Whereas kidney allograft tolerance has been achieved in nonhuman primates (NHPs) [1–3] and in humans [4–7], protocols that achieve tolerance of kidney allografts in NHPs fail to induce tolerance of heart allografts . The reasons for this organ-specific difference are not clear. However, it is clear that all transplanted organs are not created equal. Not only does the strength of the immune response to a particular organ vary with the organ transplanted but the nature of response itself, rejection versus tolerance, varies from organ-to-organ. In most experimental transplant models, kidney, and liver allografts evoke a weaker rejection response than heart and lung allografts. Moreover, kidney and liver allografts can actively participate in the induction and maintenance of tolerance and thus, can be considered ‘tolerance-prone’ organs. The same cannot be said for heart and lung allografts which are, for the most part, ‘tolerance-resistant.’ Finally, kidney and liver allografts also possess the unique ability to confer unresponsiveness upon cotransplanted, tolerance-resistant organs like hearts. Understanding the mechanisms underlying these organ-specific differences could contribute to the development of strategies that extend tolerance to recipients of tolerance-resistant organs. Here, we review organ-specific differences in tolerance induction, focusing on the dissimilarities between tolerogenic kidney and liver allografts and the more stringent heart and lung allografts.
ORGAN DIFFERENCES IN THE DEVELOPMENT OF OPERATIONAL TOLERANCE FOLLOWING WITHDRAWAL OF IMMUNOSUPPRESSION
Operational tolerance in solid organ transplantation, defined as spontaneous graft acceptance without histological evidence of rejection for at least 1 year after cessation of immunosuppression , has been observed in human kidney and liver transplant recipients  with clear benefits to quality of life . Examination of the natural history of 27 kidney transplant patients rendered operationally tolerant after withdrawing immunosuppression revealed that 70% maintained stable graft function for an average of 9 years after transplantation . In adult liver transplantation, 5–33% of patients who withdraw from immunosuppression exhibited operational tolerance [13–17], although the incidence was higher in the pediatric population . In contrast, there exist only anecdotal cases of operational tolerance in a lung recipient or heart recipient .
Similar differences have been observed in the spontaneous acceptance of murine organ allografts transplanted into untreated recipients. Murine skin, hearts, intestines, lungs, and hepatocytes are largely rejected when transplanted across multiple major histocompatibility factor (MHC) barriers [20–24]. In contrast, kidneys and livers are commonly accepted across the same MHC barriers [21,25–30]. In a direct comparison of liver, kidney, and heart allograft survival after transplantation across the same full MHC disparities in untreated murine recipients, most of liver allografts (57–72%) were spontaneously accepted long-term, whereas hearts were all rejected in less than 10 days . The pattern of kidney allograft rejection was mixed with 20–50% organs surviving long-term . Among higher order animals, spontaneous tolerance has only been reported after liver  or kidney  transplantation in swine. These experimental results and others [33–36] support the fact that abdominal allografts have a much greater propensity for spontaneous acceptance compared with thoracic organs transplanted across the same MHC barrier.
ORGAN DIFFERENCES FOLLOWING THE ACTIVE INDUCTION OF ACQUIRED TOLERANCE
Organ-specific differences in the predisposition toward tolerance is even more pronounced when a tolerant state is actively induced using a variety of short-term immunosuppressive protocols. For instance, MHC class I disparate hearts or fully mismatched hearts transplanted into miniature swine treated with 12 days of a calcineurin inhibitor (CNI), all rejected within 60 days [37,38]. In contrast, kidneys transplanted across the same genetic barriers and treated identically all became tolerant and maintained excellent renal function long-term [39,40]. The survival of lungs was in between that of hearts and kidneys with graft survival ranging from 67 to more than 605 days but with most developing obliterative bronchiolitis . A similar dichotomy was observed in cynomolgus monkeys treated with a mixed chimerism conditioning regimen, wherein kidney allografts survived long-term while hearts or lungs allografts were rejected early despite the identical treatment and similar MHC disparities [3,8]. Thus, the ability to induce tolerance of an organ varies dramatically with the organ transplanted. The clinical implications of these findings are that successful tolerance protocols will not be directly transferable from one organ system to another and that the preclinical testing of tolerance protocols for human transplantation will have to proceed in an organ-specific manner .
