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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2005  |  Volume : 16  |  Issue : 4  |  Page : 520-539
Injury to Allografts: Innate Immune Pathways to Acute and Chronic Rejection


Baskent University, Ankara, Turkey

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   Abstract 

An emerging body of evidence suggests that innate immunity, as the first line of host defence against invading pathogens or their components [pathogen-associated molecular patterns, (PAMPs)], plays also a critical role in acute and chronic allograft rejection. Injury to the donor organ induces an inflammatory milieu in the allograft, which appears to be the initial key event for activation of the innate immune system. Injury-induced generation of putative endogenous molecular ligand, in terms of damage/danger-associated molecular patterns ("DAMPs") such as heat shock proteins, are recognized by Toll-like receptors (TLRs), a family of pattern recognition receptors on cells of innate immunity. Acute allograft injury (e.g. oxidative stress during donor brain-death condition, post-ischemic reperfusion injury in the recipient) induces "DAMPs" which may interact with, and activate, innate TLR-bearing dendritic cells (DCs) which, in turn, via direct allo-recognition through donor-derived DCs and indirect allo-recognition through recipient-derived DCs, initiate the recipient´s adaptive alloimmune response leading to acute allograft rejection. Chronic injurious events in the allograft (e.g. hypertension, hyperlipidemia, CMV infection, administration of cell-toxic drugs [calcineurin-inhibitors]) induce the generation of "DAMPs", which may interact with and activate innate TLR-bearing vascular cells (endothelial cells, smooth muscle cells) which, in turn, contribute to the development of atherosclerosis of donor organ vessels (alloatherosclerosis), thus promoting chronic allograft rejection.

Keywords: Allograft injury, Innate immunity, Organ transplantation

How to cite this article:
Land WG. Injury to Allografts: Innate Immune Pathways to Acute and Chronic Rejection. Saudi J Kidney Dis Transpl 2005;16:520-39

How to cite this URL:
Land WG. Injury to Allografts: Innate Immune Pathways to Acute and Chronic Rejection. Saudi J Kidney Dis Transpl [serial online] 2005 [cited 2019 Aug 19];16:520-39. Available from: http://www.sjkdt.org/text.asp?2005/16/4/520/32844

   Introduction Top


The first evidence that initial events of innate immunity may subsequently lead to both acute and chronic rejection of allografts comes from clinical observations. In 1994, without virtually mentioning the term "innate immunity", we had described a phenomenon of this host defence system, namely a non-antigen-dependent, reperfusion-induced inflammatory injury to renal allografts that affects their short-term and long-term outcomes. [1] Since the rediscovery of innate immunity at the end of the 20 th century (1996-1998), [2],[3],[4],[5] the underlying mecha­nisms have become clearer by which these innate pathways may determine the short­term and long-term survival of allografts. Subsequently, we have recently reviewed the role of innate immunity in organ transplant­ation in more detail. [6] In this article, further recently reported mosaic-stones in favour of the concept of the "Injury Hypothesis" are collected and cited and special emphasis is laid on the role of innate immunity in the development of chronic allograft dysfunction.


   Infection and Innate Immunity Top


The innate immune system, the inherited resistance to infectious disease, is an evolu­tionarily conserved, rapid first-line of host defence against invading microbial pathogens with the aim to eliminate them. It is now well established that the activation of adaptive immune responses requires direction from the innate immune system and is dependent upon up-regulation of co-stimulatory molecules on antigen-presenting cells such as dendritic cells (DCs). Indeed, one of the principal avenues of communication between innate and adaptive immune systems are the Toll-like receptor (TLR)-bearing DCs. TLRs expressed by immature DCs, upon binding their respective ligands, deliver activation and maturation signals that cause the DCs to migrate to lymphoid tissue and switch from antigen acquisition and processing to antigen present­ation to naive T-cells [7] [Figure - 1]. In addition, other cells of the innate immune system such as vascular cells, intestinal cells (Paneth cells), renal epithelial cells, and dermal cells (keratino­cytes), also represent first-line barriers against microbes that may invade the body via the blood stream, the intestinal and urinary tract, or the skin. Those cells, once activated, elicit a local antimicrobial response by producing antimicrobial proteins such as pro-inflammatory cytokines, chemokines as well as defensins and cathelicidins. [8],[9],[10],[11],[12],[13]

