University of Texas Health Science Center at San Antonio, Texas, USA.
The prevalence of obesity and the metabolic syndrome (MS) is on the rise, and subsequently the hepatic manifestation of MS, nonalcoholic fatty liver disease (NAFLD), has become a common entity in clinical practice. Most patients with NAFLD face medical complications related to their underlying MS in other organ systems; however, a small but significant group of patients with the more aggressive form of fatty liver, nonalcoholic steatohepatitis (NASH), are at risk of developing cirrhosis and hepatocellular carcinoma. As patients are generally asymptomatic, often their disease goes unrecognized. This is particularly true for NASH, where liver biopsy is currently required to make the diagnosis. Once diagnosed, no one treatment has been shown to be universally efficacious and those that are of benefit are not without side effects. Effective treatment regimens directed at both decreasing insulin resistance as well as the processes leading to necroinflammation and hepatic fibrosis have been investigated and include lifestyle modification, surgical therapies, and pharmacotherapy. This review focuses on current and potential future therapies for NASH.
Saturday, March 21, 2009
Role of fatty acids in the pathogenesis of obesity and fatty liver: impact of bariatric surgery.
Department of Medicine, Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, New York 10032, USA.
Nonalcoholic fatty liver disease (NAFLD) spans a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) to cirrhosis. Simple steatosis is the substrate upon which the more serious entities in the spectrum develop; it is the first "hit" in the multistep pathogenesis of NASH, which is considered the hepatic manifestation of the metabolic syndrome. Demonstration of the existence of regulatable fatty acid transport mechanisms has contributed to clarifying the role of fatty acid disposition in obesity, the various components of NAFLD, and the metabolic syndrome. Hepatic steatosis is closely linked to obesity. This linkage is based on the fact that obesity results in marked enlargement of the intraabdominal visceral fat depots. The eventual development of insulin resistance leads to continuous lipolysis within these depots, releasing fatty acids into the portal circulation, where they are rapidly translocated to the liver and reassembled into triglycerides. Reactive oxygen species, generated in the liver from oxidation of fatty acids, are precipitating factors in the cascade of events leading from simple steatosis to NASH. Dysregulation of fatty acid disposition, with ectopic lipid accumulation in other tissues, is a major contributing factor to other components of the metabolic syndrome. Bariatric surgery is an effective treatment for severe obesity, but its role in the management of the various forms of fatty liver disease is unclear. Our review of the literature that includes both initial and follow-up liver biopsies suggests that most obese patients with simple steatosis and NASH who undergo bariatric surgery will achieve improvement in hepatic histology, but that occasional patients, especially those who lose weight very rapidly, may show worsening of either fibrosis or steatohepatitis.
Nonalcoholic fatty liver disease (NAFLD) spans a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) to cirrhosis. Simple steatosis is the substrate upon which the more serious entities in the spectrum develop; it is the first "hit" in the multistep pathogenesis of NASH, which is considered the hepatic manifestation of the metabolic syndrome. Demonstration of the existence of regulatable fatty acid transport mechanisms has contributed to clarifying the role of fatty acid disposition in obesity, the various components of NAFLD, and the metabolic syndrome. Hepatic steatosis is closely linked to obesity. This linkage is based on the fact that obesity results in marked enlargement of the intraabdominal visceral fat depots. The eventual development of insulin resistance leads to continuous lipolysis within these depots, releasing fatty acids into the portal circulation, where they are rapidly translocated to the liver and reassembled into triglycerides. Reactive oxygen species, generated in the liver from oxidation of fatty acids, are precipitating factors in the cascade of events leading from simple steatosis to NASH. Dysregulation of fatty acid disposition, with ectopic lipid accumulation in other tissues, is a major contributing factor to other components of the metabolic syndrome. Bariatric surgery is an effective treatment for severe obesity, but its role in the management of the various forms of fatty liver disease is unclear. Our review of the literature that includes both initial and follow-up liver biopsies suggests that most obese patients with simple steatosis and NASH who undergo bariatric surgery will achieve improvement in hepatic histology, but that occasional patients, especially those who lose weight very rapidly, may show worsening of either fibrosis or steatohepatitis.
Effects of weight loss on nonalcoholic fatty liver disease.
Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia 22042, USA.
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases worldwide, affecting men, women, and children. This is due, in part, to the obesity epidemic, which is associated with increased prevalence of NAFLD. The NAFLD spectrum ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), which is the potentially progressive form. NAFLD is associated with metabolic syndrome and insulin resistance. Treatment recommendations include weight reduction through both diet and physical activity, and weight-loss surgery for extreme obesity. Most medical regimens target components of the metabolic syndrome or oxidative stress associated with the pathogenesis of NASH. These include antiobesity regimens, insulin sensitizers, antihyperlipidemics, and antioxidants. Bariatric surgery is effective for achieving and maintaining weight loss and reversing the complications of metabolic syndrome. On the other hand, the literature lacks well-designed, randomized control trials that assess the efficacy of anti-obesity regimens on histologic and long-term outcomes of NAFLD.
