Published online before print September 18, 2008, doi: 10.1161/ATVBAHA.107.161232
© 2008 American Heart Association, Inc.
Brief Reviews |
The Role of Chemokines in Transplant Graft Arterial Disease
From the Cardiovascular Division, Department of Medicine (K.S.), and Department of Pathology (R.N.M.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Richard N. Mitchell, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB7, Boston, MA 02115. E-mail rmitchell{at}rics.bwh.harvard.edu
Series Editor: Christian Weber
ATVB In Focus
Chemokines in Atherosclerosis, Thrombosis, and Vascular Biology
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Abstract |
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 Top Abstract IntroductionPathogenesis of GADChemokines in TransplantationSummaryReferences |
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Despite the development of effective immunosuppressive therapy, transplant graft arterial disease (GAD) remains the major limitation to long-term graft survival. Multiple immune and nonimmune risk factors contribute to this vasculopathic intimal hyperplastic process. Thus, initial interplay between host inflammatory cells and donor endothelial cells triggers alloimmune responses, whereas alloantigen-independent factors such as prolonged ischemia, surgical manipulation, ischemia-reperfusion injury, and hyperlipidemia enhance the antigen-dependent events. Intrinsic to all stages of this process are chemokines, a family of 8- to 10-kDa proteins mediating directional migration of immune cells to sites of inflammation and injury. Beyond their role in immune-cell chemotaxis, chemokines also contribute to cellular activation, vascular remodeling, and angiogenesis. Expression of chemokines and their cognate receptors in allografts correlates with acute organ rejection, as well as GAD. Moreover, chemokine or chemokine receptor blockade prolongs graft survival and attenuates GAD in experimental models. Further studies will likely confirm a substantial utility for antichemokine therapy in human organ transplantation.
Key Words: atherosclerosis pathophysiology • other arteriosclerosis • transplantation • vascular biology, smooth muscle proliferation and differentiation
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Introduction |
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TopAbstractIntroductionPathogenesis of GADChemokines in TransplantationSummaryReferences |
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Graft arterial disease (GAD), also termed allograft arteriopathy, graft vasculopathy, or transplant-associated arteriosclerosis is a vascular intimal proliferative process leading to ischemia and the progressive deterioration of allograft function. GAD is the major limitation to long-term graft and recipient survival after heart transplantation.1 One-year, 3-year, 5-year, and 10-year survival afte adult heart transplantation is 92%, 80%, 73%, and 49%, respectively,2 with the majority of mortality attributable to GAD. Intimal thickening, medial attenuation, adventitial fibrosis, and vasoconstriction characterize GAD lesions.3 These can develop and progress at any time and at variable rates; significant vasculopathy can develop as early as 6 to 12 months posttransplant. Intravascular ultrasound (IVUS) demonstrates GAD in 75% of patients at 3 years after transplantation.4
Clinical diagnosis of GAD is limited by the lack of ischemic symptoms in the largely denervated allograft, by the relative insensitivity of coronary angiography—which frequently underestimates the extent and severity of diffuse disease—and by the extensive involvement of small intramyocardial vessels. For most cases, retransplantation is the only effective therapy for established GAD, because disease diffuseness usually precludes angioplasty, endarterectomy, or bypass grafting.
The mechanisms underlying GAD include antibody-mediated and cell-mediated inflammation, followed by tissue remodeling. T cells, B cells, macrophages, dendritic cells, platelets, natural killer (NK) cells, or neutrophils, and vascular cells such as endothelial cells (ECs) and smooth muscle cells (SMCs) all contribute to this process. Integral components include cytokines and chemokines, adhesion molecules, immunoglobulin, complement, and reactive oxygen species.5 Each factor interacts with the other and modifies the overall alloimmune response, and in each case with cellular elements, chemokines ultimately direct recruitment and activation—or modulation—of these mediators.
Chemokines are a large family of soluble 8- to 10-kDa proteins expressed by endothelial cells, smooth muscle cells, or lymphocytes that attract and activate a variety of inflammatory and noninflammatory cells and mediate directional migration of immune cells to sites of inflammation and injury.6 To date, more than 50 chemokines have been identified, with effects ranging from leukocyte recruitment and activation to angiogenesis and vascular remodeling. The chemokines are grouped into C, CC, CXC, and CX3C subfamilies on the basis of the position of highly conserved cysteine (C) and a noncysteine amino acids (X) near the amino terminus of each molecule (Table 1
). The CXC chemokine family is further distinguished by the presence or absence of an amino acid sequence, glutamic acid-leucine-arginine (ELR motif), which precedes the CXC sequence. The former are chemotactic in vitro for neutrophils but not for mononuclear cells, whereas the latter exhibit chemotactic activity toward monocytes and lymphocytes.7 Human ELR+ CXC chemokines include interleukin (IL)-8, growth-related oncogene family (GRO-alpha, -beta) epithelial cell-derived neutrophil activating protein 78 (ENA-78), neutrophil activating peptide 2, and granulocyte chemotactic peptide 2 (GCP-2), whereas the murine ELR+ CXC chemokines include macrophage inflammatory protein 2 (MIP-2), KC, lipopolysaccharide (LPS)-induced CXC chemokine (LIX), and Lungkine.