Certainly, the overwhelming research work in the field of innate immunity has been carried out with pathogens and microbial compounds respectively, infection models in animals and in patients with infectious diseases. Evolutionarily conserved pattern recognition receptors (PRRs) enable innate cells to sense pathogens. In particular, the family of innate immune Toll-like receptors as also the family of the nucleotide-binding site / leucine-rich repeat (NBS/ LRR) proteins "NOD1", "NOD2", and "Cryopyrin" (other name: nucleotide-binding oligomerization domain/ leucine-rich repeat [NOD/LRR] proteins), have proven to be essential in the detection and signalling of infection. [14],[15],[16],[17],[18] Thus, the most important mammalian TLRs comprise a family of germ line-encoded membrane­bound receptors which recognize conserved bacterial, viral, fungal, and protozoal molecular structures in the extracellular compartment. They are called pathogen-associated molecular patterns ("PAMPs"). Of them, the most pro­minent is lipopolysaccharide (LPS) from gram-negative bacteria. Until today, eleven TLRs, expressed partially on the cell surface, partially in intracellular compartments, have been cloned in mammals, and each receptor appears to be involved in the recognition of a unique set of "PAMPs" which act as exogenous ligands of TLRs. [15],[16],[19],[20],[21],[22] The other family of proteins, the NBS/LRR proteins, now a days included in the novel gene family "CATERPILLER" [23] , is involved in intracellular recognition of microbes and their products within the cytoplasmic compartment. Two of these family members, NOD1 and NOD2, play a role in the regulation of pro- inflammatory pathways through NF-κB induced by bacterial ligands. The dysregulation of these processes due to mutations in the genes encoding these proteins is involved in certain auto-inflammatory disorders, such as Crohn´s disease. [24],[25]

By triggering intracellular signalling cascades, resulting in the expression of genes and subsequent generation of effector molecules, the whole repertoire of these different recognition molecules provide effective pathogen resi­stance. Most importantly are TLR-signalling pathways, which are finely regulated by TIR domain-containing adaptors, such as myeloid differentiation marker 88 (MyD88), TIR­associated protein (TIRAP), TIR-domain­containing adaptor inducing INF-β (TRIF) and TRIF-related adaptor molecule (TRAM).

Differential utilization of these TIR domain­containing adaptors provides specificity of individual TLR-mediated signalling pathways ultimately leading to activation of different transcriptional factors such as nuclear factor­kappa B (NF-E1B), activator protein-1 (AP-1), and interferon regulatory factor 3 (IFR3). Studies with LPS showed that up-regulation of the co-stimulatory molecules CD80, CD86, and CD40, involving an autocrine or paracrine loop via secretion of interferon-β , occurs in a TRIF-dependent and MyD88-independent manner whereas up-regulation of B7RP-1 (ICOS-L) is dependent primarily on the MyD88 signalling pathway. 26,27 Post-ischemic reperfusion injury signals through (at least) TLR4, TLR4 signalling pathways are of special importance [Figure - 2]. Taken together, acti­vation of these factors in cells of the innate immune system results in the expression of pro-inflammatory genes related to inflammatory, alloimmune, autoimmune, and antiviral responses. [6],[16]

The rediscovery of the innate immune system is of clinical relevance. There is growing evidence suggesting that the ability of certain indi­viduals to respond properly to TLR ligands may be impaired by single nucleotide polymorphisms (SNPs) within TLR genes, resulting in an altered susceptibility to, or course of, infections or inflammatory diseases. Most studies have focused on two co-segregating SNPs, Asp299gly and Thr399Ile, within the gene encoding TLR4. These SNPs are present in about 10% of white individuals, and have been found to be positively correlated with several infectious diseases. [28]