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases worldwide, affecting men, women, and children. This is due, in part, to the obesity epidemic, which is associated with increased prevalence of NAFLD. The NAFLD spectrum ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), which is the potentially progressive form. NAFLD is associated with metabolic syndrome and insulin resistance. Treatment recommendations include weight reduction through both diet and physical activity, and weight-loss surgery for extreme obesity. Most medical regimens target components of the metabolic syndrome or oxidative stress associated with the pathogenesis of NASH. These include antiobesity regimens, insulin sensitizers, antihyperlipidemics, and antioxidants. Bariatric surgery is effective for achieving and maintaining weight loss and reversing the complications of metabolic syndrome. On the other hand, the literature lacks well-designed, randomized control trials that assess the efficacy of anti-obesity regimens on histologic and long-term outcomes of NAFLD.
Liver transplantation: the current situation.
AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France.
Over the years, an improving liver transplant (LT) survival rate (1- and 5-year survival of 83% and 75%, respectively) has been instrumental in establishing transplant surgery as a durable therapy for all forms of end-stage liver disease and for some malignant conditions. The success of such treatment has resulted in a progressively increasing demand for liver transplantation. However, at the same time the availability of donor organs has diminished, resulting in the number of potential recipients for liver transplantation exceeding organ supply. Several strategies have been explored with the aim to increase access to liver transplantation, including: obtaining organs from non-heart-beating donors and live donors, and splitting and using livers from expanded donor criteria. This article discusses the utility of the mentioned techniques along with other strategies (e.g., Model for End-Sage Liver Disease [MELD] score), as well as the evolution of indications, contraindications, and postoperative care.
Over the years, an improving liver transplant (LT) survival rate (1- and 5-year survival of 83% and 75%, respectively) has been instrumental in establishing transplant surgery as a durable therapy for all forms of end-stage liver disease and for some malignant conditions. The success of such treatment has resulted in a progressively increasing demand for liver transplantation. However, at the same time the availability of donor organs has diminished, resulting in the number of potential recipients for liver transplantation exceeding organ supply. Several strategies have been explored with the aim to increase access to liver transplantation, including: obtaining organs from non-heart-beating donors and live donors, and splitting and using livers from expanded donor criteria. This article discusses the utility of the mentioned techniques along with other strategies (e.g., Model for End-Sage Liver Disease [MELD] score), as well as the evolution of indications, contraindications, and postoperative care.
Candidate selection and organ allocation in liver transplantation.
Liver Transplant Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
Optimal candidate selection and organ allocation should offer liver transplantation to those who are sufficiently sick to justify the procedure but not too sick to benefit from it, in an order determined by patients' projected survival benefit, matching organs of sufficiently good quality to the appropriate recipients. Significant steps have been made in recent years toward devising selection and allocation criteria based on more objective and evidence-based definitions of candidate disease severity, transplant futility, organ quality, and appropriate donor-recipient matching. However, much work remains to be done in the future.
Optimal candidate selection and organ allocation should offer liver transplantation to those who are sufficiently sick to justify the procedure but not too sick to benefit from it, in an order determined by patients' projected survival benefit, matching organs of sufficiently good quality to the appropriate recipients. Significant steps have been made in recent years toward devising selection and allocation criteria based on more objective and evidence-based definitions of candidate disease severity, transplant futility, organ quality, and appropriate donor-recipient matching. However, much work remains to be done in the future.
Pathways of allorecognition: implications for transplantation tolerance.
Department of Immunology, Imperial College School of Medicine, London, UK.
Allorecognition occurs when the host immune system detects same-species, non-self antigens and this is the trigger for allograft rejection. Host T cells detect these 'foreign' antigens which are mostly derived from a highly polymorphic region of the genome called the major histocompatibility complex. Allorecognition can occur by two distinct, but not mutually exclusive pathways: direct and indirect. The direct pathway results from the recognition of foreign major histocompatibility molecules, intact, on the surface of donor cells. Indirect allorecognition occurs when donor histocompatibility molecules are internalised, processed, and presented as peptides by host antigen presenting cells--this is the manner in which the immune system normally sees antigen. However, in addition to antigen recognition, T cell activation requires the provision of costimulatory signals, the prerogative of bone marrow-derived, specialised antigen-presenting cells (APC). Once these have been depleted from a transplanted organ, as occurs within weeks of transplantation, the parenchymal cells of the transplant are incapable of driving direct pathway activation of recipient T cells. Alloantigen recognition on these non-professional APCs may have a tolerising effect and indeed, the frequency of T cells reactive to the direct pathway diminishes with time irrespective of whether or not chronic transplant rejection occurs. This implies that while the direct pathway plays a dominant role in acute rejection, it is unlikely to contribute to chronic rejection. Assays of T cell responses have, however, found an association between the indirect pathway and chronic rejection and animal models support a role for the indirect pathway in both acute and chronic rejection. The indirect pathway is likely to be permanently active due to traffic of recipient APCs through the graft. The challenge that this poses in the pursuit of clinical tolerance is how to induce tolerance in T cells with indirect allospecificity. The answer may lie in manipulation of the environment of the interaction between the T cell and APC. Apart from recognition without costimulation, there are other circumstances when recognition without activation can occur although the in vivo relevance is uncertain. The presence of regulatory cytokines or inhibitory surface molecules either from a distinct regulatory cell, or as a negative feedback loop may prevent activation; this could also happen without sufficient stimulatory support: the final outcome is likely to be decided by the overall balance. Furthermore, some peptides may act as antagonists to T cell activation, usually when the agonist peptide is structurally very similar. It is hoped that the careful study of these mechanisms will reveal ways of ensuring allorecognition without activation and thus donor-specific tolerance.