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Despite structural similarities, chemokines within a particular class can have widely varying targets or effector functions.6 Chemokines elicit their effects by binding to 7-transmembrane domain G protein–coupled receptors (GPCR). Chemokines can also bind to glycosaminoglycan (GAG) on the cell-surface or within the extracellular matrix. Although this binding does not generate cell signals, it maintains stable concentration gradients from the site of chemokine production.8 Most chemokine-receptor interactions are characterized by redundancy and promiscuity; thus several chemokines can bind the same receptor, and a single chemokine can bind to many different receptors, but it does not mean that ligation of the same chemokine receptor by different chemokines function similar way. For example, MIP-1
and RANTES both bind to CCR1 and CCR5. However, MIP-1 has significant stem cell inhibitory effects, whereas RANTES appears to be devoid of this activity, suggesting that this is not a function of the activated shared receptor for these two chemokines.9
Chemokines attract and recruit subsets of immune cells as they mature and traffic through different lymphoid organs; they also play an important role in inducing, maintaining, and amplifying inflammatory responses in peripheral tissues. Both infiltrating and resident cells produce chemokines at sites of inflammation, with a relatively stereotypical relationship to the phases of the inflammatory response. Enhanced production of chemokines and the relative blood flow within inflamed tissues influence the levels of chemokines in serum and other biological fluids. Consequently, that detection and quantification of chemokines in biological fluids could provide useful information.
Although important for protection against microbes, chemokines can also inappropriately maintain and amplify chronic inflammatory reactions, (ie, when a stimulus persists), as well as sustain responses in autoimmune diseases. Thus, chemokine blockade can potentially modulate these disorders.
For purposes of this review, it is important to emphasize that chemokines can also have nonchemotactic functions including vascular remodeling, angiogenesis, and immune regulation. In solid organ transplantation, the expression of chemokines and their cognate receptors correlates with allograft rejection. Moreover, chemokine or chemokine receptor blockade can prolong graft survival or attenuate GAD in a number of animal models; however, it remains unclear whether these effects are secondary to changes in inflammatory cell trafficking or other mechanisms.
This review summarizes general concepts of the mechanisms underlying GAD, focuses on the role of chemokines in this process, and discusses the therapeutic promise of antiinflammatory agents based on targeted blockade of chemokine receptors.
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Pathogenesis of GAD |
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TopAbstractIntroductionPathogenesis of GADChemokines in TransplantationSummaryReferences |
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GAD shares a number of pathological features with other stenosing vascular pathologies (eg, stent restenosis); however, GAD morphology differs considerably from typical atherosclerosis which preferentially affects proximal vessels in a focal manner driven by systemic risk factors (eg, hypertension, hypercholesterolemia, etc.) but dictated by local flow characteristics.10 GAD develops circumferentially and diffusely within small distal vessels and ultimately involves both intramyocardial and epicardial allograft vessels.11
GAD lesions are characterized by concentric intimal proliferations of myofibroblasts and smooth muscle–like cells with associated extracellular matrix. Lymphocyte infiltration varies from almost none to quite prominent; early lesions typically exhibit lymphocytes in a subendothelial location.
Although the precise mechanisms of graft vasculopathy pathogenesis are incomplete, both host allo-response (immunologic factors) and alloantigen-independent factors (nonimmunologic factors) contribute to GAD. Known factors include older donor and recipient age, donors with intracranial hemorrhage, major histocompatibility mismatch, ischemia-reperfusion injury, hyperlipidemia, insulin resistance, and cytomegalovirus infection.12–14 Preferential involvement of the engrafted vessels—with sparing of the host’s native vessels—suggests that immunologic factors are probably most important, and this has been borne out in animal studies.
Humoral Immunity
After engraftment, de novo generation of antibodies almost certainly contributes to allograft rejection.15 Human allograft recipients often produce high levels of graft-reactive antimajor histocompatibility complex (MHC; human lymphocyte antigen, HLA) alloantibodies,16 and these antibodies have been implicated in GAD development.17,18 Murine studies also show that B cell–deficient mice did not develop GAD,17 and that passive alloantibody transfer promotes GAD.