   Tissue Injury and Innate Immunity Top


The notion that acute and chronic outcome of allografts is dominated by events of the innate immune system is based on the concept that, not only pathogen-induced tissue injury but, any tissue injury results in an activation of innate immune pathways. In fact, from an evolutionary point of view, there is no reason to assume that an alloimmune-mediated des­truction of an allograft uses other pathways than those developed in the course of an effective immune-mediated host defence during billions of years. Allogeneic organ transplant­ation is being performed just since around 50 years, too short a period of time for nature, to develop novel immune pathways for allograft rejection. Hence, in view of this background, we must assume that the ancient innate pathways are also operating in organ transplantation. What we have to do, therefore, is to search for mechanistic links between the elimination of pathogens on one hand and destruction of an allograft on the other hand. One of the most plausible links is the initial tissue injury caused by microbial pathogens on one side and by non-microbial conditions such as organ reper­fusion on the other side. Indeed, there is accumulating evidence suggesting that certain molecules arising during any tissue damage are able, in the sense of those links, to interact as putative endogenous ligands with TLR­bearing cells of innate immunity as do exogenous ligands from microbial components. One of those evidences was the early observation that danger signalling stress proteins, namely heat shock proteins (HSPs), known to be released as a result of any stressful tissue injury, may act as endogenous ligands of TLRs and, by this interaction, are able to activate cells of the innate immune system. Upon intense stress, e.g. associated with cell necrosis, HSPs may act independently from their intracellular protective function by being extracellularly released as molecular chaperones in a cytokine­like manner and may be regarded as chapero­kines. The chaperokine activity of HSPs is mediated in part by interaction with TLRs leading to the activation of the innate immune system. [29] Accordingly, endogenous ligands of TLRs were first described in studies with HSPs including HSP60, HSP70, and gp96. The immuno-stimulatory and inflammatory activity of these molecules is mediated by Toll­like receptors, such as TLR2 and TLR4. [30],[31],[32],[33],[34] Most of these studies were performed using recombinant heat shock protein preparations from which LPS is notoriously difficult to remove. Consequently, contradictory reports were published by raising the question whether or not the activation of TLR4 was really induced by these endogenous ligands, or via an exogenous ligand, in form of a tightly bound LPS-contaminant. [35] Nevertheless, ostensibly, HSPs could engage TLRs upon release from necrotic cells and thereby induce an inflammatory response. [15] In addition, recent experiments showing activation of NF-LB B in human endothelial cells in response to recombinant purified mycobacterial HSP65 and HSP70, emphasize the unlikeliness that their signalling through TLR4 and TLR2 is influenced by LPS contamination. [36] Other sets of studies revealed additional damage­induced molecules which are able to interact with TLR2 or TLR4, including the inducible host antibiotic β-defensin and extracellular matrix components, such as fibronectin, hyaluronan fragments, heparan sulfate, and extravascular fibrin deposits which are early and persistent hallmarks of inflammation accompanying injury. In addition, nucleic chromatin/IgG-complexes as well as mRNA released from damaged cells have been shown to represent endogenous ligands, which signal via TLR9 and TLR3 respectively [37],[38],[39],[40],[41],[42],[43] [Table - 1]. In analogy to PAMPs, all these injury-induced putative endogenous ligands may be called damage-associated molecular patterns ("DAMPs"), [44] although there is no definite proof yet but only suggestions that such endo­genous ligands can stimulate TLRs (wherreas PAMPs undoubtedly signal via TLRs). Regardless of a presumed interaction with TLRs, numerous experimental studies in different organs and species have clearly shown a release of such "DAMPs" from damaged tissue, such as HSPs, heparan sulfate, hyaluronic acid, and fibronectin. [45],[46],[47],[48] Further, it is now well recognized that endogenous ligands of TLRs, like pathogen-derived exogenous ligands, are able to induce activation and maturation of dendritic cells by inducing a cross-talk with natural killer cells. In addition to secretion of cytokines and chemokines, as well as present­ation of peptides in the frame of MHC molecules to naive T cells, mature DCs provide T cells with the required "second signal" by expressing co-stimulatory molecules on their surface [14],[15],[49] [Figure - 1].