Allorecognition occurs when the host immune system detects same-species, non-self antigens and this is the trigger for allograft rejection. Host T cells detect these 'foreign' antigens which are mostly derived from a highly polymorphic region of the genome called the major histocompatibility complex. Allorecognition can occur by two distinct, but not mutually exclusive pathways: direct and indirect. The direct pathway results from the recognition of foreign major histocompatibility molecules, intact, on the surface of donor cells. Indirect allorecognition occurs when donor histocompatibility molecules are internalised, processed, and presented as peptides by host antigen presenting cells--this is the manner in which the immune system normally sees antigen. However, in addition to antigen recognition, T cell activation requires the provision of costimulatory signals, the prerogative of bone marrow-derived, specialised antigen-presenting cells (APC). Once these have been depleted from a transplanted organ, as occurs within weeks of transplantation, the parenchymal cells of the transplant are incapable of driving direct pathway activation of recipient T cells. Alloantigen recognition on these non-professional APCs may have a tolerising effect and indeed, the frequency of T cells reactive to the direct pathway diminishes with time irrespective of whether or not chronic transplant rejection occurs. This implies that while the direct pathway plays a dominant role in acute rejection, it is unlikely to contribute to chronic rejection. Assays of T cell responses have, however, found an association between the indirect pathway and chronic rejection and animal models support a role for the indirect pathway in both acute and chronic rejection. The indirect pathway is likely to be permanently active due to traffic of recipient APCs through the graft. The challenge that this poses in the pursuit of clinical tolerance is how to induce tolerance in T cells with indirect allospecificity. The answer may lie in manipulation of the environment of the interaction between the T cell and APC. Apart from recognition without costimulation, there are other circumstances when recognition without activation can occur although the in vivo relevance is uncertain. The presence of regulatory cytokines or inhibitory surface molecules either from a distinct regulatory cell, or as a negative feedback loop may prevent activation; this could also happen without sufficient stimulatory support: the final outcome is likely to be decided by the overall balance. Furthermore, some peptides may act as antagonists to T cell activation, usually when the agonist peptide is structurally very similar. It is hoped that the careful study of these mechanisms will reveal ways of ensuring allorecognition without activation and thus donor-specific tolerance.
New strategies for early diagnosis of heart allograft rejection.
Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
BACKGROUND: Allograft rejection is mediated by T cells that recognize allogeneic major histocompatibility complex (MHC) molecules via the direct and indirect pathway. The direct pathway involves T cells that react against MHC/peptide complexes expressed on the surface of donor antigen-presenting cells (APCs). In contrast, T cells involved in the indirect pathway recognize peptides derived from processing and presentation of allogeneic MHC molecules by self (recipient) APCs. To explore the relative contribution of these two pathways to rejection, we have evaluated the response of peripheral blood T cells from 50 heart transplant recipients against donor APCs (direct recognition) and against self APCs pulsed with synthetic peptides corresponding to the hypervariable region of the mismatched HLA-DR antigens of the donor (indirect recognition). METHODS: T cell reactivity against donor APCs was quantitated by measuring the expression of CD69 on allostimulated CD3+ LDA1+ cells. Reactivity to synthetic allopeptides was determined in limited dilution assays. RESULTS: Serial studies of the kinetics of direct and indirect recognition showed that both pathways contribute to early acute rejection episodes. Primary rejection was accompanied invariably by indirect recognition of a dominant allopeptide. Intermolecular spreading of T cell epitopes was observed during recurrent rejections. Enhanced recognition of donor alloantigens via the direct pathway was found predominantly during early rejection episodes. A single form of allorecognition was shown to occur in some rejection episodes. CONCLUSIONS: Monitoring of the direct and indirect pathway of allorecognition provides a reliable method for prediction and differential diagnosis of acute rejection of heart allografts.
BACKGROUND: Allograft rejection is mediated by T cells that recognize allogeneic major histocompatibility complex (MHC) molecules via the direct and indirect pathway. The direct pathway involves T cells that react against MHC/peptide complexes expressed on the surface of donor antigen-presenting cells (APCs). In contrast, T cells involved in the indirect pathway recognize peptides derived from processing and presentation of allogeneic MHC molecules by self (recipient) APCs. To explore the relative contribution of these two pathways to rejection, we have evaluated the response of peripheral blood T cells from 50 heart transplant recipients against donor APCs (direct recognition) and against self APCs pulsed with synthetic peptides corresponding to the hypervariable region of the mismatched HLA-DR antigens of the donor (indirect recognition). METHODS: T cell reactivity against donor APCs was quantitated by measuring the expression of CD69 on allostimulated CD3+ LDA1+ cells. Reactivity to synthetic allopeptides was determined in limited dilution assays. RESULTS: Serial studies of the kinetics of direct and indirect recognition showed that both pathways contribute to early acute rejection episodes. Primary rejection was accompanied invariably by indirect recognition of a dominant allopeptide. Intermolecular spreading of T cell epitopes was observed during recurrent rejections. Enhanced recognition of donor alloantigens via the direct pathway was found predominantly during early rejection episodes. A single form of allorecognition was shown to occur in some rejection episodes. CONCLUSIONS: Monitoring of the direct and indirect pathway of allorecognition provides a reliable method for prediction and differential diagnosis of acute rejection of heart allografts.