Despite these findings, skepticism persists regarding the importance of antibody-mediated rejection, because a mechanistic connection and direct link to allografted tissue has been lacking. Indeed, progression of vascular lesions is more often associated with a decline or complete disappearance of detectable antidonor antibody titers. Nevertheless, early humoral injury could conceivably set in motion cell recruitment and activation that eventually results in GAD.
Cellular Immunity
Host alloreactive T cells can directly recognize intact donor major histocompatibility complex (MHC) molecules expressed on the cell surface of "passenger" donor antigen presenting cells (APC) in the transplanted tissue. Host APCs can also process foreign antigen derived from donor MHC molecules and present them "indirectly" to alloreactive T cells. Donor coronary endothelium is a target of the immune response but can also serve as APCs. For complete T cell activation, costimulatory molecules such as CD40, B7 molecules (CD80, CD86), OX40L, ICOS ligand, or PDL1 and PDL2 (programmed cell death ligand) must also ligate host T cell cognate receptors; β-integrins can also affect antigen presentation.19
Recruited and activated T cells then secrete cytokines such as tumor necrosis factor (TNF)- and IFN-
that amplify the immune response, increase EC adhesion molecule expression, and lead to further recruitment of macrophages and T lymphocytes. In turn, activated macrophages and lymphocytes express cytokines and growth factors such as platelet-derived growth factor, fibroblast growth factor, and transforming growth factor (TGF)-beta (TGF-β), that promote the recruitment and proliferation of smooth muscle-like cells in the intima and drive extracellular matrix synthesis. It is important to note that ongoing "smoldering" acute rejection is not required for GAD development; acute rejection can initiate responses that can autonomously progress to GAD. Thus, immune cell depletion or retransplant into donor-strain hosts does not prevent the progression of chronic rejection despite the apparent lack of an ongoing immunologic response.20 Indeed, even induction of allograft tolerance does not preclude GAD development.21
Nonspecific Responses in GAD Development
Syngeneic or isogeneic grafts can also develop lesions similar to typical GAD; nonimmunologic insults including perioperative ischemia and reperfusion injury, hyperlipidemia, and cytomegalovirus infection illustrate the influence of alloantigen-independent events.1 In such cases, alternate nonspecific pathways of EC activation and SMC recruitment can engender a similar outcome.
Vascular Remodeling
Vascular wall cellularity and extracellular matrix can change dynamically in response to physiological and pathological stimuli22; these changes can initially preserve luminal diameter. Thus, outward (positive) remodeling can potentially compensate for increased intimal thickness. However, GAD lesions exhibit intimal thickening and medial degeneration as well as adventitial fibrosis. With adventitial fibrosis, the artery cannot expand (negative remodeling), leading to reduced luminal caliber.
Intimal Thickening
ECs in arterial neointima of long-term grafts or sites of vascular injury can be either host or donor-derived depending on the severity of injury and frequency of endothelial progenitor cells.23,24 GAD intimal lesions consist mainly of recruited (and proliferating) SMCs and their associated extracellular matrix (ECM). Although previous investigators had tacitly believed that the intimal cells of the GAD originated entirely from underlying donor medial SMCs, we and others demonstrated in animal models that the majority of intimal SMCs are host-derived.25 Indeed, host-origin precursors—some of which are marrow-derived—also contribute to human heart and kidney transplant GAD.24,26,27 Because numerous important functional differences exist between intimal and medial SMCs, we refer to the intimal SMCs as smooth muscle–like cells (SMLCs).26 The frequency of host-origin SMLCs in intimal lesions varies with the severity of rejection.25 Thus, host intimal SMLCs routinely exceed 90% in animal aortic and cardiac transplant GAD lesions in the absence of immunosuppression; the frequency of host SMLCs in human GAD is closer to 15% in the setting of standard immunosuppression and less vascular injury.28 Regardless of source, these SMLCs must be recruited into the newly forming neointima.
Medial Degeneration
Medial SMCs drop out or ECM degradation can partially compensate to maintain luminal diameter (positive remodeling) despite focal intimal thickening.29 Alloreactive T cells, macrophages, and antibodies can contribute to medial SMC apoptosis.30 Host inflammatory cells as well as donor ECs and medial SMCs can direct matrix remodeling via matrix metalloproteinases (MMP),31 lysosomal cysteine proteases,32 and other proteolytic enzymes.31 In contrast, relative overproduction of protease inhibitors such as tissue inhibitors of metalloproteinases (TIMP) or cystatin C potentially can reduce ECM degradation and thus contribute to negative remodeling.31 Increased medial SMC contractility or relative inability to relax will also significantly impact negative remodeling.