Interestingly enough, from studies in knockout mice, there is now first experimental evidence showing that full-scale reperfusion-induced organ injury is, at least in part, mediated via activation of TLR4-bearing cells. In an experi­mental model of liver reperfusion injury in TLR4-, MyD88-, and IRF3- deficient mice, it could be shown that the full-scale liver reperfusion injury is initiated and induced by activation of TLR4. The study showed that the reperfusion injury activates TLR4 through a MyD88-independent, but IRF3­dependent pathway to induce the chemokine interferon-γ-inducible protein-10 (IP-10) which may then be responsible for the recruitment/ activation of T cells. [53] Similar results were obtained in studies in another TLR4-deficient mouse model of hepatic ischemia/reperfusion injury. [54] In a murine model of myocardial ischemia-reperfusion injury (2 strains of TLR4-deficient mice), it could be shown that TLR4-deficient mice sustain smaller infarctions and exhibit less inflammation after myocardial reperfusion injury. [55] Notably, apart from defined ROS-mediated injury, there are obviously various sources of injury which might activate the innate immune system as has recently been shown in other injury models including severe hemorrhage-induced acute lung injury. [56],[57]


   Allograft Injury, Innate Immunity and Acute Rejection (Alloimmunity) Top


There are accumulating experimental and clinical data in support of the notion that the injury to the donor organ leads to activation of the innate immune response initiating the adaptive allo-immune response. As described in more detail elsewhere, one has to discriminate between an injury to potential allografts occurring already in the brain-dead donor and injuries to these organs occurring during/after transplantation in the recipient. [44],[45] The central catastrophical injury during brain-death promotes release of inflammatory mediators such as cytokines, chemokines, and adhesion molecules as detected in kidney, heart, and peripheral blood and documented by up­ regulation of gene expression. [58],[59],[60] Oxidative stress may induce this condition or may be the result of it. In fact, there is recent convincing clinical evidence suggesting that donor kidneys are exposed to oxidative stress already in brain­dead organisms leading to an intrarenal early-phase inflammatory process. [61],[62] Plausibly, innate immature dendritic cells in those inflamed organs of brain-dead donors mature and get activated. Post-ischemic reperfusion of the donor organ in the recipient induces a second burst of injury associated with activation of donor DCs already residing in the graft as well as recipient DCs entering the graft; processes which are followed by travel of those matured DCs from the graft into the secondary lymphoid tissue where they interact with T cells (direct / indirect alloactivation) [Figure - 1]. There is growing indirect evidence in support of the notion that the reperfusion injury to allografts, via induction of HSP70, activates TLR4-bearing cells of innate immunity resulting in subsequent activation of adaptive allo-immunity: First, by reviewing numerous experimental studies, our group was able to directly demonstrate the generation of reactive oxygen species during reperfusion of human renal allografts which is associated with a dramatic up-regulation of an endogenous ligand of TLR4, namely HSP70; [63],[64] second, as mentioned, there is already experimental proof showing that full-scale reperfusion­induced organ injury is mediated via activation of TLR4-bearing cells, [53],[54],[55] and third, there is also recent experimental proof demonstrating that HSP-70 is an innate immune ligand that promotes DC maturation and T cell allo-immunity. [65]

Besides reperfusion injury, other types of acute allograft damage may occur following organ transplantation. Of note here is that an allo-immune-mediated acute rejection episode represents a further injury to the transplant. This specific injury may again initiate the activation of events of innate immunity, which in turn, may fuel the ongoing adaptive response. This phenomenon of a positive feedback regulation of "innatity" by "adaptivity" was recently described and confirmed by a thorough analysis of 60 intra-graft inflammatory para­meters following experimental isogeneic and allogeneic cardiac transplantation. [66] Successful reversal of acute rejection episodes by intra­venous administration of methylprednisolone in "high pulse doses" may be due to an interruption of this inflammatory feedback mechanism.

Active CMV infection represents another acute allograft injury. As known, CMV infection may trigger acute rejection episodes. On the basis of recent experimental studies, this phenomenon may also be cautiously explained on the basis of innate immune mechanisms. Thus, it could be shown that the Toll-like receptor 2 and its cofactor CD14 recognize CMV virions already during the entry stage of infection and subsequently trigger inflam­matory cytokine production. [67] TLR-bearing dendritic cells as well as TLR-bearing natural killer (NK) cells, that are also part of the innate immune system, are among the first immune effecter cells to arrive at a CMV­induced intra-graft inflammation. In reciprocal cross talks with dendritic cells, the NK cells get activated and are able to lyse CMV infected cells. [51],[68],[69],[70] From those necrotic graft cells, endogenous legends such as heat shock proteins as well as allo-antigenic material may be released which lead to activation of another set of dendritic cells which, in turn, via interaction with allo-reactive T-cells, lead to activation of adaptive allo-immunity [Figure - 3].