Rejection mechanisms in transplantation.
Department of Immunology, Imperial College School of Medicine, Hammersmith Campus, London, U.K.
While major improvements have been made in the prevention and treatment of hyperacute and acute transplant rejection, most grafts will succumb to chronic rejection: this reflects the extent of our knowledge of the mechanisms that drive these processes. Clinically, transplant rejection is classified according to timeframe and histology into hyperacute (minutes to hours), acute (days to months) and chronic rejection (months to years). Hyperacute and acute rejection are reasonably well understood and occur by immune mediated events whereas chronic rejection probably has immune and non-immune components. The trigger to cell-mediated rejection is allorecognition, where same-species, non-self antigens are detected by the host immune system. This occurs by two distinct mechanisms, called the direct and indirect pathways. The direct pathway results from the recognition of foreign major histocompatibility molecules, intact, on the surface of donor cells. Indirect allorecognition occurs when donor histocompatibility molecules are internalised, processed, and presented as peptides by host antigen presenting cells. Animal and human studies strongly suggest that acute rejection is predominantly triggered by the direct pathway although if the latter is blocked then the indirect pathway can suffice. Donor antigen presenting cells within the graft become depleted with time and the frequency of T cells reactive to the direct pathway diminishes irrespective of whether or not chronic rejection occurs. This implies that the direct pathway is unlikely to contribute to chronic rejection. Assays of T cell responses have, however, found an association between the indirect pathway and chronic rejection although it is unlikely that this is the whole story: there are numerous non-immunological risk factors for chronic rejection which probably interact with immune components causing gradual graft failure. Xenotransplantation, where tissue is transferred across species, causes rejection by processes analogous to those seen in allografts but they are faster and more vigorous. Novel approaches have overcome some early antibody mediated rejection events but then reveal a huge, intense, adaptive cellular response. We believe that by the careful study of the mechanisms of rejection, the problems of chronic rejection and xenograft rejection will be overcome, thus reversing the widening gap between organ demand and supply.
While major improvements have been made in the prevention and treatment of hyperacute and acute transplant rejection, most grafts will succumb to chronic rejection: this reflects the extent of our knowledge of the mechanisms that drive these processes. Clinically, transplant rejection is classified according to timeframe and histology into hyperacute (minutes to hours), acute (days to months) and chronic rejection (months to years). Hyperacute and acute rejection are reasonably well understood and occur by immune mediated events whereas chronic rejection probably has immune and non-immune components. The trigger to cell-mediated rejection is allorecognition, where same-species, non-self antigens are detected by the host immune system. This occurs by two distinct mechanisms, called the direct and indirect pathways. The direct pathway results from the recognition of foreign major histocompatibility molecules, intact, on the surface of donor cells. Indirect allorecognition occurs when donor histocompatibility molecules are internalised, processed, and presented as peptides by host antigen presenting cells. Animal and human studies strongly suggest that acute rejection is predominantly triggered by the direct pathway although if the latter is blocked then the indirect pathway can suffice. Donor antigen presenting cells within the graft become depleted with time and the frequency of T cells reactive to the direct pathway diminishes irrespective of whether or not chronic rejection occurs. This implies that the direct pathway is unlikely to contribute to chronic rejection. Assays of T cell responses have, however, found an association between the indirect pathway and chronic rejection although it is unlikely that this is the whole story: there are numerous non-immunological risk factors for chronic rejection which probably interact with immune components causing gradual graft failure. Xenotransplantation, where tissue is transferred across species, causes rejection by processes analogous to those seen in allografts but they are faster and more vigorous. Novel approaches have overcome some early antibody mediated rejection events but then reveal a huge, intense, adaptive cellular response. We believe that by the careful study of the mechanisms of rejection, the problems of chronic rejection and xenograft rejection will be overcome, thus reversing the widening gap between organ demand and supply.
Microchimerism, dendritic cell progenitors and transplantation tolerance.
Pittsburgh Transplantation Institute, University of Pittsburgh Medical Center, Pennsylvania 15213, USA.
The recent discovery of multilineage donor leukocyte microchimerism in allograft recipients up to three decades after organ transplantation implies the migration and survival of donor stem cells within the host. It has been postulated that in chimeric graft recipients, reciprocal modulation of immune responsiveness between donor and recipient leukocytes may lead, eventually, to the induction of mutual immunologic nonreactivity (tolerance). A prominent donor leukocyte, both in human organ transplant recipients and in animals, has invariably been the bone marrow-derived dendritic cell (DC). These cells have been classically perceived as the most potent antigen-presenting cells but evidence also exists for their tolerogenicity. The liver, despite its comparatively heavy leukocyte content, is the whole organ that is most capable of inducing tolerance. We have observed that DC progenitors propagated from normal mouse liver in response to GM-CSF express only low levels of major histocompatibility complex (MHC) class II antigen and little or no cell surface B7 family T cell costimulatory molecules. They fail to activate resting naive allogeneic T cells. When injected into normal allogeneic recipients, these DC progenitors migrate to T-dependent areas of host lymphoid tissue, where some at least upregulate cell surface MHC class II. These donor-derived cells persist indefinitely, recapitulating the behavior pattern of donor leukocytes after the successful transplantation of all whole organs, but most dramatically after the orthotopic (replacement) engraftment of the liver. A key finding is that in mice, progeny of these donor-derived DC progenitors can be propagated ex vivo from the bone marrow and other lymphoid tissues of nonimmunosuppressed spontaneously tolerant liver allograft recipients. In humans, donor DC can also be grown from the blood of organ allograft recipients whose organ-source chimerism is augmented with donor bone marrow infusion. DC progenitors cannot, however, be propagated from the lymphoid tissue of nonimmunosuppressed cardiac-allografted mice that reject their grafts. These findings are congruent with the possibility that bidirectional leukocyte migration and donor cell chimerism play key roles in acquired transplantation tolerance. Although the cell interactions are undoubtedly complex, a discrete role can be identified for DC under well-defined experimental conditions. Bone marrow-derived DC progenitors (MHC class II+, B7-1dim, B7-2-) induce alloantigen-specific hyporesponsiveness (anergy) in naive T cells in vitro. Moreover, costimulatory molecule-deficient DC progenitors administered systemically prolong the survival of mouse heart or pancreatic islet allografts. How the regulation of donor DC phenotype and function relates to the balance between the immunogenicity and tolerogenicity of organ allografts remains to be determined.
