphoid precursor, but are more frequently derived from a common monocyte-DC precursors in the bone marrow [6]. However, the fact that DCs acquire the expression of the marker CD8α only after their maturation may suggest that some DCs come from lymphoid cells that acquire the CD8 + phenotype on CD40CD40L engagement [7]. Monocyte-derived DCs, also known as inflammatory DCs, are a heterogeneous group of cells that are originated from phlogistic monocitic infiltrates, as supported by their expression of CD64/FcγRI [8,9] in addition to CD11c, CD11b and Ly6C [10]. These cells produce TNFα and iNOS and were shown to favor Th17 polarization [11].
http://dx.doi.org/10.1016/j.trre.2015.04.001 0955-470X/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Podestà MA, et al, The diverging roles of dendritic cells in kidney allotransplantation, Transplant Rev (2015), http:// dx.doi.org/10.1016/j.trre.2015.04.001
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Table 1 Characterization of murine and human DCs subsets identified by the most commonly employed cellular markers. Localization
Origin
DC subset
Markers (mouse)
Markers (human)
Proposed function
Lymphoid tissue
Myeloid
cDC type 1
CD1c (BDCA-1) [11]
Induction of CD4+ T-cell proliferation
Myeloid
cDC type 2
CD141 (BDCA-3) [11]
Antigen presentation to CD8+ T-cells
Myeloid
moDC
CD11c, CD14 [11,22]
Inflammation, tissue repair
Plasmacytoid
pDC
cDC type 1
CD303 (BDCA-2), CD304(BDCA-4), CD123 (IL-3R) [21] CD1c (BDCA-1) [24]
Interferon production, tolerance (?)
Myeloid
Myeloid Myeloid
cDC type 2 moDC
CD11b, CD11c [5,13] CD8α, CD11c [5,13] CD11c, CD11b, Ly6C, CD64 [9,10] mPDCA1, CD4, CD45RA [13,14] CD11b, CX3CR1, F4/80, SIRPα [17] CD103 [17]
Antigen presentation to CD8+ T-cells Inflammation, tissue repair
Plasmacytoid
pDC
CD141 (BDCA-3) [26] CD209 (DC-SIGN) CD1c (BDCA-1) CD68 [24] CD303 (BDCA-2) CD123 (IL-3R) [24]
Kidney
Plasmacytoid DCs are circulating dendritic cells mainly found in lymphoid organs and characterized by a well developed secretory apparatus that produces high doses of type I interferon upon viral infections [12]. pDCs express high levels of mPDCA1, but display a rather low expression of CD11c or CD14, which distinguishes them from cDCs or monocytes, respectively [13,14]. While it is relatively simple to purify DCs from lymphoid organs, consistent efforts were required to identify and characterize non-
Induction of CD4+ T-cell proliferation
Interferon production, tolerance (?)
lymphoid tissue DCs. Renal resident DCs have been localized in close proximity to peritubular capillaries in mice by identification of CD11c through immunohistochemistry [15]. These cDCs are originated from bone marrow progenitors, but a derivation from circulating Ly6C + monocytes, which infiltrate the kidney upon inflammation, has also been considered [16]. CD11c + renal cDCs can be further divided in two different subsets, based on the expression of either CD103 or CD11b, CX3CR1 and F40/80 [17].
Fig. 1. Schematic representation of DCs subsets and their main functions. cDCs are originated from a common monocyte-DC precursor, and can be further divided in two subsets in mice + /CD103+ type 2 and CD11b+ type 1) that share common features with human BDCA-3+ and BDCA-1+ DCs respectively. Type 1 cDCs show superior induction of CD4+ T-cell pro(CD8α liferation, while type 2 cDCs play a major role in antigen presentation to CD8+ T-cells. moDCs are originated from inflammatory monocitic infiltrates and favor Th17 polarization. pDCs are circulating DCs that produce high doses of type I interferon upon viral infections.
