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.
Saturday, March 21, 2009
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)
Alcohol and substance abuse.
Section of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
Alcoholic liver disease is an important cause of cirrhosis, liver-associated death, and need for liver transplant. Up to 50% of recipients use some alcohol, and perhaps 10% drink addictively. Careful evaluation by an addiction medicine specialist is the best predictive instrument before transplant surgery, whereas the 6-month rule lacks sensitivity and specificity. Addictive drinking, but not minor slips, is associated with increased mortality. There is no standard therapy for alcoholism in alcoholics waiting for a transplant or for those who have undergone a transplant. Stably abstinent, methadone-maintained opiate-dependent patients should continue methadone; are generally good candidates for liver transplant; and show low relapse rates. Pre- and post-transplant smoking rates are high and cause significant morbidity and mortality. Transplant teams should encourage smoking cessation treatments. Marijuana use in liver transplant recipients is common, although risks associated with this practice are unknown.
Alcoholic liver disease is an important cause of cirrhosis, liver-associated death, and need for liver transplant. Up to 50% of recipients use some alcohol, and perhaps 10% drink addictively. Careful evaluation by an addiction medicine specialist is the best predictive instrument before transplant surgery, whereas the 6-month rule lacks sensitivity and specificity. Addictive drinking, but not minor slips, is associated with increased mortality. There is no standard therapy for alcoholism in alcoholics waiting for a transplant or for those who have undergone a transplant. Stably abstinent, methadone-maintained opiate-dependent patients should continue methadone; are generally good candidates for liver transplant; and show low relapse rates. Pre- and post-transplant smoking rates are high and cause significant morbidity and mortality. Transplant teams should encourage smoking cessation treatments. Marijuana use in liver transplant recipients is common, although risks associated with this practice are unknown.
Unique aspects of rejection and tolerance in liver transplantation.
Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia.
Spontaneous acceptance of liver allografts occurs in several species. However, tolerance is rare in human transplant patients even though rejection is relatively easily reversed. Histological features of acute rejection in liver transplantation are similar to those in other organs. Nevertheless, mechanisms of rejection of liver transplants may differ in degrees and cellular involvement. Liver-specific cell populations, such as Kupffer cells (KCs), liver sinusoidal epithelial cells (LSECs), and hepatic stellate cells (HSCs), may contribute to liver tolerogenicity. Other mechanisms, such as microchimerism, soluble major histocompatibility complex (MHC molecules), donor human leukocyte antigen (HLA)-C genotype, and regulatory T cells, may participate in inducing tolerance. The low incidence of hyperacute or antibody-mediated rejection in liver might be linked to the infrequency of chronic rejection of liver transplants. Understanding the mechanisms of liver transplant rejection/tolerance and the availability of better immune monitoring could help develop strategies to recognize tolerance and reduce rejection.
Spontaneous acceptance of liver allografts occurs in several species. However, tolerance is rare in human transplant patients even though rejection is relatively easily reversed. Histological features of acute rejection in liver transplantation are similar to those in other organs. Nevertheless, mechanisms of rejection of liver transplants may differ in degrees and cellular involvement. Liver-specific cell populations, such as Kupffer cells (KCs), liver sinusoidal epithelial cells (LSECs), and hepatic stellate cells (HSCs), may contribute to liver tolerogenicity. Other mechanisms, such as microchimerism, soluble major histocompatibility complex (MHC molecules), donor human leukocyte antigen (HLA)-C genotype, and regulatory T cells, may participate in inducing tolerance. The low incidence of hyperacute or antibody-mediated rejection in liver might be linked to the infrequency of chronic rejection of liver transplants. Understanding the mechanisms of liver transplant rejection/tolerance and the availability of better immune monitoring could help develop strategies to recognize tolerance and reduce rejection.
Long-term care of the liver allograft recipient.
The Liver Unit, Addenbrooke's Hospital, Cambridge, United Kingdom.