The recent discovery of multilineage donor leukocyte microchimerism in allograft recipients up to three decades after organ transplantation implies the migration and survival of donor stem cells within the host. It has been postulated that in chimeric graft recipients, reciprocal modulation of immune responsiveness between donor and recipient leukocytes may lead, eventually, to the induction of mutual immunologic nonreactivity (tolerance). A prominent donor leukocyte, both in human organ transplant recipients and in animals, has invariably been the bone marrow-derived dendritic cell (DC). These cells have been classically perceived as the most potent antigen-presenting cells but evidence also exists for their tolerogenicity. The liver, despite its comparatively heavy leukocyte content, is the whole organ that is most capable of inducing tolerance. We have observed that DC progenitors propagated from normal mouse liver in response to GM-CSF express only low levels of major histocompatibility complex (MHC) class II antigen and little or no cell surface B7 family T cell costimulatory molecules. They fail to activate resting naive allogeneic T cells. When injected into normal allogeneic recipients, these DC progenitors migrate to T-dependent areas of host lymphoid tissue, where some at least upregulate cell surface MHC class II. These donor-derived cells persist indefinitely, recapitulating the behavior pattern of donor leukocytes after the successful transplantation of all whole organs, but most dramatically after the orthotopic (replacement) engraftment of the liver. A key finding is that in mice, progeny of these donor-derived DC progenitors can be propagated ex vivo from the bone marrow and other lymphoid tissues of nonimmunosuppressed spontaneously tolerant liver allograft recipients. In humans, donor DC can also be grown from the blood of organ allograft recipients whose organ-source chimerism is augmented with donor bone marrow infusion. DC progenitors cannot, however, be propagated from the lymphoid tissue of nonimmunosuppressed cardiac-allografted mice that reject their grafts. These findings are congruent with the possibility that bidirectional leukocyte migration and donor cell chimerism play key roles in acquired transplantation tolerance. Although the cell interactions are undoubtedly complex, a discrete role can be identified for DC under well-defined experimental conditions. Bone marrow-derived DC progenitors (MHC class II+, B7-1dim, B7-2-) induce alloantigen-specific hyporesponsiveness (anergy) in naive T cells in vitro. Moreover, costimulatory molecule-deficient DC progenitors administered systemically prolong the survival of mouse heart or pancreatic islet allografts. How the regulation of donor DC phenotype and function relates to the balance between the immunogenicity and tolerogenicity of organ allografts remains to be determined.
Cooperation of liver cells in health and disease.
Medical University of Gdansk, Department of Histology and Immunology, 80211 Gdansk, Poland. zkmiec@amg.gda.pl
The liver lobule is formed by parenchymal cells, i.e., hepatocytes and nonparenchymal cells. In contrast to hepatocytes that occupy almost 80% of the total liver volume and perform the majority of numerous liver functions, nonparenchymal liver cells, which contribute only 6.5% to the liver volume, but 40% to the total number of liver cells, are localized in the sinusoidal compartment of the tissue. The walls of hepatic sinusoid are lined by three different cell types: sinusoidal endothelial cells (SEC), Kupffer cells (KC), and hepatic stellate cells (HSC, formerly known as fat-storing cells, Ito cells, lipocytes, perisinusoidal cells, or vitamin A-rich cells). Additionally, intrahepatic lymphocytes (IHL), including pit cells, i.e., liver-specific natural killer cells, are often present in the sinusoidal lumen. It has been increasingly recognized that both under normal and pathological conditions, many hepatocyte functions are regulated by substances released from neighboring nonparenchymal cells. Liver sinusoidal endothelial cells constitute the lining or wall of the hepatic sinusoid. They perform important filtration function due to the presence of small fenestrations that allow free diffusion of many substances, but not of particles of the size of chylomicrons, between the blood and the hepatocyte surface. SEC show huge endocytic capacity for many ligands including glycoproteins, components of the extracellular matrix (ECM; such as hyaluronate, collagen fragments, fibronectin, or chondroitin sulphate proteoglycan), immune complexes, transferrin and ceruloplasmin. SEC may function as antigen-presenting cells (APC) in the context of both MHC-I and MHC-II restriction with the resulting development of antigen-specific T-cell tolerance. They are also active in the secretion of cytokines, eicosanoids (i.e., prostanoids and leukotrienes), endothelin-1, nitric oxide, and some ECM components. Kupffer cells are intrasinusoidally located tissue macrophages with a pronounced endocytic and phagocytic capacity. They are in constant contact with gut-derived particulate materials and soluble bacterial products so that a subthreshold level of their activation in the normal liver may be anticipated. Hepatic macrophages secrete potent mediators of the inflammatory response (reactive oxygen species, eicosanoids, nitric oxide, carbon monoxide, TNF-alpha, and other cytokines), and thus control the early phase of liver inflammation, playing an important part in innate immune defense. High exposure of Kupffer cells to bacterial products, especially endotoxin (lipopolysaccharide, LPS), can lead to the intensive production of inflammatory mediators, and ultimately to liver injury. Besides