Please cite this article as: Podestà MA, et al, The diverging roles of dendritic cells in kidney allotransplantation, Transplant Rev (2015), http:// dx.doi.org/10.1016/j.trre.2015.04.001
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Mouse and human DCs system share some similarities; however murine markers such as CD8α and CD11b are not expressed on human cDCs. Consistent efforts have been directed towards the creation of a unified classification (Table 1). For instance, based on transcriptomic and functional studies, human CD1c +/BDCA1 + lymphoid tissueresident and human CD207 − CD14 + non-lymphoid cDCs have been grouped as CD11b +-like cDCs, while it was demonstrated that CD141/ + cDCs BDCA3 + shares a distinct gene signature with mouse CD8α [18–20]. pDCs in humans are characterized by the expression of CD123/IL-3R, CD303/BDCA-2 and CD304/BDCA-4, and by the absence of the common myeloid markers [21]. Human moDCs have been only recently identified in psoriatic skin and malignant ascites, but their full characterization remains somewhat controversial [22,23]. Woltman et al. reported the first detailed analysis of DC subsets in the human kidney. They described two different subsets of myeloid DCs in donor pre-transplant biopsies, defined by either positive staining for BDCA-1+, CD68+ and DC-SIGN+ (moDCs) or single positive staining for BDCA-1+ (cDCs type 1) [24,25]. In addition, the authors also detected a minor population of BDCA-2+ plasmacytoid DCs in tubulointerstitial areas. Interestingly, none of these cellular subsets were positive for DC-LAMP, thus indicating that renal DCs are immature [24]. BDCA-3 + cDCs were identified in kidney biopsies from patients with active lupus nephritis, although they were not present in normal kidneys [26]. 3. DCs as regulators of the immune response The ability of DCs to regulate immunity is dependent on their maturation in an inflammatory milieu. Pathogen associated molecular patterns (PAMPs) and danger associated molecular patterns (DAMPs) are recognized by Toll-like receptors (TLRs) and other receptors of the innate immunity, such as NOD-like and RIG-I receptors. TLRs activate a number of adapter proteins (i.e. MyD88, IRAK, TRAM, TRAF, TRIF) that mediate specific protein–protein interactions eventually leading to the formation of transcription factors—nuclear factor kinase B, interferon regulator3, mitogen-activated protein3—which induce or inhibit the genes that organize the inflammatory response [27]. A variety of factors favoring an inflammatory environment can induce maturation of DCs, including bacterial-derived antigens, viral products, inflammatory cytokines, CD40/CD40L engagement. Mature DCs exert three distinctive
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functions: (i) a sentinel role in which antigens are captured and presented, (ii) a migratory function, in which DCs move to the T-dependent areas of lymphoid organs and bind antigen-specific T cells, (iii) an activation role, in which T-cell growth and effector function are induced (Fig. 2). Interestingly, DCs may present captured antigen on both MHC-I and MHC-II class molecules. The former mechanism, which relies on endocytosis and proteasome processing, leads to CD8 + T-cell activation through a process termed cross-presentation, which enables immune response against intracellular pathogens. In contrast, MHC-II molecules assembly is attained through lysosome breakdown of endocytic vesicles, which results in antigen presentation and activation of CD4 + T-cells. This function is tightly controlled by a number of factors leading to DCs maturation, such as Toll-like receptor (TLR) signaling and exposure to inflammatory cytokines [28]. On the other hand, immature DCs may induce tolerance by immune response down-regulation. When antigens are experimentally delivered to DCs without maturation stimuli, MHC–peptide complexes are formed in the steady state. Naïve T cells, after recognizing their ligands on these DCs, divide repeatedly but are then deleted [29] and favor the generation of Foxp3+ T regulators (Tregs), which can be specific for either self- or non-self antigens [30]. Furthemore, thymoid DCs present self-antigens to naïve T-cells, inducing the process of clonal deletion and positively selecting natural Tregs [31]. Thus, DCs can no longer be considered as a homogeneous cell type performing a single function of defense against pathogens and foreign antigens. Their phenotype and function depend on white cell lineages and maturation stimuli that can activate divergent arms of the immune system. Further studies will be required to fully elucidate the role of human subsets of DCs. 4. Innate immunity in allotransplant Innate immunity plays a pivotal role in initiating an autoimmune response and in defending against oncogenic events [32,33]. In allotransplantation, innate immunity can be triggered in the donor even before the transplant. In the case of deceased donor the sympathetic system hyperactivity, associated with brain death, causes a generalized ischemia aggravated by the use of vasoconstrictor agents, which are necessary to sustain the circulation. After clamping the kidney vessels, the
Fig. 2. Maturation and migration of DCs: from a tolerant to an immunogenic phenotype. In a quiescent environment DCs release cytokines that can favor the development of immunological tolerance. However, in presence of pathogen aggression or release of endogenous substances by stressed cells, the molecular patterns of PAMPs or DAMPs are recognized by TLRs and other receptors of the innate immune recognition system. These receptors recruit adapter proteins which activate several kinases that amplify the signal, leading to activation of nuclear factor kB and interferon regulator 3. These transcription factors can induce genes that orchestrate the immune and inflammatory response. In an inflammatory environment, DCs become mature and migrate to lymphonodes where they present the antigen to the T cells so allowing the activation of the adaptive immunity.