The concept of injury-induced activation of the innate immune response also includes the notion that allo-grafting in mice, with deficiencies in signalling molecules of cells of innate immunity or, under treatment of ROS-mediated reperfusion injury, should lead to prolongation of allograft survival. In fact, first reports of such studies have recently been published. In experiments in mice with targeted deletion of universal TLR signal adaptor protein MyD88, minor antigen-mis­matched (HY-mismatched) allograft rejection did not occur in the absence of MyD88 sig­nalling, indicating that, at least in this system, innate immunity is linked to the initiation of the adaptive allo-immune response. Furthermore, the study demonstrated that the inability to reject these allografts results from a reduced number of mature DCs in draining lymph nodes, leading to impaired generation of anti­graft-reactive T cells and impaired Th1, but not Th2, adaptive response. [71] However, in similar experiments in these MyD88-deficient mice performed by the same group, fully MHC-mismatched skin and cardiac allografts were promptly rejected emphasizing the importance of MyD88-independent pathways in innate recognition of fully MHC-mismatched allografts. [72] Nevertheless, other experimental studies on a murine transplant model across the complete H-2 allo-barrier showed a pro­longation of skin allograft survival in both MyD88- and TRIF-deficient mice. [73]

Moreover, treatment of the reperfusion injury with an antioxidant, e.g. the novel free radical scavenger MCI-186 (edaravone) during trans­plantation of hearts from C57BL/10 mice onto CBA mice, induced a significant prolongation of graft survival. Interestingly enough in this study, the transfer of cells from permanent cardiac allografts bearing CBA mice into untreated CBA mice recipients of heart trans­plants again significantly prolonged the survival of fully allogeneic cardiac grafts, suggesting a kind of T regulator cell-mediated tolerant state. [74] Indeed, this experiment reminds our early clinical trial in which the administration of the free radical scavenger superoxide dis­mutase during surgery led to a significant reduction of acute (and chronic) rejection in cyclosporin-treated kidney transplant patients. [1]


   Allograft Injury, Innate Immunity and Chronic Rejection (Allo-atherosclerosis) Top


Chronic rejection in terms of chronic allograft dysfunction is believed to be the result of multi­factorial events influenced by both specific antigen-dependent (allo-immune) and non­specific antigen-independent risk factors. Pathohistologically, chronic allograft failure is dominated by development of allo­atherosclerosis and allo-fibrosis. Originally, antigen-dependent events only, such as acute rejection episodes, had been identified as "bad predictors" for allograft outcome and believed to contribute, at least in part, to allo-atherogenesis. Soon, however, antigen­independent risk factors came into play.

In fact, already in the late nineties, increasing interest had focused on the potential role of infectious agents and components of the innate immune system as contributors to atheroscle­rosis. [75] Today, atherosclerosis is well recognized to be a chronic inflammatory and autoimmune process of the arterial wall initiated by innate immune mechanisms, and characterized by subendothelial proliferation of smooth muscle cells as well as accumulation of atherogenic lipoproteins, extracellular matrix, neovessels, calcium, and inflammatory and immune cells such as macrophages, dendritic cells, natural killer cells, mast cells, neutrophils, and T- and B-cells. [76],[77],[78],[79] In particular, cellular and humoral adaptive immunity to heat shock protein 60 as an endogenous ligand of TLRs on vascular cells appears to be the initiating mechanism in the earliest stages of athero­sclerosis. Due to a high degree of sequence homology between microbial and human HSPs, this acquired immune response may be interpreted as a cross-reacting response against microbial HSP60 or even as a bona fide autoimmune response against autologous HSP60 derived from pathogen-damaged vas­cular cells. [80] Provokingly, one might conclude that development of atherosclerosis reflects the price to be paid for protection of pathogens invading from the blood stream!