typical macrophage activities, Kupffer cells play an important role in the clearance of senescent and damaged erythrocytes. Liver macrophages modulate immune responses via antigen presentation, suppression of T-cell activation by antigen-presenting sinusoidal endothelial cells via paracrine actions of IL-10, prostanoids, and TNF-alpha, and participation in the development of oral tolerance to bacterial superantigens. Moreover, during liver injury and inflammation, Kupffer cells secrete enzymes and cytokines that may damage hepatocytes, and are active in the remodeling of extracellular matrix. Hepatic stellate cells are present in the perisinusoidal space. They are characterized by abundance of intracytoplasmic fat droplets and the presence of well-branched cytoplasmic processes, which embrace endothelial cells and provide focally a double lining for sinusoid. In the normal liver HSC store vitamin A, control turnover of extracellular matrix, and regulate the contractility of sinusoids. Acute damage to hepatocytes activates transformation of quiescent stellate cells into myofibroblast-like cells that play a key role in the development of inflammatory fibrotic response. Pit cells represent a liver-associated population of large granular lymphocytes, i.e., natural killer (NK) cells. They spontaneously kill a variety of tumor cells in an MHC-unrestricted way, and this antitumor activity may be enhanced by the secretion of interferon-gamma. Besides pit cells, the adult liver contains other subpopulations of lymphocytes such as gamma delta T cells, and both "conventional" and "unconventional" alpha beta T cells, the latter containing liver-specific NK T cells. The development of methods for the isolation and culture of main liver cell types allowed to demonstrate that both nonparenchymal and parenchymal cells secrete tens of mediators that exert multiple paracrine and autocrine actions. Co-culture experiments and analyses of the effects of conditioned media on cultures of another liver cell type have enabled the identification of many substances released from non-parenchymal liver cells that evidently regulate some important functions of neighboring hepatocytes and non-hepatocytes. To the key mediators involved in the intercellular communication in the liver belong prostanoids, nitric oxide, endothelin-1, TNF-alpha, interleukins, and chemokines, many growth factors (TGF-beta, PDGF, IGF-I, HGF), and reactive oxygen species (ROS). Paradoxically, the cooperation of liver cells is better understood under some pathological conditions (i.e., in experimental models of liver injury) than in normal liver due to the possibility of comparing cellular phenotype under in vivo and in vitro conditions with the functions of the injured organ. The regulation of vitamin A metabolism provides an example of the physiological role for cellular cross-talk in the normal liver. The majority (up to 80%) of the total body vitamin A is stored in the liver as long-chain fatty acid esters of retinal, serving as the main source of retinoids that are utilized by all tissues throughout the body. Hepatocytes are directly involved in the uptake from blood of chylomicron remnants, and the synthesis of retinol-binding protein that transfers retinol to other tissues. However, more than 80% of the liver retinoids are stored in lipid droplets of hepatic stellate cells. HSC are capable of both uptake and release of retinol depending on the body's retinol status. The activity of some major enzymes of vitamin A metabolism have been found to be many times higher per protein basis in stellate cells than in hepatocytes. Despite progress in the understanding of the roles played by these two cell types in hepatic retinoid metabolism, the way in which retinoids move between the parenchymal cells, stellate cells, and blood plasma has not been fully elucidated. Sinusoidal blood flow is, to a great extent, regulated by hepatic stellate cells that can contract due to the presence of smooth muscle alpha-actin. The main vasoactive substances that affect constriction or relaxation of HSC derive both from distant sources and from neighboring hepatocytes (carbon monoxide, leukotrienes), endothelial cells (endothelin, nitric oxide, prostaglandins), Kupffer cells (prostaglandins, NO), and stellate cells themselves (endothelin, NO). The cellular cross-talk reflected by the fine-tuned modulation of sinusoidal contraction becomes disturbed under pathological conditions, such as endotoxemia or liver fibrosis, through the excess synthesis of vasoregulatory compounds and the involvement of additional mediators acting in a paracrine way. The liver is an important source of some growth factors and growth factor-binding proteins. Although hepatocytes synthesize the bulk of insulin-like growth factor I (IGF-I), also other types of nonparenchymal liver cells may produce this peptide. Cell-specific expression of distinct IGF-binding proteins observed in the rat and human liver provides the potential for specific regulation of hepatic IGF-I synthesis not only by growth hormone, insulin, and IGF-I, but also by cytokines released from activated Kupffer (IL-1, TNF-alpha, TGF-beta) or stellate cells (TGF-alpha, TGF-beta). Hepatic stellate cells may affect turnover of hepatocytes through the synthesis of potent positive as well as negative signals such as, respectively, hepatocyte-growth-factor or TGF-beta. Although hepatocytes seem not to produce TGF-beta, a pleiotropic cytokine synthesized and secreted in the latent form by Kupffer and stellate cells, they may contribute to its actions in the liver by the intracellular activation of latent TGF-beta, and secretion of the biologically active isoform. Many mediators that reach the liver