As outcomes after liver transplant surgery continue to improve, management of the long-term consequences of the procedure and the associated immunosuppression become increasingly important. Liver allograft recipients have, compared with age and sex-matched controls, increased risk for cardiovascular and cerebrovascular events and death, for bone disease, and for some cancers. Early recognition and treatment of modifiable risk factors, especially of hypertension (present in up to 77% recipients), diabetes (in up to 22%), obesity (up to 40%), renal impairment (in up to 50%), and hyperlipidemia (in up to 66%) are necessary to maintain prolonged and healthy survival. Early recognition of de novo cancers (which occur in up to 26% recipients) indicates the need for additional monitoring for skin cancer and lymphoproliferative disorders, as well as cancers of the lung, colon, and upper gastrointestinal track. Early recognition of bone disease and appropriate intervention will allow introduction of strategies to reduce bone fracture. In this article, we review the evidence for the extent and treatment of these modifiable conditions in the allograft recipient.
As outcomes after liver transplant surgery continue to improve, management of the long-term consequences of the procedure and the associated immunosuppression become increasingly important. Liver allograft recipients have, compared with age and sex-matched controls, increased risk for cardiovascular and cerebrovascular events and death, for bone disease, and for some cancers. Early recognition and treatment of modifiable risk factors, especially of hypertension (present in up to 77% recipients), diabetes (in up to 22%), obesity (up to 40%), renal impairment (in up to 50%), and hyperlipidemia (in up to 66%) are necessary to maintain prolonged and healthy survival. Early recognition of de novo cancers (which occur in up to 26% recipients) indicates the need for additional monitoring for skin cancer and lymphoproliferative disorders, as well as cancers of the lung, colon, and upper gastrointestinal track. Early recognition of bone disease and appropriate intervention will allow introduction of strategies to reduce bone fracture. In this article, we review the evidence for the extent and treatment of these modifiable conditions in the allograft recipient.
Evolving surgical approaches in liver transplantation.
The Dumount-UCLA Transplant Center, Ronald-Reagan UCLA Medical Center, Los Angeles, California.
The growing discrepancy between the need and the availability of donor livers has resulted in evolving surgical approaches in liver transplantation during the last two decades to expand the donor pool. One approach is to transplant partial grafts, obtained either from a living donor or splitting a cadaveric donor liver. For both surgical methods, it is important to obtain a minimal viable graft volume to prevent small-for-size syndrome and graft failure. This minimal volume, expressed as graft-to-whole body ratio, must be between 0.8 and 1%. Living donor liver transplantation (LDLT) became the primary transplant option in many Asian countries and is increasingly performed as an adjunct transplant option in countries with low donation rates. Split liver transplantation (SLT) is a surgical method that creates two allografts from one deceased donor. The most widely used splitting technique is the division of the liver into a left lateral sectoral graft (segments 2 and 3) for a pediatric patient and a right trisegmental graft (segments 1 and 4 to 8) for an adult patient. Both LDLT and SLT are also important and established methods for the treatment of pediatric patients. Another evolving surgical approach is auxiliary liver transplantation, which describes the transplanting a whole or partial graft with preservation of the partial native liver. This bridging technique is applied in patients with fulminate liver failure and should allow the regeneration of the injured liver with the potential to discontinue immunosuppression. Other methods such as xenotransplantation, as well as hepatocyte and stem cell transplantation, are promising approaches that are still in experimental phases.
The growing discrepancy between the need and the availability of donor livers has resulted in evolving surgical approaches in liver transplantation during the last two decades to expand the donor pool. One approach is to transplant partial grafts, obtained either from a living donor or splitting a cadaveric donor liver. For both surgical methods, it is important to obtain a minimal viable graft volume to prevent small-for-size syndrome and graft failure. This minimal volume, expressed as graft-to-whole body ratio, must be between 0.8 and 1%. Living donor liver transplantation (LDLT) became the primary transplant option in many Asian countries and is increasingly performed as an adjunct transplant option in countries with low donation rates. Split liver transplantation (SLT) is a surgical method that creates two allografts from one deceased donor. The most widely used splitting technique is the division of the liver into a left lateral sectoral graft (segments 2 and 3) for a pediatric patient and a right trisegmental graft (segments 1 and 4 to 8) for an adult patient. Both LDLT and SLT are also important and established methods for the treatment of pediatric patients. Another evolving surgical approach is auxiliary liver transplantation, which describes the transplanting a whole or partial graft with preservation of the partial native liver. This bridging technique is applied in patients with fulminate liver failure and should allow the regeneration of the injured liver with the potential to discontinue immunosuppression. Other methods such as xenotransplantation, as well as hepatocyte and stem cell transplantation, are promising approaches that are still in experimental phases.