Consequently, in regard to organ transplant­ation, atherosclerosis of allograft arteries (allo­atherosclerosis), concomitant with interstitial fibrosis (allo-fibrosis), as characteristic and dominant features of chronic allograft dys­function, may be regarded as processes induced by inflammatory, "iso-immune", and allo­immune responses, the latter event obviously being responsible for the rapid development of allo-atherosclerosis compared to "native" atherosclerosis. In fact, as a common root of these three responses, innate mechanisms can be seriously discussed. Thus, further growing amounts of data suggest that atherogenesis reflects an event of innate immunity where exogenous and endogenous ligands of TLRs, such as HSPs, located within the vessel wall, interact with TLR- bearing vascular cells (e.g. TLR4 as detected in atherosclerotic plaques) and lead to local inflammatory processes via cytokine, chemokine, and growth factor secretion as well as adhesion molecule over expression. [44],[80],[81],[82],[83] Thus, heat shock proteins appear to have a general role in the response of the arterial wall to stressful injuries and may serve, in their function as "DAMPs", as contributors to allo-atherosclerosis and native atherosclerosis by interacting with Toll-like receptors.

As reviewed earlier, [44] acute and chronic risk factors for the development of chronic allograft dysfunction, known to be simul­taneous risk factors for the development of atherosclerosis, can be regarded as acute/chronic injuries to vascular cells and, by this, evoke over expression of endogenous ligands in form of heat shock proteins in endothelial cells, macrophages, and smooth muscle cells. These risk factors include acute rejection episodes, acute and chronic oxidative stress (reperfusion injury, application of CNIs, smoking), hyper­tension, hyperlipidemia (oxidized low density lipoproteins), and viral (CMV) infections, diabetes mellitus, and administration of calci­neurin-inhibiting drugs. In the following, they shall be briefly discussed by quoting more recent reports from the literature [Figure - 4].

Acute Rejection Episodes

As mentioned, acute rejection episodes causing allograft injury may initiate intragraft events of innate immunity in terms of a positive feedback regulation. [66] Hence, acute rejection­associated "endothelitis" may activate vascular cells, which in turn, may contribute to allo­atherogenesis via innate mechanisms.

Oxidative Stress

That acute oxidative stress, associated with reperfusion injury, may affect the long-term outcome of renal allografts, was already shown in our original SOD-trial where we discussed an impact of the generation of free oxygen radicals on the development of allo-athero­sclerosis. [1] During the past years, an emerging body of evidence has been reported in support of this concept: clinical, epidemiologic, and basic molecular science studies have identified oxidative stress as a factor contributing to the development and progression of athero­sclerosis. Oxidative stress also participates in the pathogenesis of endothelial dysfunction and hypertension, two important factors in many patients with atherosclerosis. Further, oxidative stress contributes to mechanisms of disease progression such as lipid peroxidation and vascular remodelling. [84],[85] In addition, from functional studies (so called "pathwayomics"), it could recently also be concluded that vascular oxidative stress, with its extensive network of genes and proteins, obviously contributes to cardiovascular dis­eases. [86] Activation by reactive oxygen species of innate TLR-bearing endothelial cells and/ or smooth muscle cells within the arterial wall may be achieved via their well-known effect to induce heat shock proteins in damaged cells. [45],[87]

Hypertension-Biomechanical Stress

Hypertension can alert inflammatory innate pathways in vascular cells by inducing stress proteins via oxidative and biomechanical stress ("stretching" of smooth muscle cells) to the vessel wall. These heat shock proteins operate as chaperokines and may activate the innate immune system via binding to TLRs. [44] In fact, acute hypertension induces HSP70 gene expression in endothelial cells, macrophages, and smooth muscle cells of the rat arterial wall mediated through activation of heat shock transcription factor 1. [88],[89] Another possibility of HSP induction during hyper­tension may be the primary generation of reactive oxygen species, e.g. stimulated by the regulatory hormone angiotensin II. [90],[91],[92] Likewise, endothelin-1, a pleiotropic hormone produced primarily by the endothelium and associated with hypertension, may activate inflammatory pathways in innate vascular cells via induction of HSP70. [91],[92],[94] The accelerated development of allo-atherosclerosis may be caused by an interaction between recipient hypertension and allo-responsive­ness as shown in an experimental model of hypertension in rats. [95]