during inflammatory processes, such as endotoxins, immune-complexes, anaphylatoxins, and PAF, increase glucose output in the perfused liver, but fail to do so in isolated hepatocytes, acting indirectly via prostaglandins released from Kupffer cells. In the liver, prostaglandins synthesized from arachidonic acid mainly in Kupffer cells in a response to various inflammatory stimuli, modulate hepatic glucose metabolism by increasing glycogenolysis in adjacent hepatocytes. The release of glucose from glycogen supports the increased demand for energetic fuel by the inflammatory cells such as leukocytes, and additionally enables enhanced glucose turnover in sinusoidal endothelial cells and Kupffer cells which is necessary for effective defense of these cells against invading microorganisms and oxidative stress in the liver. Leukotrienes, another oxidation product of arachidonic acid, have vasoconstrictive, cholestatic, and metabolic effects in the liver. A transcellular synthesis of cysteinyl leukotrienes (LTC4, LTD4, and LTE4) functions in the liver: LTA4, an important intermediate, is synthesized in Kupffer cells, taken up by hepatocytes, converted into the potent LTC4, and then released into extracellular space, acting in a paracrine way on Kupffer and sinusoidal endothelial cells. Thus, hepatocytes are target cells for the action of eicosanoids and the site of their transformation and degradation, but can not directly oxidate arachidonic acid to eicosanoids. (ABSTRACT TRUNCATED)
The liver lobule is formed by parenchymal cells, i.e., hepatocytes and nonparenchymal cells. In contrast to hepatocytes that occupy almost 80% of the total liver volume and perform the majority of numerous liver functions, nonparenchymal liver cells, which contribute only 6.5% to the liver volume, but 40% to the total number of liver cells, are localized in the sinusoidal compartment of the tissue. The walls of hepatic sinusoid are lined by three different cell types: sinusoidal endothelial cells (SEC), Kupffer cells (KC), and hepatic stellate cells (HSC, formerly known as fat-storing cells, Ito cells, lipocytes, perisinusoidal cells, or vitamin A-rich cells). Additionally, intrahepatic lymphocytes (IHL), including pit cells, i.e., liver-specific natural killer cells, are often present in the sinusoidal lumen. It has been increasingly recognized that both under normal and pathological conditions, many hepatocyte functions are regulated by substances released from neighboring nonparenchymal cells. Liver sinusoidal endothelial cells constitute the lining or wall of the hepatic sinusoid. They perform important filtration function due to the presence of small fenestrations that allow free diffusion of many substances, but not of particles of the size of chylomicrons, between the blood and the hepatocyte surface. SEC show huge endocytic capacity for many ligands including glycoproteins, components of the extracellular matrix (ECM; such as hyaluronate, collagen fragments, fibronectin, or chondroitin sulphate proteoglycan), immune complexes, transferrin and ceruloplasmin. SEC may function as antigen-presenting cells (APC) in the context of both MHC-I and MHC-II restriction with the resulting development of antigen-specific T-cell tolerance. They are also active in the secretion of cytokines, eicosanoids (i.e., prostanoids and leukotrienes), endothelin-1, nitric oxide, and some ECM components. Kupffer cells are intrasinusoidally located tissue macrophages with a pronounced endocytic and phagocytic capacity. They are in constant contact with gut-derived particulate materials and soluble bacterial products so that a subthreshold level of their activation in the normal liver may be anticipated. Hepatic macrophages secrete potent mediators of the inflammatory response (reactive oxygen species, eicosanoids, nitric oxide, carbon monoxide, TNF-alpha, and other cytokines), and thus control the early phase of liver inflammation, playing an important part in innate immune defense. High exposure of Kupffer cells to bacterial products, especially endotoxin (lipopolysaccharide, LPS), can lead to the intensive production of inflammatory mediators, and ultimately to liver injury. Besides typical macrophage activities, Kupffer cells play an important role in the clearance of senescent and damaged erythrocytes. Liver macrophages modulate immune responses via antigen presentation, suppression of T-cell activation by antigen-presenting sinusoidal endothelial cells via paracrine actions of IL-10, prostanoids, and TNF-alpha, and participation in the development of oral tolerance to bacterial superantigens. Moreover, during liver injury and inflammation, Kupffer cells secrete enzymes and cytokines that may damage hepatocytes, and are active in the remodeling of extracellular matrix. Hepatic stellate cells are present in the perisinusoidal space. They are characterized by abundance of intracytoplasmic fat droplets and the presence of well-branched cytoplasmic processes, which embrace endothelial cells and provide focally a double lining for sinusoid. In the normal liver HSC store vitamin A, control turnover of extracellular matrix, and regulate the contractility of sinusoids. Acute damage to hepatocytes activates transformation of quiescent stellate cells into myofibroblast-like cells that play a key role in the development of inflammatory fibrotic response. Pit cells represent a liver-associated population of large granular lymphocytes, i.e., natural killer (NK) cells. They spontaneously kill a variety of tumor cells in an MHC-unrestricted way, and this antitumor activity may be enhanced by the secretion of interferon-gamma. Besides pit cells, the adult liver contains other subpopulations of lymphocytes such as