Chronic rejection preceded by central perivenulitis, rapidly ensuing after liver transplantation in a pediatric patient.
Department of Pediatrics, Mount Sinai School of Medicine, New York, New York.
A 15-year-old boy who underwent liver transplantation for fulminant Wilson's disease, presented with elevated transaminases 2 months post-transplant. He had recently seroconverted from previous Epstein-Barr virus (EBV) naive status and by polymerase chain reaction (PCR) had increasing viral load copies of EBV in blood. A liver biopsy was obtained 6 weeks post-transplant, which showed isolated central perivenulitis (CP). His immunosuppresion was reduced and antiviral therapy was added with subsequent increase in liver transaminases. A second liver biopsy 6 weeks later again showed isolated CP. Subsequent further reduction in immunosuppression was followed by the appearance of portal-based moderate acute cellular rejection that was resistant to immunosuppressive treatment and rapidly evolved into ductopenic chronic rejection. This case report underlines the difficulties in interpreting isolated perivenulitis, especially in the setting of EBV seroconversion, and suggests that it may not only represent a form of acute rejection but also a predictor of rapidly progressing chronic rejection.
A 15-year-old boy who underwent liver transplantation for fulminant Wilson's disease, presented with elevated transaminases 2 months post-transplant. He had recently seroconverted from previous Epstein-Barr virus (EBV) naive status and by polymerase chain reaction (PCR) had increasing viral load copies of EBV in blood. A liver biopsy was obtained 6 weeks post-transplant, which showed isolated central perivenulitis (CP). His immunosuppresion was reduced and antiviral therapy was added with subsequent increase in liver transaminases. A second liver biopsy 6 weeks later again showed isolated CP. Subsequent further reduction in immunosuppression was followed by the appearance of portal-based moderate acute cellular rejection that was resistant to immunosuppressive treatment and rapidly evolved into ductopenic chronic rejection. This case report underlines the difficulties in interpreting isolated perivenulitis, especially in the setting of EBV seroconversion, and suggests that it may not only represent a form of acute rejection but also a predictor of rapidly progressing chronic rejection.
Germany To Provide $31.7M To Philippines For HIV/AIDS, Malaria, TB Efforts
Germany's government has offered to provide 25 million euros, or about $31.7 million, to the Philippines in the form of a debt exchange to support health programs related to the United Nations Millennium Development Goals, including efforts to control HIV/AIDS, malaria and tuberculosis, the Philippine Daily Inquirer reports.
Ralph Recto, director-general of the Philippines' National Economic and Development Authority, said the debt servicing program will allow the Philippines to use unpaid debt to fund health projects rather than to repay certain loans, according to information from Germany's Federal Ministry for Economic Cooperation and Development. Recto said NEDA appreciates Germany's proposal and will await an indication of which projects the debt exchange will cover. According to NEDA, UNICEF also recently announced that it will extend until 2011 its Sixth Country Program for Children promoting child welfare in the Philippines. UNICEF plans to sign an agreement with NEDA to provide $11.54 million for various projects, the Daily Inquirer reports (Domingo, Philippine Daily Inquirer, 3/11).
Reprinted with kind permission from http://www.kaisernetwork.org. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at http://www.kaisernetwork.org/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation.