Adventitial Fibrosis Causes Negative Remodeling
Initially positive adventitial remodeling can increase the diameter of the external elastic lamina and thus maintain vessel luminal caliber.33 When adventitial fibrosis supervenes at later time points, the vessel cannot expand and the same thickness of intimal hyperplasia results in luminal stenosis.33 The fibrosis results from adventitial myofibroblast recruitment and proliferation, and synthesis of ECM.34 Perivascular alloreactive inflammatory cells likely induce adventitial scarring and contraction in a manner comparable to wound healing in transplanted organs.1 Thus, a cytokine milieu rich in IFN and TNF can drive adventitial fibrosis and negative remodeling35; TGF beta (TGFβ) also likely contributes to interstitial collagen synthesis and adventitial fibrosis.36 Adventitial myofibroblasts also express functional endothelin receptors and endothelin-converting enzyme; active endothelin induces SMC contraction and mitogenesis, as well as ECM formation.37 Although adventitial scarring drives negative remodeling within the first year post-transplantation, later luminal stenosis derives more from intimal hyperplasia.38
In summary, ischemia-reperfusion injury, allo-specific humoral and cellular immunologic factors, donor and host APCs, and atherogenic factors all contribute to the initial leukocyte emigration into donor allografts, as well as the subsequent SMLC migration and proliferation in the intimal lesions, eventually culminating in GAD lesions. In the next section, we will describe the chemokines that participate in the early through late stages of allograft rejection through the regulation of leukocyte transmigration, SMC recruitment, and the subsequent vascular remodeling.
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Chemokines in Transplantation |
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TopAbstractIntroductionPathogenesis of GADChemokines in TransplantationSummaryReferences |
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Ischemia and reperfusion injury early after transplantation is marked predominantly by the accumulation of neutrophils and monocytes/macrophages; subsequent acute rejection is characterized by T cells, NK cells, and macrophages, followed by GAD development which involves the accumulation of intimal smooth muscle like cells. B cells, dendritic cells, mast cells, platelet, endothelial cells and other parenchymal cells all contribute to these processes (Table 2
). Chemokines likely affect all phases of transplantation injury by regulating intragraft leukocyte recruitment and inflammatory responses, as well as through modulation of APC homing to secondary lymphoid organs and clonal expansion or tolerance induction of alloantigen-specific T cells (Figure). The following discussion of chemokines will be organized according to these general phases experienced by allografts.
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Chemokines in Ischemia/Reperfusion Injury
Ischemia or reperfusion injury in allografts induces an initial innate immune response (neutrophils and monocytes/macrophages) associated with endothelial dysfunction, microvascular collapse, myocardial apoptosis, and infarction.39 Neutrophils primarily cause myocardial ischemia/reperfusion injury via degranulation, releasing intracellularly stored cysteine and serine proteinases and neutrophil elastases and reactive oxygen species (ROS).40 Proinflammatory cytokines (eg, TNF, IFN, IL-1), complement C5a, as well as several chemokines (eg, IL-8/CXCL8) stimulate neutrophil degranulation as well as ROS production.41 The extent of ischemia/reperfusion injury also correlates with subsequent cardiac GAD.42,43
The ischemia and reperfusion associated with organ transplantation leads to an early recruitment of neutrophils, NK cells, and monocytes/macrophages. Ischemic ECs produce proinflammatory cytokines (eg, TNF- and IL-1) within minutes of organ reperfusion.44 These cytokines in turn stimulate ECs, SMCs, cardiomyocyte, and parenchymal cell production of chemokines that are detected as early as 1 hour after transplantation. CC chemokines (TCA3/CCL1, MCP-1/CCL2, MIP-1/CCL3, MIP-1β/CCL4, RANTES/CCL5) and the CXC chemokines (eg, KC/CXCL1, MIP-2/CXCL2, ENA-78/LIX/CXCL5, and IL-8/CXCL8, MIG/CXCL9, IP-10/CXCL10) all appear during the first 24 hours, and quickly return to baseline by 48 hours.45,46 In murine cardiac transplantation, KC/CXCL1 and MIP-2/CXCL2 immediately appear within 1 hour after transplantation and commence neutrophil infiltration. JE/CCL2, MIP-1/CCL3, LIX/CXCL5, MIG/CXCL9, and IP-10/CXCL10 subsequently begin to appear 3 hours after engraftment and serve to recruit neutrophils as well as monocytes, NK cells, and T cells.45