TOLERANCE OF A RESISTANT ORGAN INDUCED BY COTRANSPLANTATION WITH A TOLERANCE-PRONE ORGAN
Even more striking than the apparent hierarchy in organ tolerogenicity, is the observation that tolerance-prone organs can confer unresponsiveness upon tolerance-resistant organs procured from the same donor. Using MHC inbred miniature swine, we have shown that instead of rejecting their hearts, recipients cotransplanted with hearts and kidneys from the same class I disparate  or fully MHC mismatched  donor developed stable tolerance after 12 days of a high-dose CNI. In addition to long-term, rejection-free survival of both kidney and heart allografts, there was no alloantibody formation or evidence of chronic rejection. Similar results have recently been observed in NHPs transplanted with heart alone or heart and kidney allografts undergoing mixed chimerism conditioning (M. Tonsho, article in preparation).
This phenomenon, now termed kidney-induced cardiac allograft tolerance (KICAT), is dependent upon several variables including MHC matching of the heart and kidney , presence of the host thymus , and the presence of a yet-to-be-determined radiosensitive cell population within the donor kidney . Of note, cotransplanting a donor lung instead of a kidney with the heart did not prolong the survival of either graft  and transplanting two donor-matched hearts did not induce tolerance, indicating the KICAT was not a function of donor antigen load . It is also noteworthy that donor nephrectomy 8 days after cotransplantation resulted in cardiac allograft vasculopathy (CAV) and rejection, reflecting the importance of the renal allograft during the induction phase of tolerance . Donor nephrectomy 100 days after transplantation resulted in CAV but not rejection, suggesting that persistence of the donor kidney is necessary for durable tolerance without chronic rejection .
ROLE OF REGULATORY T CELLS
When the phenotypes of graft infiltrating lymphocytes retrieved from isolated porcine kidneys allografts were examined, the number of cells expressing the phenotypic markers of T regulatory cells (Tregs) were substantially higher in acceptor than in rejector transplants at all time points . Also, we have shown that CD25+ T cells in peripheral blood leukocytes from heart/kidney recipients but not isolated heart recipients could fully suppress the antidonor response of naïve-matched T cells in coculture cell-mediated lympholysis assays . Based on these results and others [50,52,53], we hypothesize that cells or cell products intrinsic to kidney, but not heart, allografts promote the activation/expansion of host Tregs.
Together, these results suggest that cardiac allografts lack one or several soluble or cellular factor(s) present in the cotransplanted kidney which is able to enhance or augment host Tregs and thereby induce a robust state of tolerance. Once identified, this cell or factor(s), could be utilized to induce tolerance of all resistant organs. For this reason, the remainder of this review will focus on the factors intrinsic to tolerance-prone organ allografts that may be responsible for promoting host regulatory mechanisms.
INTRINSIC MECHANISMS OF ORGAN-SPECIFIC DIFFERENCES IN TRANSPLANT TOLERANCE
The tolerance potential of a particular organ (it's tolerogenicity) is the product of intrinsic and, in the case of barrier organs like lung and intestine, extrinsic factors such as environmental antigens (reviewed in ). Intrinsic factors include organ homeostatic functions, cell-surface antigens, donor-derived, tissue-resident immune cells and their cell products, and soluble factors produced by parenchymal cells secondary to their normal physiological function.
Organ homeostatic functions
The propensity for a given organ to elicit a proinflammatory versus anti-inflammatory response after sustaining an insult or encountering allo-antigen likely contributes to its threshold for tolerance induction. This threshold is largely dependent upon the nature of the network of resident immunological cells including macrophages, dendritic cells, and selective subsets of adaptive immune cells found within the tissue parenchyma. For example, when the epithelium of the lung, a barrier organ, is presented with a respiratory pathogen, host survival depends upon generation of a robust inflammatory response. The generation of damage-associated molecular patterns secondary to respiratory infections in lung transplant recipients initiates an innate immune response through Toll-like receptors, resulting in the generation of proinflammatory cytokines and chemotactic responses, setting off a cascade of events that ultimately favor graft rejection [55–57]. Conversely, in tolerance-prone organs such as the liver and kidney, whose physiological functions include detoxifying and filtering the blood, resident immunological cells dampen the response to alloantigens and autoantigens to prevent tissue damage and autoimmunity . Cross-talk between epithelial cells and the resident immunocytes appears to be a strong anti-inflammatory mechanism in the kidney. For instance, renal tubular epithelial cells (RTECs) exposed to proinflammatory INFγ express the programed cell death-ligand 1 (PD-L1), which promotes tolerance to alloantigens via activation of Tregs [59–61], as discussed further below. Injured RTECs and renal endothelial cells also produce TGFβ, a known activator of Tregs and plasmacytoid dendritic cell (pDCs) (see below) [62–64].
