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Background and Aims HCV is a worldwide cause of chronic liver disease, particularly in Egypt where the most prevalent is genotype 4. HCV-associated cirrhosis is the most common indication for orthotopic liver transplantation (OLT) among adults. HCV infection remains a problem after transplantation, and recurrent hepatic infection is the leading cause of graft failure. Little is known about the long-term effects of direct acting antiviral therapy in patients after liver transplantation. We examined the incidence and severity of liver transplantation rejection in patients treated for HCV, post liver transplantation, with DAAs relative to the incidence and severity of liver transplantation rejection in patients treated for HCV, post liver transplantation, with Interferon based therapy and patients who didn’t receive any treatment for HCV after transplantation. Patients and Methods The study was conducted on 90 patients who had underwent liver transplantation between 2010 and 2017 at Ain Shams Center for Organ Transplantation (ASCOT) with a minimum follow up period of 6 months. Patients were divided into three groups: group I included 16 patients that didn’t receive antiviral treatment after liver transplantation, group II included 20 patients that had received interferon based therapy after liver transplantation and group III included 54 patients that had received direct acting antivirals after liver transplantation. Results Amongst group I, 2 patients (12.5%) developed acute graft rejection while in group II 2 patients (10%) developed chronic graft rejection and in group III 6 patients (11.11%) developed chronic rejection. In group I, all the patients (100%) had developed rejection that was diagnosed within one year of liver transplantation. In group II, 2 patients (100%) developed chronic graft rejection which occurred after one year of liver transplantation, one of them was on treatment with peg interferon and the other had already completed treatment. In group III, 2 patients (40%) had developed chronic rejection within one year of transplantation, while 4 patients (60%) had developed chronic rejection after one year of transplantation. One patient (16.67%) had developed rejection on treatment while 5 patients (83.33%) had developed rejection after the end of treatment. Conclusion It was found that the incidence of chronic rejection was more in patients that had received antiviral treatment after liver transplantation, however no difference was noted between DAAs and peg-interferon. Chronic rejection was found to be more common when treatment was given over one year after liver transplantation (6 cases) as compared to within the 1st year (2 cases). This may be related to the withdrawal of immunosuppression treatment after one year of transplantation and maintenance on monotherapy.

Renal transplantation is the best modality of treatment for end stage renal disease in children when compared to chronic dialysis. The growth, development and quality of life in these children are significantly better after transplantation. There has been a marked increase in the number of children undergoing renal transplantation in the recent years. The short term graft survival rates have increased with improved immunosuppression, but the long term outcome is still poor due to chronic graft rejection and opportunistic infections. In developing countries renal transplantation is not accessible to many children due to economic issues, lack of expertise and the absence of a strong deceased donor program. This article is a brief review of the indications and other aspects of pre-operative evaluation of pediatric renal transplant recipients.

In the current era of rapidly advancing and evolving medicine, a huge emphasis has been placed on the utilization of diagnostic tests and imaging, as well as on following updated guidelines, at the expense of focusing on clinical exams and honing these skills. Poor physical exam skills is a definite risk to patient safety, as they might lead to the misdiagnosis of, sometimes, fatal diseases. In this case, we discuss a case of complicated aortic dissection type A that initially presented to us as a case of worsening chronic graft rejection. Aortic dissection type A was solely uncovered by clinical exam despite unusual presenting symptoms and grossly benign basic labs and initial chest radiograph.