Activated macrophages also produce MCP-1/CCL2, with transcripts of its cognate receptor CCR2, peaking 4 to 10 hours after injury;46,47 notably, CCR2 and MCP-1 congenital deficiencies both result in reduced ischemia and reperfusion injury.48
Although most of these early chemokines are chemotactic for neutrophils and monocytes, RANTES/CCL5 is also a major mediator of antigen-independent T cell recruitment and activation,49 and may set the stage for onset of acute allograft rejection. MIP-1/CCL2, MIP-1β/CCL3, and MIP-2/CXCL2 and 3 transcripts elevate at peak 4 hours with murine myocardial ischemic injury.46 The ECs express chemokines Mig/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11 in liver ischemia/reperfusion injury; these chemokines also recruit activated T lymphocytes, NK cells, and monocytes/macrophages by binding to CXCR3 receptors.50 In murine cardiac transplantation, IP-10/CXCL10, MIP-2/CXCL2 and 3, and MCP-1/CCL2 mRNA are expressed in cardiac isograft 1 day after transplantation,51,52 and Mig and I-TAC mRNAs are expressed in cardiac allograft not in isograft 3 days after transplantation.52
NK cells and CD8+ T cells serve as potent effectors of the innate and adaptive immune response, respectively. They use the FasL and the perforin/granzyme pathway to kill target cells. MCP-1/CCL2, MIP-1/CCL3, RANTES/CCL5, and IP-10/CXCL10 activate NK cells and induce degranulation. A combination of direct ischemia and the secondary effects of degranulating neutrophils and NK cells and activated macrophages leads to further endothelial dysfunction with impaired vessel relaxation, an increased procoagulant phenotype, and augmented inflammation and vascular permeability.53
Chemokines in Acute and Ongoing Rejection
Donor ECs, intimal and medial SMCs, T cells, B cells, NK cells, and monocytes/macrophages/ dendritic cells all interact each other and secrete specific chemokines in a time-dependent manor in the allografts or draining lymphoid organs (eg, lymph nodes and spleen), orchestrating inflammatory lymphocyte accumulation and activation. Thus, this next wave of chemokines contributes to the onset and persistence of acute rejection. As early as 1 to 3 days after transplantation, levels of CC chemokines (eg, MCP-1/CCL2, MIP-1/CCL3, MIP-1β/CCL4, and RANTES/CCL5), CXC chemokines (MIG/CXCL9, IP-10/CXCL10, I-TAC/CXCL11, CXCL13), and fractalkine/CX3CL1 in cardiac allografts increase, peaking within 1 to 2 weeks after transplantation (Figure); these regulate the recruitment of activated T cells, NK cells, monocytes/macrophages, and eosinophils, and mediate acute allograft rejection.51,54 Early expression of the chemokines also correlates with subsequent GAD development,55 suggesting that generation of an initial chemokine/cytokine milieu can inexorably lead to graft vasculopathy. Thus, CC chemokines (eg, MCP-1/CCL2 and RANTES/CCL5) as well as proinflammatory cytokines (eg, IFN, TNF, and IL-6) are hallmarks of GAD.56,57
Chemokines and ECs
Emigration of host leukocytes into allografts is an essential component of acute rejection; ECs critically contribute to this inflammatory cell recruitment via chemokine as well as adhesion molecule expression.58 Similar pathways likely contribute to the eventual accumulation and proliferation of intimal SMCs.25,59,60 In broad strokes, chemokines such as MCP-1, IL-8, and RANTES regulate the recruitment of leukocytes. Later macrophage and then SMC migration and activation lead to mature GAD lesions.25,59,60
ECs in rejecting human allografts express RANTES,61 and RANTES expression correlates with both mononuclear cell infiltration and GAD development.62 Consistent with this, RANTES blockade reduces acute organ transplant rejection.57 MCP-1 also plays an important contributory role in the pathogenesis of acute organ rejection and GAD.63 Interestingly, statins attenuate the production of these chemokines in ECs, SMCs, and monocytes,19,64 and also reduce CCR2 and CCR5 expression by both ECs and macrophages, attenuating GAD.65
Chemokines and Effector and Regulatory T Cells and NK Cells
Allograft rejection requires the recruitment and binding of host T cells within the transplanted organ. Various cell-surface molecules and chemokines (eg, MCP-1) regulate leukocyte transmigration in an allograft vasculature. Recruited activated T cells then secrete cytokines such as TNF- and IFN- that amplify the immune response, increase EC adhesion molecule expression, and lead to further chemokine-mediated recruitment of macrophages and T lymphocytes.66 The sequence of chemoattractants encountered during migration as well as the signals transduced by the T cell antigen receptor determine the final destination of migrating T cells.67 CC- and CXC-chemokines both contribute to this process,68 and although donor ECs constitute a primary source of chemokines, graft-infiltrating leukocytes also contribute to chemokine production.