A commonality between the tolerance-prone kidney and liver is the extensive network of tissue-resident leukocytes present within the organ parenchyma [58,65]. The liver exhibits the highest propensity for tolerance without immunosuppression [29,66,67] and the importance of nonparenchymal cells in this observation is supported by the fact that isolated hepatocyte transplants are acutely rejected . The liver plays a critical role in immune surveillance, pathogen detection, and host defense as it is constantly exposed to blood-borne pathogens, particularly via the portal vein, which drains the gut [58,69]. It contains the largest reticuloendothelial system in the body, with the largest population of resident macrophages (Kupffer cells) . The liver acts as an immunological filter in that the concentration of pathogen-derived products such as lipopolysaccharide decreases by 100-fold after traveling through the liver . At the same time, depletion of Kupffer cells in mice results in nearly 100% mortality after exposure to a dose of bacteria that is sublethal in wild-type mice, thus indicating that the liver is essential in immune-activation and pathogen defense [71,72]. Additional cellular compartments that participate in antigen detection and the maintenance of hepatic immune tolerance include: liver sinusoidal endothelial cells, which are the most abundant nonparenchymal cell in the liver and serve regulatory functions via antigen presentation and cross-presentation associated with PD-L1 expression [73–75]; dendritic cells, which promote T-cell tolerance rather than activation via IL-10 [76–78]; and hepatic stellate cells (HSCs), which are discussed in detail below. Whether nonparenchymal cells in other tolerance-prone organs such as the kidney play a role in lowering the threshold for allorecognition by T cells and subsequent rejection is less well understood. However, the kidney serves a similar functional role in filtering blood and is comprised of a diverse network of nonparenchymal cells, including resident yolk-sac and bone marrow-derived macrophages and dendritic cells, lymphocytes, pericytes, and podocytes. Furthermore, in the context of systemic inflammation from sepsis, the kidney is able to undergo metabolic adaptations and reprograming of cellular signaling to limit organ dysfunction and the progression of fibrosis to chronic kidney disease [79▪]. Whether similar mechanisms are activated in response to noninfectious insults such as organ transplantation and whether these mechanisms are present in other tolerance-prone organs is an important area for future study.
Renal tubule epithelial cells
RTECs represent an intriguing candidate population to mediate KICAT. IFNγ-treated human RTECs have been shown to participate in the induction allospecific tolerance . Potential mechanisms for RTEC-induced tolerance include the upregulation of programmed cell death 1 (PD-1) and indoleamine 2,3-dioxygenase (IDO) [60,81] as PD-1 signaling results in the conversion of human TH1 cells into Treg cells . Indeed, Foxp3+ T cells are enriched in the tubules in mouse  and human renal allografts . RTECs are also known to produce and activate TGFβ , which is a major inducer of Foxp3+ Tregs  and tolerogenic pDCs .
As mentioned earlier, conventional resident dendritic cells in the liver are thought to be mediators of liver tolerance. They can dampen inflammation after ischemia-reperfusion injury (IRI) [86,87] thus blunting T-cell responses and ultimately prolonging graft survival [88,89] via expression of anti-inflammatory molecules such as IL-10  and PD-L1 . After transplantation, donor-derived dendritic cells are rapidly replaced by recipient dendritic cells, over half of which display donor MHC class I molecules on their surface. Such intercellular transfer of membrane proteins was initially recognized in immunity to viral infection and has been termed cross-dressing (XD) . XD-dendritic cells are characterized by robust expression of PD-L1 and IL-10. They not only fail to stimulate alloreactive T-cells, but also they actively suppress antidonor T-cell proliferation [92▪]. Significantly, while graft expression of PD-L1 is necessary for liver tolerance , XD-dendritic cells in the heart and kidney have been shown to play a different role (i.e., favor rejection) [94,95,96▪]. These findings not only highlight the importance of tissue-resident dendritic cells in liver tolerance, but also suggest that the function of dendritic cells can be organ-specific [92▪].
Plasmacytoid dendritic cells
pDCs represent a distinctive dendritic cell population that can act as suppressive cells when expressing the inducible tolerogenic enzyme IDO, the inducible costimulator ligand, and/or PD-L1. They can facilitate the generation of Tregs and the suppression of autoreactive and alloreactive cells, inducing tolerance to hearts in mice [97–99]. Results from our laboratory suggest that the presence of PDCA-1+B220+pDCs in DBA/2 kidneys but not hearts allografts may explain why DBA/2 kidneys are spontaneously accepted when transplanted into B6 WT recipients, whereas DBA/2 hearts are rejected (Alessandrini et al., unpublished data).