Another kind of biomechanical stress to the vessel wall is represented by shear stress. Physiologic levels of 1-7 N/m² shield against atherosclerosis via effects on the endothelium, whereas decreased shear stress at branches, bifurcations, and curvatures permits endothelial activation. It has been shown that shear stress has differential effects on several receptors involved in inflammation: TLR4 expression was insensitive to flow whereas expression of TLR2 was strongly inhibited by higher shear stresses indicating an effect of TLR2 on atherosclerotic lesion development. [96]

Hyperlipidemia

Hyperlipidemia, in form of accumulation of oxidized low-density lipoprotein (oxLDL) and minimally modified low-density lipoprotein, (mmLDL), is being regarded as another factor contributing to atherogenesis by initiating innate signalling pathways. However, whilst accumulating evidence for fundamental links between innate immunity, inflammation, and atherogenesis, described above, has been mostly indirect, direct proof of the concept comes from experimental and clinical studies related to hyperlipidemia, in particular, epidemiological studies in patients and experiments on a genetically deficient hyper­cholesterolemic mouse model. In studies on atherosclerosis-prone apolipoprotein E (Apoe)­deficient mice, it could be demonstrated that mice with a defect in the innate immune system (lack of the MyD88 molecule) evinced a marked reduction in early atherosclerosis. [97] In subsequent similar studies, it could be demonstrated that genetic deficiency of TLR4 and of MyD88 is associated with a significant reduction of aortic plaque areas in Apoe-deficient mice, despite persistent hypercholesterolemia. Apoe-deficient mice that also lacked TLR4 or MyD88 demonstrated reduced aortic atherosclerosis that was asso­ciated with reduction in circulating levels of pro-inflammatory cytokines interleukin-12 (IL-12) or monocyte chemo attractant protein-1 (MCP-1), plaque lipid content, numbers of macrophages, as well as cyclooxyenase 2 (COX-2) immunoreactivity in their plaques. [98] The question is, what kind of endogenous ligands to TLR4 are involved in hyper­lipidemia-induced atherosclerosis? In fact, in vitro studies may assist in answering this question. They have shown that minimally oxidized low-density lipoprotein (mmLDL), is pro-inflammatory and pro-atherogenic lipoprotein, which is recognized by TLR4 and its co-receptor CD14 on macrophages. Binding of this lipoprotein by TLR4 (but also other receptors) leads to secretion of pro-inflammatory cytokines, a finding which again indicates the inflammatory origin of atherogenesis. [99] Accordingly, in studies on human endothelial cells, it was found that the recognition of mmLDL by TLR4 results in the secretion of IL-8, a chemokine imp­ortant in monocyte transmigration and retention in the vessel wall. [100] In addition, further support to a close relationship between innate immunity, inflammation and athero­sclerosis comes from studies showing that defensins and cathelicidins, as essential elements of innate immunity, are involved in the lipoprotein metabolism in the vessel wall, favouring LDL and lipoprotein-a accumulation in the endothelium and enhancing endothelial proliferation. [13] Patients expressing a poly­morphism in the TLR4 gene (Asp299Gly) manifest lipopolysaccharide hyporesponsive­ness, and are protected from carotid artery atherosclerosis as well as acute coronary events, [101],[102] and derive greater benefit from risk reduction with statins. [103] Collectively, these experimental and clinical findings firmly suggest that TLR signalling may play a role in the development of atherosclerotic plaques.

CMV Infection

According to experimental and clinical studies, CMV is one of the pathogens that has been most convincingly implicated in the pathophysiology of native atherosclerosis and allo-atherosclerosis. A large body of data indicates that CMV can affect cells that are relevant to atherosclerosis, including endothelial cells, smooth muscle cells, and macrophages/ monocytes. [104] Consequently, active CMV infection is assumed to act as a risk factor for the development of both chronic allograft dysfunction and cardiovascular diseases of the recipient. Again, there is growing evidence suggesting that initial virus-triggered innate mechanisms may be involved in these patho­logical conditions. DNA micro-assay analyses have shown that mere cell contact by CMV particles, in particular by the viral envelope glycoprotein B (gB), leads to profound modulation and reprogramming of cellular gene expression, including induction of inflammatory cytokines, heat shock protein 70, and interferon-stimulated genes indicating a robust activation of the innate immune system. [105],[106] Recently, it could be shown that the Toll-like receptor 2 and its cofactor CD14 recognize human CMV virions already during the entry stage of infection and sub­sequently trigger inflammatory cytokine production. Induction of inflammatory cytokines has been shown to be mediated via TLR2­dependent activation of NF-κB. [67] Further studies in CMV-infected human aortic smooth muscle cells suggest that the pro-inflammatory response to CMV infection in the vessel wall leads to activation of the novel IkappaB kinase (IKK)-related kinase, Tank-binding kinase-1 (TBK1), [107] a major signalling effector molecule of the cellular innate immune response, as described elsewhere. [6]