Please cite this article as: Podestà MA, et al, The diverging roles of dendritic cells in kidney allotransplantation, Transplant Rev (2015), http:// dx.doi.org/10.1016/j.trre.2015.04.001
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short warm ischemia and the longer cold ischemia further reduce the oxygen and energetic supply leading to generation of reactive oxygen species, intra-cellular acidosis caused by the increased production of lactic acid from anaerobic glycolysis, and cell swelling caused by the impaired function of ATP-dependent sodium–potassium pumps [34]. These changes can cause damage to all cellular components that may ultimately result in cell cycle arrest and even cell death. The reperfusion of an ischemic kidney may result in further inflammation and oxidative damage, a paradoxical phenomenon termed ischemia–reperfusion injury (IRI). The microvascular injury caused by ischemia enhances fluid filtration and leukocyte plugging in capillaries and in postcapillary venules. After reperfusion, damaged endothelial cells secrete additional reactive oxygen species and favor the release of inflammatory mediators and proteolytic enzymes. Among them, caspases can mediate apoptosis in a significant number of sub-lethally injured cells. In addition to endothelial cells, proximal tubular epithelial cells are particularly vulnerable to the toxic effects of reperfusion and tend to undergo more necrosis in comparison with the less sensitive segments, because they have higher metabolic demands [35,36]. The dying cells release in the extra-cellular space endogenous molecules that are recognized as DAMPs from the pattern recognition receptors of the innate immunity.
deletion of the T clone or generation of Tregs. Nevertheless, mature DCs can transfer these molecules to other immune cells (i.e. B-cells and monocytes) that can operate as APCs [48,49]. The antigen may be presented to T cells by the donor DCs (direct pathway), by the recipient DCs in case of donor DCs depletion (indirect pathway) or by a passage of alloantigen from donor to recipient DCs (semidirect pathays). T cell polarization is of paramount importance in determining the effect of the immune response on the allograft. Differentiation towards the pro-inflammatory Th1 and Th17 phenotypes has a pivotal role in rejection, whereas Th2 and Treg polarization results in a protective effect on the transplanted organ. This polarization is guided by DCs and is controlled by cytokines, transcription factors and environmental factors. Aside from TCR and B7-group signaling, other DCs receptors seem to greatly influence microenvironment and skew T-cell polarization. Sphingosine-1 phosphate (S1P), a sphingolipid produced by phosphorilation of sphngosine, is the natural ligand for a family of five G-protein coupled receptors. The absence of S1P3 on DCs prevents their maturation and skews T-cell polarization towards a Th2 phenotype, thus attenuating IRI [50]. These findings suggest the importance of DCs S1P3 in modulating T cell function and support the development of S1P3 antagonist in tolerance induction in organ transplantation. 6. The dual role of DCs in rejection
5. DCs as the bridge between innate and adaptive immunity IRI and inflammation are the essential steps that lead to maturation of DCs in kidney transplant. Even before undergoing necrosis, damaged cells release several DAMPs, among which the best studied are HighMobility Group Box 1 Protein (HMGB1) and heat-shock proteins (HSPs), such as HSP72. Generation of reactive oxygen species (ROS) can moreover damage extra-cellular proteins, creating fragments of hyaluronan, fibronectin and heparan sulfate that can elicit TLRsmediated DCs activation [37]. Upon receptor engagement with these DAMPs, DCs modify their phenotype, increasing expression of MHCrelated proteins, which are essential to intercept the antigen. In addition, upon challenge with DAMPs, DCs express chemokine receptors that lead them to the T-dependent zone of secondary lymphoid organs, where the interaction between innate and adaptive immunity finally occurs. Their capacity to migrate, their constitutive expression MHC-I and MHC-II, as well as co-stimulatory and adhesion molecules, make DCs ideal cells for the activation of naïve T cells [38]. An important role is played by interleukin 12 [39] and chemokine receptors that help DCs to migrate into the T-cell zone of lymphoid organs [40]. Complement can also contribute to the link between innate and adaptive immunity: for instance, the component C3 can modulate cell-mediated response [41]. Moreover, the C3d component binds to the CR2 receptor on the surface of follicular DCs and favors the interaction with the CR2-associated antigen on B cells, triggering antibodymediated response [42]. The C5a component expressed on DCs favors their maturation and their capacity of activate T cells [43]. The terminal components C5b-C9 bind to APC and help them in the direct recognition of the antigen [44]. Thus, DCs are critical early initiators of innate immunity in the kidney and orchestrate inflammation subsequent to IRI. They are capable of inducing sterile inflammation after reperfusion directly through the production of proinflammatory cytokines and other soluble inflammatory mediators or indirectly through activation of effector T lymphocytes and natural killer T cells (NKT), innate-like lymphocytes that bind to glycolipid antigens presented by CD1d [45]. T-cell activation by DCs requires two signals: the first one is provided by the contact between the MHC-mounted antigen and the specific T-cell receptor (TCR). The second signal of co-stimulation is generated by the contact between molecules of the B7 group on the surface of DCs (CD80 and CD86) and adhesion molecules on the surface of the T cell (CD28). The presence of co-stimulatory molecules is a typical prerogative of DCs [46,47] and their absence favors tolerance, leading to
Monocyte–macrophages have been found as the predominant cellular infiltrate in kidney allograft rejection and represent a major outcome indicator [51,52]. Zuidwijk et al. analyzed and quantified DC subsets in a setting of acute rejection, finding an exceptionally high number of mature renal DC-SIGN + myeloid DCs (moDCs), which exceeded the renal BDCA-1 + (type 1) cDCs. The increased moDC/cDC ratio supports the theory of a monocitic infiltration of the kidney in the setting of acute rejection, with subsequent local differentiation to moDCs. The density of both myeloid subsets of mature DCs was associated with high inflammation score of the Banff 07 classification, graft interstitial fibrosis/ tubular atrophy and loss of renal function in the long term [53], showing that both myeloid subsets are involved in acute allograft rejection. Plasmacytoid DCs have been frequently associated to tolerance induction [54,55]. However, pDCs were found to be increased in acute allograft rejection, and their density appeared to correlate with inflammation and chronic injury [53]. Experimental studies suggest that localization of DCs may influence their function: graft-resident DCs and locally recruited systemic DCs may indeed exert different roles that can influence the outcome of the kidney allograft. Studies in rat showed that renal cold IRI caused loss of graft DCs and progressive infiltration of host DC and CD4 + T cells with effector/effector-memory phenotypes. These changes in graft/ host DC populations were associated with development of tubulointerstitial lesions, suggesting that graft–resident DCs might have a protective role while infiltrating host DCs exert deleterious effects on graft function [56]. In addition to origin and localization, also soluble mediators of the microenvironment are likely to influence DCs phenotype and function in the kidney. In conditions of cellular stress such as hypoxia/IRI, adenosine extracellular concentrations increase by enhanced conversion of ATP. Adenosine, acting on several specific receptors (i.e. A1AR, A2AR, A2BR and A3R), mediates adaptation to hypoxia, conferring an antiinflammatory state and a protective effect at cellular level [57]. By contrast, ATP released by apoptotic cells acts as both a DAMP and a chemoattractant for neutrophils and monocytes [58]. The enzymatic conversion steps from ATP to adenosine are regulated by two enzymes, CD39 and CD73 [59]. Activation of A2AR expressed on DCs and T cells suppresses the immune response in allograft rejection [60]. Consistent with this finding, the expression of human CD39 in transgenic mice enhances the conversion of extracellular ATP to adenosine, and was shown to be protective in a murine renal transplant model characterized by prolonged cold
Please cite this article as: Podestà MA, et al, The diverging roles of dendritic cells in kidney allotransplantation, Transplant Rev (2015), http:// dx.doi.org/10.1016/j.trre.2015.04.001