The unique and often divergent roles of different macrophage populations within a given organ is currently a topic of intense study, but the functional consequence of these differences has not been well defined in the context of solid organ transplantation . In swine, when intrapulmonary passenger leukocytes were MHC-matched to recipients, lung allograft survival was significantly higher than in nonmatched controls . In the human and mouse heart, distinct macrophage populations can be identified based on the expression of CCR2. Although CCR2− macrophages are derived from the primitive yolk sac, entering the heart during embryonic development and are maintained by in-situ proliferation without contribution from blood or bone marrow, CCR2+ macrophages are generated by hematopoietic precursors and are maintained via monocyte recruitment [102–104]. These macrophage subsets also exhibit distinct functions. CCR2− macrophages are active in cardiac regeneration and functional recovery after injury, while CCR2+ macrophages are activated after IRI and propagate the postinjury inflammatory response [105▪▪]. In the liver, Kupffer cells scavenge circulating antigens and present them to T-cells, which ultimately results in expansion of IL-10 producing Tregs, thus preventing local and systemic inflammation. These tolerogenic features are not characteristic of resident hepatic macrophages derived from monocytes (i.e., non-Kupffer cell macrophages), which produce a proinflammatory response when activated during systemic inflammation . How individual resident macrophage subsets are affected by transplantation and whether they play a role in tolerance or rejection is an important area of future study. This is particularly true because phenotypically and functionally distinct macrophage subsets are present in all organs, and their proliferation, activation, migration, and quantity before and after transplantation undoubtedly plays a role in the proclivity of a given organ to develop tolerance.
Hepatic stellate cells
There are other unique cell types in tolerance-prone organs that possess tolerogenic properties. In the liver, HSCs are weak antigen presenting cells that store vitamin A and have strong immunoregulatory properties through induction of T cell apoptosis, generation of myeloid-derived suppressor cells, inhibition of CD8+ T-cell responses and enrichment of Tregs . Importantly, HSCs can confer unresponsiveness and long-term survival upon tolerance-resistant islet allografts by inducing Tregs  and myeloid-derived suppressor cells . HSC cotransplantation with isolated hepatocytes also improves hepatocyte engraftment by preventing their acute rejection . Whether organ-specific homologues to HSCs exist in the kidney but are absent in tolerance-resistant organs has not been studied.
Mesenchymal stem cells
Other potential intraorgan tolerogenic cells that differ in character and quantity between organs include mesenchymal stem cells (MSCs), a cell type shown to inhibit activated lymphocytes and induce the survival and activation of regulatory macrophages and T-cells . Significantly, MSCs derived from different tissues have phenotypic and functional differences , which may contribute to organ-specific differences in the propensity to develop posttransplant tolerance. This is particularly possible because MSCs from the heart , lung , liver  and kidney  remain functional for many years posttransplant. Indeed, liver mesenchymal nonparenchymal cells have been shown to promote liver-specific tolerance by eliminating alloreactive T effector cells via expression of B7-H1, IL-10, and TGF-β as well as enhancing Tregs myeloid-derived suppressor cells [116▪▪].
T regulatory cell-rich organized lymphoid structures
The appearance of novel FoxP3+Treg-rich organized lymphoid structures (TOLS) in the parenchyma of spontaneously accepted murine kidney allografts has recently been described . TOLS developed as prominent lymphoid sheaths around central arterioles in accepted DBA/2 kidneys in B6.Foxp3DTR+/y recipients and contained large numbers of CD3+Foxp3+Tcells (∼30% of T cells), pDCs, and B cells. They were distinct from tertiary lymphoid structures (TLO) found in chronic inflammation as they lacked high endothelial venules (MECA79−) and germinal centers and contained few CD8 cells and macrophages. Depletion of Foxp3+ cells led to TOLS disintegration and acute cellular rejection  suggesting that TOLS contribute to the tolerogencity of kidney allografts in a fundamental way. We have also observed TOLS with abundant FoxP3+T cells in the kidney allografts of long-term tolerant heart/kidney NHP recipients and even in human recipients tolerant of kidney allografts. Elucidating the factors involved in the generation of TOLS and the function of these unique TLO in promoting tolerance are areas of active investigation.
In addition, soluble factors produced by the kidney or liver such as erythropoietin (EPO), bilirubin, and vitamin D may play a role in the tolerance-prone phenotype.