gamma delta T cells, and both "conventional" and "unconventional" alpha beta T cells, the latter containing liver-specific NK T cells. The development of methods for the isolation and culture of main liver cell types allowed to demonstrate that both nonparenchymal and parenchymal cells secrete tens of mediators that exert multiple paracrine and autocrine actions. Co-culture experiments and analyses of the effects of conditioned media on cultures of another liver cell type have enabled the identification of many substances released from non-parenchymal liver cells that evidently regulate some important functions of neighboring hepatocytes and non-hepatocytes. To the key mediators involved in the intercellular communication in the liver belong prostanoids, nitric oxide, endothelin-1, TNF-alpha, interleukins, and chemokines, many growth factors (TGF-beta, PDGF, IGF-I, HGF), and reactive oxygen species (ROS). Paradoxically, the cooperation of liver cells is better understood under some pathological conditions (i.e., in experimental models of liver injury) than in normal liver due to the possibility of comparing cellular phenotype under in vivo and in vitro conditions with the functions of the injured organ. The regulation of vitamin A metabolism provides an example of the physiological role for cellular cross-talk in the normal liver. The majority (up to 80%) of the total body vitamin A is stored in the liver as long-chain fatty acid esters of retinal, serving as the main source of retinoids that are utilized by all tissues throughout the body. Hepatocytes are directly involved in the uptake from blood of chylomicron remnants, and the synthesis of retinol-binding protein that transfers retinol to other tissues. However, more than 80% of the liver retinoids are stored in lipid droplets of hepatic stellate cells. HSC are capable of both uptake and release of retinol depending on the body's retinol status. The activity of some major enzymes of vitamin A metabolism have been found to be many times higher per protein basis in stellate cells than in hepatocytes. Despite progress in the understanding of the roles played by these two cell types in hepatic retinoid metabolism, the way in which retinoids move between the parenchymal cells, stellate cells, and blood plasma has not been fully elucidated. Sinusoidal blood flow is, to a great extent, regulated by hepatic stellate cells that can contract due to the presence of smooth muscle alpha-actin. The main vasoactive substances that affect constriction or relaxation of HSC derive both from distant sources and from neighboring hepatocytes (carbon monoxide, leukotrienes), endothelial cells (endothelin, nitric oxide, prostaglandins), Kupffer cells (prostaglandins, NO), and stellate cells themselves (endothelin, NO). The cellular cross-talk reflected by the fine-tuned modulation of sinusoidal contraction becomes disturbed under pathological conditions, such as endotoxemia or liver fibrosis, through the excess synthesis of vasoregulatory compounds and the involvement of additional mediators acting in a paracrine way. The liver is an important source of some growth factors and growth factor-binding proteins. Although hepatocytes synthesize the bulk of insulin-like growth factor I (IGF-I), also other types of nonparenchymal liver cells may produce this peptide. Cell-specific expression of distinct IGF-binding proteins observed in the rat and human liver provides the potential for specific regulation of hepatic IGF-I synthesis not only by growth hormone, insulin, and IGF-I, but also by cytokines released from activated Kupffer (IL-1, TNF-alpha, TGF-beta) or stellate cells (TGF-alpha, TGF-beta). Hepatic stellate cells may affect turnover of hepatocytes through the synthesis of potent positive as well as negative signals such as, respectively, hepatocyte-growth-factor or TGF-beta. Although hepatocytes seem not to produce TGF-beta, a pleiotropic cytokine synthesized and secreted in the latent form by Kupffer and stellate cells, they may contribute to its actions in the liver by the intracellular activation of latent TGF-beta, and secretion of the biologically active isoform. Many mediators that reach the liver during inflammatory processes, such as endotoxins, immune-complexes, anaphylatoxins, and PAF, increase glucose output in the perfused liver, but fail to do so in isolated hepatocytes, acting indirectly via prostaglandins released from Kupffer cells. In the liver, prostaglandins synthesized from arachidonic acid mainly in Kupffer cells in a response to various inflammatory stimuli, modulate hepatic glucose metabolism by increasing glycogenolysis in adjacent hepatocytes. The release of glucose from glycogen supports the increased demand for energetic fuel by the inflammatory cells such as leukocytes, and additionally enables enhanced glucose turnover in sinusoidal endothelial cells and Kupffer cells which is necessary for effective defense of these cells against invading microorganisms and oxidative stress in the liver. Leukotrienes, another oxidation product of arachidonic acid, have vasoconstrictive, cholestatic, and metabolic effects in the liver. A transcellular synthesis of cysteinyl leukotrienes (LTC4, LTD4, and LTE4) functions in the liver: LTA4, an important intermediate, is synthesized in Kupffer cells, taken up by hepatocytes, converted into the potent LTC4, and then released into extracellular space, acting in a paracrine way on Kupffer and sinusoidal endothelial cells. Thus, hepatocytes are target cells for the action of eicosanoids and the site of their transformation and degradation, but can not directly oxidate arachidonic acid to eicosanoids. (ABSTRACT TRUNCATED)
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