Ralph Recto, director-general of the Philippines' National Economic and Development Authority, said the debt servicing program will allow the Philippines to use unpaid debt to fund health projects rather than to repay certain loans, according to information from Germany's Federal Ministry for Economic Cooperation and Development. Recto said NEDA appreciates Germany's proposal and will await an indication of which projects the debt exchange will cover. According to NEDA, UNICEF also recently announced that it will extend until 2011 its Sixth Country Program for Children promoting child welfare in the Philippines. UNICEF plans to sign an agreement with NEDA to provide $11.54 million for various projects, the Daily Inquirer reports (Domingo, Philippine Daily Inquirer, 3/11).
Reprinted with kind permission from http://www.kaisernetwork.org. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at http://www.kaisernetwork.org/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation.
Aid Achievements In Solomon Islands: The Key To Good Foreign Aid
Health aid contributes 60% of funding to the Solomon Islands. The Islands have considerable health concerns including a double burden of both infectious and chronic diseases. This, coupled with damages from natural disasters, political instability and tensions between ethnic groups means most Islands in the Pacific, rely heavily on donations and externally funded programs. According to Australian research conducted in the Solomon Islands, simple cooperation between agencies and local governments is the key to good health care aid.
"As more and more agencies work to rebuild and strengthen health services and delivery, it's vital that these efforts are coordinated. In some cases there has been little alignment of priorities between the funding agencies and the local needs of the Solomon's Ministry of Health," says lead author Dr Alexandra Martiniuk at The George Institute for International Health in Australia.
"But what we are seeing now is a move towards more coordination and longer-term commitment to improve the health landscape in the Solomon's. We hope this trend gains pace among more foreign aid agencies."
WHO and AusAID are reported as examples of organisations providing good health aid. The Australian Government's AusAID program has been flexible with a focus on local priorities. The World Health Organization (WHO) is also seen as a good partner, who has made some sustainable changes including long-term training of local health care professionals. Both organisations have set out to base programs on the Solomon's government's National Health Strategic Plan, which was recognised as having real benefits for health system strengthening and planning.
"We know that coordination of aid in developing countries is important and commitment must be long-term. This research demonstrates Solomon Islanders' current needs for health care management skills, mentorship and the desire to learn more from other Pacific Island nations," added Dr Martiniuk.
A response from a local interview with the Ministry of Health included: Initially it was necessary to provide stop gap measure and fight fires, while now the focus is more towards recovery and development….
Researchers conducted in-depth interviews with government and nongovernment leaders from rural and urban regions in the Solomon Islands. The respondents suggest it is essential for donors to know current plans and determine with the Ministry of Health where they may be able to fit in. "If all donors and partners would support the five-year plan set by the Ministry of Health, resources could be used more efficiently to achieve greater impact."
Another local response: "Best way is to ask-what are you planning this year in the region and how can we help?. [referring to volunteers from overseas]...their flight costs alone are equal to the entire provincial health construction budget for an entire year."
"If aid is not coordinated, it can serve to undermine the government reform process and hamper efforts to build political stability by interfering with systematic policy making and planning. Locals expressed the desire to strengthen health committees, work towards long-term sustainability and integrating programs," added Dr Martiniuk.
The Solomon Islands are the fourth greatest recipient of Australia's aid (US$4.72m). The Australian government announced that it would take a lead role in supporting the Solomon Islands health sector by providing $60 million over five years in March 2008. These funds will include up-scaling its response to HIV and other sexually transmitted infections in the Pacific by increasing community prevention programs and expanding testing and treatment.
Source: Emma Orpilla
Research Australia
"As more and more agencies work to rebuild and strengthen health services and delivery, it's vital that these efforts are coordinated. In some cases there has been little alignment of priorities between the funding agencies and the local needs of the Solomon's Ministry of Health," says lead author Dr Alexandra Martiniuk at The George Institute for International Health in Australia.
"But what we are seeing now is a move towards more coordination and longer-term commitment to improve the health landscape in the Solomon's. We hope this trend gains pace among more foreign aid agencies."
WHO and AusAID are reported as examples of organisations providing good health aid. The Australian Government's AusAID program has been flexible with a focus on local priorities. The World Health Organization (WHO) is also seen as a good partner, who has made some sustainable changes including long-term training of local health care professionals. Both organisations have set out to base programs on the Solomon's government's National Health Strategic Plan, which was recognised as having real benefits for health system strengthening and planning.