Recent studies suggest that EPO, a kidney-based hormone of erythropoiesis, may also play an unanticipated role in kidney tolerance induction/maintenance. EPO can inhibit T-cell proliferation and cytokine production while augmenting murine Treg induction and stability . EPO has also been shown to increase macrophage-mediated T-cell suppression in vitro . Moreover, exogenous administration of EPO in a murine heart transplant model prolonged allograft survival while its pharmacological depletion prevented renal allograft tolerance [119▪▪]. To achieve its protolerogenic effect, EPO may have to act locally and directly on donor cells or infiltrating recipient alloreactive T cells within the renal allograft and do so in concentrations not present in physiological circulating levels. This would explain why the native kidneys that produce EPO do not dampen alloimmunity in recipients of other organs, for example, isolated heart allografts. The EPO hypothesis provides an intriguing alternative explanation for the protolerogenic phenotype of kidney allografts.
Bilirubin is one of the most potent naturally occurring antioxidants [120,121]. Patient's with Gilbert's syndrome, an inborn error in bilirubin conjugation that results in elevated circulating levels of unconjugated bilirubin, have lower incidences of diabetic nephropathy, coronary artery disease, cerebral vascular disease, metabolic syndrome, and transplant rejection . Along with iron and carbon monoxide, bilirubin is a byproduct of heme metabolism by the anti-inflammatory, antiapoptotic, and immune-regulatory enzyme, heme oxygenase-1 (HO-1) . HO-1 is an inducible enzyme most highly expressed in organs densely populated by innate immunological cells, such as the spleen . Significantly, animal studies have demonstrated that HO-1 is robustly induced in tolerance-prone organs such as the kidney and liver after injury, while its basal expression and postinjury induction is lower, but still important, in the tolerance-resistant heart. Using organ-specific and cell-specific transgenic models to reduce or amplify postinjury induction of HO-1 has demonstrated that the enzyme influences immune cell trafficking , polarization , and cytokine production  in a way that favors graft tolerance [127–131]. Bilirubin is partially responsible for the anti-inflammatory properties of HO-1 expression. Its antioxidant properties blunt the effects of oxidative stress induced by posttransplant inflammation and reperfusion injury [132–134,135▪▪], improve posttransplant hemodynamics by providing resistance to angiotensin II and increased bioavailability of nitric oxide [136,137], promote Treg expansion , and blunt expression of proinflammatory cytokines such as IL-2 . Furthermore, the tolerance-prone liver, and to a lesser extent, kidney, are involved in bilirubin metabolism and excretion, suggesting that this molecule, as well as the HO-1 system, may contribute to their propensity for tolerance.
The kidney and liver play a vital role in vitamin D biogenesis and metabolism. Vitamin D3 is generated in the skin and is then metabolized in the liver to 25(OH)D3, which is converted to its active form, 1,25(OH)2D3 by CYP27H1 in the kidney. Given the importance of vitamin D in calcium and phosphate metabolism as well as immune function, it is not surprising that vitamin D deficiency is a significant determinant of all-cause mortality in patients with chronic kidney disease . More specifically, vitamin D prevents dendritic cell maturation , increases IL-10 expression in dendritic cell and B cells , and inhibits expression of IL-2, IFNγ, and IL-17 (and thus development of TH1 and TH17 subsets) while at the same time favoring Treg production . Even after transplantation, vitamin D deficiency is more prevalent in kidney transplant recipients than controls  and in liver transplant recipients who experience acute cellular rejection . The lack of vitamin D may impair the development of allograft tolerance in these populations .
Attaining safe and reliably durable tolerance would transform the field of transplantation by protecting patients from detrimental effects of chronic immunosuppression and allograft rejection. Clinically and experimentally, it is recognized that different organs have specific thresholds for tolerance, achieved either spontaneously or using a variety of techniques for immunomodulation including mixed chimerism, targeted depletion strategies or short courses of immunosuppression. It is likely that the tolerogencity of a particular organ depends on how factors intrinsic to that organ interact to shift the balance of the overall immune response towards or away from tolerance. Understanding the mechanisms that underlie these organ-specific differences in transplant tolerance has important clinical relevance. Identification and isolation of the potent protolerance factor(s) associated with liver and kidney allografts could be used to design novel tolerance protocols in clinical transplantation that would encompass all organs, even those resistant to tolerance.
Financial support and sponsorship
The work was supported in part by grants from the National Institutes of Health to J.C.M. (PO1HL018646, PO1AI123086, UO1AI131470) and to G.B. (R21AI100278, R01DK115618).
Conflicts of interest
There are no conflicts of interest.
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