CXCR3, expressed on Th1 effector T cells, some B cells, and NK cells, provides an important receptor for 3 ligands: MIG/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11. Th1 T cells, macrophages, dendritic cells, and NK cells express CCR5, which can bind to RANTES/CCL5, MIP-1/CCL3, and MIP-1β/CCL4. IP-10 and Mig preferentially attract Th1 lymphocytes, NK cells, and macrophages, and IP-10 also drives T cell proliferation and IFN- secretion.1 Mig/CXCL9 antibody neutralization attenuates graft T cell infiltration and prolongs cardiac allograft survival.69 IP-10–deficient cardiac allografts also survived longer, consistent with donor-derived IP-10 triggering allograft rejection.70 Blockade of CXCR3 or any of its 3 ligands reduces allogenic T lymphocyte proliferation and effector cytokine production,71 and cardiac allografts in CXCR3-deficient hosts can exhibit prolonged allograft survival.70
Nevertheless, in fully MHC-mismatched cardiac allografts in robust murine or rat models, isolated CXCR3 deficiency or pharmacological blockade did not diminish graft infiltration, tempo, or severity of rejection,72 although additional CCR5 deficiency did. Cardiac allografts in WT, CCR5–/–, CXCR3–/–, and CXCR3–/– CCR5–/– (double knockout, DKO) recipients experienced mean survival times of 8, 11, 12, and 14 days, respectively, with the slight prolongation in DKO mice attributed to relative changes in CD4+CD25+Foxp3+ regulatory T cell (Treg) recruitment73; Tregs regulate expansion and activation of effector T cells, contributing to allograft rejection.74–76 Thus, in the fully MHC-mismatched cardiac allografts, combined CXCR3 and CCR5 blockade associated with increased intragraft Treg infiltration, which can theoretically restrict the clonal expansion of alloreactive T cells.77 Importantly, chemokine receptors CCR4 and CCR8 regulate Treg trafficking.78,79 The expression of chemokine receptors depends on the activation status or T cell differentiation; activated Th1 cells express CCR5, 6, and CXCR3, whereas Th2 cells express CCR3, CCR4, CCR8 and the lipid prostaglandin (PG) receptor CRTH280 that interact with TARC (thymus and activation-regulated chemokines)/CCL17 and MDC (monocytes-derived chemokines)/CCL22.81 The intriguing finding of the role of chemokine receptors in modulating Treg development deserves further investigation.
Fractalkine/CX3CL1 binds to the CX3CR1 and mediates leukocyte recruitment and adhesion and contributes to cardiac allograft rejection.82 Treatment with cyclosporin of CX3CR1-deficient hosts prolongs cardiac allograft survival with reduction of graft-infiltrating CD8+ T cells, NK cells, and macrophages bearing CX3CR1.
Chemokines and Monocytes/Macrophages/Dendritic Cells
In solid organ transplants, donor-origin macrophages are transferred with the organ ("passenger" leukocytes) and can proliferate locally. They can persist within the recipient for at least 4 weeks, but then decline in number. Host-origin monocytes/macrophages infiltrate the graft beginning 24 hours after surgery in both nonrejecting and rejecting allografts.83 Macrophages promote both acute rejection and GAD. Activated macrophages express a large number of proinflammatory mediators such as IL-1, -12, -18, TNF-, IFN-, and nitric oxide, and growth factors such as platelet-derived growth factor, fibroblast growth factor, and TGF-β, which promote the recruitment and proliferation of host-derived SMCs and drive extracellular matrix synthesis. Macrophages can also function as a potent APCs.19
The CC chemokines (eg, MCP-1/CCL2, MIP-1/CCL3, and RANTES/CCL5) are the dominant mediators in recruiting monocytes to rejecting organs.61 Genetic deletion, antibody blockade, or inhibition of either MCP-1 or RANTES substantially reduces intragraft macrophage and T cell accumulation and attenuates allograft rejection.56,57
Dendritic cells (DCs) are powerful APCs with a unique ability to transport and present processed and intact alloantigens to naï;ve T cells in secondary lymphoid tissues (eg, spleen and lymph nodes). T cell-DC interactions within secondary lymphoid organs are critical for the priming of alloimmune responses and the induction of tolerance.84 Splenectomized hosts or hosts lacking lymph nodes demonstrate a requirement for lymphocyte activation in secondary lymphoid tissue in alloantigen dependent graft rejection; cardiac allografts in these mice are able to survive indefinitely and do not develop alloantibody responses.84 Immature DCs express CCR1, CCR5, CCR6, and CXCR1. Immature host DCs migrate into grafts in response to several inducible CC chemokines (CCL2–5)85; there they acquire allograft antigen, undergo maturation, reduce expression of the inflammatory receptors CCR1, CCR5, CCR6, CXCR1 and increase CCR4, CCR7, and CXCR4 surface levels. CCR7 facilitates DC immigration to secondary lymphoid organs via the afferent lymphatics and traffic to draining lymphoid tissue.