"We know that coordination of aid in developing countries is important and commitment must be long-term. This research demonstrates Solomon Islanders' current needs for health care management skills, mentorship and the desire to learn more from other Pacific Island nations," added Dr Martiniuk.
A response from a local interview with the Ministry of Health included: Initially it was necessary to provide stop gap measure and fight fires, while now the focus is more towards recovery and development….
Researchers conducted in-depth interviews with government and nongovernment leaders from rural and urban regions in the Solomon Islands. The respondents suggest it is essential for donors to know current plans and determine with the Ministry of Health where they may be able to fit in. "If all donors and partners would support the five-year plan set by the Ministry of Health, resources could be used more efficiently to achieve greater impact."
Another local response: "Best way is to ask-what are you planning this year in the region and how can we help?. [referring to volunteers from overseas]...their flight costs alone are equal to the entire provincial health construction budget for an entire year."
"If aid is not coordinated, it can serve to undermine the government reform process and hamper efforts to build political stability by interfering with systematic policy making and planning. Locals expressed the desire to strengthen health committees, work towards long-term sustainability and integrating programs," added Dr Martiniuk.
The Solomon Islands are the fourth greatest recipient of Australia's aid (US$4.72m). The Australian government announced that it would take a lead role in supporting the Solomon Islands health sector by providing $60 million over five years in March 2008. These funds will include up-scaling its response to HIV and other sexually transmitted infections in the Pacific by increasing community prevention programs and expanding testing and treatment.
Source: Emma Orpilla
Research Australia
WFP Scales Up Feeding In Kenya In New Response To Food Crisis
Now at South by Southwest (SXSW) through March 26th, Stand Up To Cancer is battling it out in the first ever Social Media Smackdown for charity to raise as much money as possible online for their cause, which aims to attack cancer once and for all by pushing promising scientific breakthroughs to the finish. Participating celebrities and bloggers have been broken out into nine different teams to raise as much money as possible for several different charities including Stand Up To Cancer's "Team Corbin" whose team members feature Corbin Bleu of High School Musical, celeb blogger Just Jared, CBS Early Show host Natalie Del Conte and social media's Howard Greenstein. We're going up against some heavy hitters though:
- Corbin Bleu - Benefitting Stand Up To Cancer
- Alec Baldwin - Benefitting The Actors Fund
- Hayden Panettiere - Benefitting The Whaleman Foundation
- Kyle Petty - Benefitting Victory Junction
- Brea Grant - Benefitting Girls Rock Camp Austin
- Pete Cashmore (Mashable) - Benefitting Livestrong
- Ernie Johnson - Benefitting Samaritan's Feet
- Linkin Park - Benefitting Music For Relief
- Elevenmoms - Benefitting Share Our Strength
Anyone can donate directly on http://www.charitysmackdown.com or take the PayPal Fundraising Widget, copy it to a MySpace page or personal blog, and challenge friends and family to support the cause. The winning team's charity will receive an additional donation from PayPal, thus the need to smack down the other celeb teams and be the ultimate winner.
- Corbin Bleu - Benefitting Stand Up To Cancer
- Alec Baldwin - Benefitting The Actors Fund
- Hayden Panettiere - Benefitting The Whaleman Foundation
- Kyle Petty - Benefitting Victory Junction
- Brea Grant - Benefitting Girls Rock Camp Austin
- Pete Cashmore (Mashable) - Benefitting Livestrong
- Ernie Johnson - Benefitting Samaritan's Feet
- Linkin Park - Benefitting Music For Relief
- Elevenmoms - Benefitting Share Our Strength
Anyone can donate directly on http://www.charitysmackdown.com or take the PayPal Fundraising Widget, copy it to a MySpace page or personal blog, and challenge friends and family to support the cause. The winning team's charity will receive an additional donation from PayPal, thus the need to smack down the other celeb teams and be the ultimate winner.
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