Calcineurin Inhibiting Drugs (CNI)

Nephrotoxic and atherogenic immunosuppre­ssive agents such as CNI contribute to the development of chronic renal allograft dys­function. There are numerous reports in the literature from experiments clearly showing an atherogenic effect of cyclosporin as indicated by induction of endothelial dysfunction, endo­thelial cell injury, and arteriitis. As described elsewhere, [108] cyclosporin is able to induce the generation of reactive oxygen species (ROS) (in particular free hydroxyl radicals in kidneys of cyclosporin-treated rats) and heat shock proteins induced by ROS, respect­ively. Thus, the chronic injury to renal allografts, induced during long-term administration of CNIs, may activate cells of innate immunity via chronic oxidative stress, in analogy to ROS-mediated reperfusion injury acting as acute oxidative stress. In this scenario again, ROS-induced heat shock proteins may serve as endogenous ligands for TLR-bearing renal cells. In fact, in recent experiments in rats, this assumption could be confirmed: [109] Long­term administration of cyclosporin resulted in the development of chronic nephropathy as revealed by histological findings. In this experimental model, activation of innate immunity was demonstrated by up-regulation of TLR2 and TLR4 mRNA as well as of their endogenous ligands HSP70 and heparan sulfate proteoglycan in renal tubular cells of cyclosporin-treated rats.


   Conclusion and Outlook Top


Growing amounts of experimental and clinical data are now available to support the notion that any stressful inflammatory tissue injury, including injury to allogenic tissue, leads to activation of innate immunity which, in turn, initiates/contributes to adaptive (allo-) immunity and (allo-) atherogenesis. Acute injuries such as reperfusion injury as well as chronic injuries such as hypertension, hyperlipidemia, viral infection and administration of toxic drugs may lead to the generation of endogenous ligands of TLRs in terms of "DAMPs", such as heat shock proteins and minimally modified low-density lipoproteins, which may be recog­nized by Toll-like receptor-bearing cells of the innate immune system, such as dendritic cells and vascular cells. Nevertheless, further careful experiments are needed to show and to prove a direct interaction between all those pro-inflammatory and pro-atherogenic endo­genous ligands and Toll-like receptors before we can conclude that TLRs do definitely recognize "DAMPs".

Interestingly, recent insight into these scenarios might lead to some future changes in definitions we have been familiar with in organ trans­plantation over the years: For example, immuno­suppressive therapy has to be divided into suppression of: a) events of innate immunity occurring in the donor and the recipient and, b) events of adaptive allo-immunity occurring in the recipient. In addition, the interrelationship between antigen-dependent and antigen­independent risk factors for chronic allograft dysfunction has to be redefined: the starting points are acute and chronic non-immune allo­graft injuries, which, antigen-independently, activate the innate immune system of the donor and the recipient. Through activated innate dendritic cells, the adaptive allo-immune res­ponse is activated leading to antigen-dependent risk factors (in their original meaning) whereas antigen-independent risk factors, represented by chronic injurious events, activate innate vascular cells contributing to the development of allo-atherosclerosis and allo-fibrosis [Figure - 5]. In addition, the new insights into the role of brain-death and reperfusion injury in activation of the donor's and recipient's innate immune system open the door for new approaches to gene therapy in organ transplantation: Thus, for example, application of siRNAs in the donor, the graft and the recipient peri-postoperatively would imply an effective method to transiently block the expression of genes of the innate immune system.

 
   References Top

1.Land W, Schneeberger H, Schleibner S, et al. The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants. Transplantation 1994;57:211-7.  Back to cited text no. 1    
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Walter G Land
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