Lymphoid tissues express CCR7 ligands (MIP-3β/CCL19 and SLC/CCL21), to constitutively attract mature DCs,85 and congenital deficiency of these chemokines reduces migration of mature DCs from allografts to the draining lymph nodes and prolongs graft survival.86 CCR7 (the cognate receptor of CCL19)-deficient animals also have defective DCs and T cell homing to lymph node.87 Because MIP-3β/CCL19 and SLC/CCL21 can attract both mature DCs and naive T cells, they likely allow antigen-loaded DC to encounter antigen-specific T cells.
DC-produced chemokines also likely contribute to allograft rejection. DCs produce MIP-3β/CCL19 and might contribute to the accumulation of mature DCs at the initial site, activating naive T-cells. DCs also secrete chemokines for initiating activated T cell migration, such as CCL3–5, MIP-1/CCL9/10), DC-CK (DC chemokine, CCL18), TARC (thymus- and activation-regulated chemokine, CCCL17), MDC (macrophage-derived chemokine, CCL22), IL-8/CXCL8, and CX3CL1.88,89 Finally, DCs secrete chemokines that recruit naïve and memory B cells, eg, CCL19–21, and SDF-1 (stromal-derived factor-1a)/CXCL12.90
Although the effect on transplantation has not been formally examined, blockade of chemokine-directed DC migration to or from transplanted organs could be an attractive therapeutic target.
Chemokines and B Cells
B cells play a key role in both humoral and cellular allograft rejection as a result of their capacity to secrete immunoglobulins, inflammatory cytokines, and chemokines, participate in antigen presentation and T cell and dendritic cell regulation, and contribute to lymphoid tissue development.91 Indirect alloantigen presentation by the host B cells figure importantly in the efficient progression of acute cardiac allograft rejection in mice.92 CXCR5 and its cognate ligand BCL/CXCL13 predominantly regulate B cell homing. BCL/CXCL13 likely recruits CXCR5+ B cells into allografts during human acute renal allograft rejection injury.93
Chemokines and Mast Cells
Mast cells have immunoregulatory properties that influence both innate and adaptive immunities; they can produce both pro- and antiinflammatory mediators, serve as antigen-presenting cells, and express a spectrum of costimulatory molecules.94 Mast cells may actually play dual roles in organ transplantation. In an acute skin allograft rejection, mast cells seem to be protective through activating and amplifying Treg cell function as well as by attenuating effector T cell responses.95 Likewise in a rat heart transplant model, mast-cell deficiency led to significantly reduced donor heart survival.96 Conversely, mast cells potentially contribute to the progression of GAD through the stimulation of fibroblasts and the increased synthesis of collagen. Patients with higher numbers of mast cells also underwent more severe rejection episodes; increased numbers of mast cells correlated with increased numbers of macrophages and mononuclear inflammatory cells in cardiac allografts with severe intimal thickening.97
Mast cells express the chemokine receptors CCR1, CCR2, CCR3, CCR5, CXCR1, CXCR2, and CXCR4.98 MCP-1/CCL2 induces mast cell chemotaxis but not degranulation, whereas RANTES/CCL5 induces mast cell chemotaxis, degranulation, and PGD2 generation. Similarly, MIP-1 also induces chemotaxis and enhances Fc RI–mediated calcium generation and degranulation in RBL-CCR1 cells (RBL 2H3 cells expressing human CCR1) and mouse bone marrow–derived mast cells.98 The role of chemokines and chemokines receptors in mast cells in GAD development requires further elucidation.