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ischemia [61]. Recent experimental data also showed that DCs tolerized with an A2AR agonist suppress NKT cell activation in vivo, attenuating IRI [62]. These studies demonstrated that renal interstitial DCs phenotype is determined at least in part by the expression of A2AR. In summary, in organ transplantation DCs have a central role in initiating alloantigen-specific immunity, but they may also favor an operational tolerance. These contrasting effects of DCs depend on their origin and state of quiescence or maturation as well as by their location and the chemical composition of the surrounding microenvironment. 7. Manipulation of DCs in allotransplant recipients Tolerogenic DCs with immunoregulatory functions have been considered as a possible target to induce and maintain immune tolerance. In murine models, adoptive transfusions of tolerogenic DCs could obtain an expansion of Tregs and reduced allotransplant sensitization in different types of transplants [63–65]. Other approaches explored in animal models comprised the inhibition of DCs maturation with agents such as vascular–endothelial growth factor [66], IL-10 [67], laquinimoid [68], shikonin [69], honokiol [70], immunoglobulins [71] and phosphodiesterase inhibitors [72]. Alternatively, drugs favoring the production of Tregs have been employed. A promising class of drugs is represented by mTOR inhibitors [73,74]. A combination therapy has been recently used to obtain an operational tolerance in primates: in Rhesus macaque, pre-transplant intravenous infusion of tolerogenic DCs, together with mTOR inhibitor rapamycin and the B7-CD28 co-stimulation blocking agent CTLA4-Igcould significantly prolong kidney allograft survival in comparison with control monkeys not receiving DCs [75]. In the clinical setting, a French multicenter study is evaluating the potential role of 1,25-α-dihydroxyvitamin D in renal transplantation, which may interfere with DCs maturation and T cell differentiation [76]. There are some encouraging data on mTOR inhibitors clinical application. Rapamycin administration to dialysis patients waiting for transplantation was able to expand the production of Tregs [77]. In addition, the conversion from cyclosporine to rapamycin increased the number of tolerogenic DCs and Tregs in renal transplant recipients [78]. Increasing attention has been paid to pDCs: as already stated, even though their capacity to prime T cell responses after infection or immunization has been well demonstrated, these DCs may also exert an opposite tolerogenic role in different systems. Plasmacytoid DCs that migrate to the thymus upon the influence of CCR9 and in the absence of TLR signaling can drive CD4+CD25 +FoxP3+ Treg development [55,79]. Some data speak in favor of a tolerogenic effect of pDCs. Among pediatric liver-transplant recipients with rejection, the number of pDCs was significantly lower and the ratio cDCs/pDCs was significantly higher than the ones in non rejecting patients [80]. Conversely, precursor pDC was significantly higher in operationally tolerant pediatric liver transplant recipients than in those with maintenance immunosuppression and correlated with the Treg frequency [81]. Pallotta et al. found that indoleamine 2,3-dioxygenase (IDO) was involved in intracellular signaling events responsible for the self-amplification and maintenance of a stably regulatory phenotype in pDCs and showed that IDO has a tonic, non-enzymatic function that contributes to TGF-β-driven tolerance in non-inflammatory contexts [82]. Although a broad definition of steady-state pDCs as tolerogenic is premature [83], these cells seem to exert better tolerogenic effect in comparison with cDCs and may represent possible targets for obtaining an operational tolerance in organ transplantation [84]. Despite this favorable data, ex vivo manipulation of DCs is limited by some factors, such as the high cost and the long time needed to handle in laboratory. Moreover, before assessing their role in clinical trials a number of problems should be better clarified including cell isolation and purification techniques, source, timing, route, frequency and dose of administration [85]. Some possible adverse events should be taken into account. Maturation of tolerogenic DCs after in vivo injection or the presence of a contaminant cell product could lead to the
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Please cite this article as: Podestà MA, et al, The diverging roles of dendritic cells in kidney allotransplantation, Transplant Rev (2015), http:// dx.doi.org/10.1016/j.trre.2015.04.001