Chemokine and Platelet
Current evidence suggests that platelets structurally and instructively participate in vascular remodeling. Platelets adhere almost immediately to exposed or activated endothelium, and they are major storage and delivery vehicles for pro- and antiangiogenic growth factors including VEGF-A and thrombospondin (TSP), as well as for cytokines, and chemokines, such as SDF-1/CXCL12. Indeed, persistent elevation of TSP-1 in human cardiac allografts correlates with subsequent GAD development.99 By site-specific deployment of these factors, platelets orchestrate the local angiogenic stimulus within a tissue and direct the recruitment and differentiation of circulating bone marrow–derived cells.100
Chemokines and GAD
Intimal SMLCs are the major components of GAD lesions. Ischemia-reperfusion, allo-specific humoral and cellular effectors, donor and host APC, and atherogenic factors contribute not only to leukocyte emigration into the donor allografts, but also SMLC migration and proliferation in the intimal lesions. Because chemokines contribute to ischemia reperfusion injury and acute rejection, they clearly indirectly affect GAD formation. However, chemokines can also directly contribute to vascular remodeling and angiogenesis beyond their role in leukocyte chemotaxis. The observation that chemokines can also potentiate the effects of proliferative signals implies that chemokines can contribute to both recruitment and expansion of intimal cells in GAD lesions.6 Although it was generally assumed that most intimal SMLC in GAD lesions derived via ingrowth of donor SMCs, it is now known that intimal SMLC are not necessarily of medial SMC origin and can be largely host derived. Regardless of the specifics, it is clear that intimal SMLC derive from multiple sources, and simple recruitment from donor medial cells is probably not a tenable paradigm. Intimal SMLCs are clonal and phenotypically distinct from medial SMCs101; they express hematopoietic markers including CD14, CD34, CD105, Thy-1, c-kit, flt1, and flt-3.102 In any event, bone marrow–derived or any other circulating precursor cell must access grafts from the circulation25,103; consistent with this, smooth muscle progenitor cells are present in human peripheral blood.102
Host ECs can also repopulate allograft vasculature, and the recruitment of both ECs and SMLCs to the sites of injury occurs through expression of unique chemokines and cognate receptors.6,104,105 CXCR3 chemokines in particular exert potent biological effects on vascular cells as well as their well-recognized effects on mononuclear inflammatory cells. Human intragraft vascular cells expressed high levels of IP-10/CXCL10, I-TAC/CXCL11, and CXCR3; plasma levels of I-TAC were elevated in patients with severe GAD.105 SDF-1/CXCR4 also appears important for ECs or SMLC progenitor cell trafficking to and from the bone marrow and for the migration to injured peripheral organs.106,107
SMCs from diseased vascular tissue express CCR1 and CCR2. MIP-1 induces calcium influx in the SMCs, suggesting functionality of the SMCs CCR1 receptor, and the CCR1 antagonist BX 471 significantly inhibited development and progression of chronic allograft damage in a rat renal transplantation.108 MCP-1/CCL2 directly induces human SMC proliferation and IL6 production by differential activation of NFkB and AP1.109
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Summary |
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TopAbstractIntroductionPathogenesis of GADChemokines in TransplantationSummaryReferences |
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Chemokines are selectively expressed during the various stages of transplantation, and play a crucial role in allograft injury and GAD development through the recruitment and activation of inflammatory cells, vascular wall cells, or intimal progenitor cells. The early chemokines such as CXCL1, CXCL2, CXCL5, and CXCL8 participate in ischemia reperfusion injury through the recruitment and activation of neutrophils and monocytes. The second phase chemokines such as CCL3–5, CXCL9–11, and CX3CL1 mediate acute rejection through the recruitment of activated CD4+ and CD8+ T cells, NK cells, and macrophages in the allografts. In the chronic phase, intragraft chemokine levels of CCL2, CCL5, and CXCL8–11 chemokines contribute to GAD development via effects on T cells, macrophages, SMCs, or smooth muscle progenitor cells. Animal studies show that blockade of chemokines and their cognate receptor signaling can provide an effective treatment in reducing all phases of allograft injury and GAD. Further studies will likely confirm substantial utility for antichemokine therapy in human organ transplantation.
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Acknowledgments |
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We thank A. Shimizu, R. Shubiki, W. Cho, and E. Simon-Morrissey for their technical expertise, and J. Perry for editorial assistance.
Sources of Funding
This work was supported by an American Heart Association Scientist Development grant (to K.S.), an American Society of Transplantation Basic Science Faculty Development Grant (to K.S.), a grant award from the Roche Organ Transplantation Research Foundation (to K.S.), a Harvard Medical School BWH Fellowship Award (to K.S.), and a Brigham Research Institute grant (to R.N.M.).
Disclosures
None.
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Footnotes |
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Original received June 5, 2008; final version accepted September 8, 2008.
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References |
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