Não recebi financiamento The growth of lung transplantation has been constant throughout the world, and with this, the results presented have been progressively better, both in the short and long term. Despite this reality, some problems of difficult solution limit these programs, such as chronic graft rejection and complications secondary to long-term immunosuppression. The immunosuppressive strategies used in lung transplantation are based on triple schemes, composed of a calcineurin inhibitor, an antimetabolic agent and corticosteroids. A fourth group of immunosuppressants consists of inhibitors of cell proliferation, in particular, mTOR inhibitors. In this sense, this review aimed to compare the immunosuppressive regimen based on a calcineurin inhibitor-associated mTOR inhibitor at reduced dose with the calcineurin inhibitor alone in the chronic rejection of the posttransplant lung graft. In order to do so, we applied the methodological design of systematic review of the literature, through searches in electronic health databases (MEDLINE, Wef of Science, Scopus, Cochrane Central, EMBASE and LILACS) and in secondary manual resources. Six scientific articles composed the corpus of analysis for the qualitative synthesis of the results, which referred to three studies named SHITRIT, NOCTET and 4EVERLUNG. The main outcomes were the safety of substitution therapy for calcineurin inhibitor-based immunosuppressive therapy by the treatment of mTOR inhibitor with low patient mortality as well as maintaining efficacy in controlling events of chronic graft rejection. The relevance of the data that indicated an improvement in the renal function of the patients when submitted to the therapy with inhibitor mTOR in relation to calcineurin inhibitors was unanimously highlighted. The studies present a high reliability index due to the manifestation of low risk of bias in most of the items evaluated for the assertive conduction of a randomized clinical trial, in addition to presenting an important recommendation force for clinical decision making. In this sense, this systematic review guides a weighting in the use of mTOR inhibitors, considering the greater risk of mortality in the first year of treatment associated with this therapy. For patients with renal dysfunction associated with the isolated use of calcineurin inhibitors, this review "recommends" a change in the therapeutic regimen for the insertion of mTOR inhibitors into calcineurin inhibitors at a reduced dose, considering the imminent risk of mortality of lung transplant patients under renal insufficiency. O crescimento do número de transplantes de pulmão tem sido constante no mundo todo, e, com isso, os resultados apresentados têm sido progressivamente melhores, tanto em curto e em longo prazo. Apesar desta realidade, alguns problemas de difícil solução limitam estes programas, como a rejeição crônica do enxerto e as complicações secundárias à imunossupressão de longa duração. As estratégias imunossupressoras utilizadas no transplante de pulmão baseiam-se em esquemas triplos, compostos de um inibidor de calcineurina, um antimetabólico e corticosteroides. Um quarto grupo de imunossupressores constitui-se de inibidores da proliferação celular, em particular, os inibidores de mTOR. Nesse sentido, esta revisão se propôs a comparar o esquema de imunossupressão baseado em inibidor de mTOR associado a inibidor de calcineurina em dose reduzida com o inibidor de calcineurina isolado na rejeição crônica do enxerto pós-tranplante de pulmão. Para tanto, aplicou-se o desenho metodológico de revisão sistemática da literatura, por meio de buscas em bases eletrônicas da saúde (MEDLINE, Wef of Science, Scopus, Cochrane Central, EMBASE e LILACS) e em recursos manuais secundários. Seis artigos científicos compuseram o corpus de análise para a síntese qualitativa dos resultados, os quais se referiam a três estudos nominados SHITRIT, NOCTET e 4EVERLUNG. Os desfechos principais apontaram para a segurança da terapêutica de substituição do tratamento imunossupressor baseado em inibidor de calcineurina pelo tratamento baseado em inibidor de mTOR, com baixo índice de mortalidade dos pacientes, assim como da manutenção da eficácia em controlar eventos de rejeição crônica do enxerto. Destacou-se de forma unânime, a relevância dos dados que apontaram melhora na função renal dos pacientes quando submetidos à terapêutica com inibidor mTOR em relação a inibidores de calcineurina. Os estudos apresentam alto índice de confiabilidade pela manifestação de baixo risco de viés na maioria dos itens avaliados para a condução assertiva de um ensaio clínico randomizado, além de apresentarem importante força de recomendação para a tomada de decisão clínica. Nesse sentido, esta revisão sistemática orienta para um ponderamento na utilização de inibidores mTOR, considerando o maior risco de mortalidade do paciente no primeiro ano de tratamento associado a essa terapêutica. Para pacientes que apresentem disfunção renal associada ao uso isolado de inibidores de calcineurina, esta revisão “recomenda” a troca de regime terapêutico para a inserção de inibidores mTOR aos inibidores de calcineurina em dose reduzida, considerando o risco iminente de mortalidade dos pacientes transplantados de pulmão sob insuficiência renal.

Vascularized composite allotransplantation (VCA) has emerged as a useful reconstructive option for patients suffering from major tissue defects and functional deficits. While the technical feasibility has been optimized and more than 130 VCAs have been performed during the last two decades, hurdles such as acute and chronic allograft rejection, graft deterioration, and eventual functional impairment need to be addressed. Recently, chronic graft rejection and progressive failure have been linked to vascular alterations observed in the allografts. Graft vasculopathy (GV) may play a pivotal role in long-term graft deterioration. The understanding of the underlying pathophysiological processes and their initial triggers is of utmost importance in the prevention, attenuation, and therapy of GV. While there are reports on the etiology and development of GV in solid organ transplantation, there are limited data with respect to chronic rejection and GV in the realm of VCA. Nevertheless, recent reports from long-term VCA recipients suggest that GV could truly jeopardize allografts in the follow-up evaluation. Chronic rejection and GV include different entities and might have different pathways in distinct organs. Herein, we reviewed the current literature on vascular changes during both acute and chronic allograft rejection, with a focus on their clinical and translational significance for VCA.

Background. With the increase of primary lung transplantation across major centers worldwide, over the last several years the need of lung retransplant (ReTX) is likely to increase. Therefore, characterization of ReTX patients is prudent and necessary. Our study aimed to investigate and characterize the covariates and outcomes associated with lung ReTX survival in a single large U.S. transplant center. Methods. Demographic, clinical diagnoses, and comorbidities were analyzed. Kaplan-Meier statistics were used to calculate and predict survival for 30 days and up to 3 years. Cox proportional modeling was used to determine the variables associated with mortality. Results. Of included 684 lung transplants performed at the Houston Methodist Hospital between January 2009 and December 2015, 49 were lung ReTX. Median age of primary lung transplant (non-ReTX) and ReTx recipients was 62 and 49 years, respectively. Chronic graft rejection in the form of restrictive chronic lung allograft dysfunction and bronchiolitis obliterans syndrome was the main indications for ReTX. Compared with non-ReTX patients, ReTX patients had higher median lung allocation score (46.2 vs 37.0, respectively) and higher mortality after 6 months posttransplant. ReTX, older age, female sex, hospitalization 15 days or longer, estimated glomerular filtration rate less than 60, 6-minute walk distance less than 400 ft, and donor/recipient height ratio less than 1 were significantly associated with decreased 1-year patient and graft survival. Chronic graft rejection was still the major cause of death in the long-term follow-up recipients. Conclusions. Our findings suggested that lung ReTX recipients have poor long-term survival outcomes. Lung ReTX should only be offered to carefully selected patients.

Abdominal wall transplants are relatively new procedures that are frequently performed in conjunction with multivisceral transplants. The skin of the abdominal wall transplant is often the first site for graft rejection to manifest itself. Prompt recognition can lead to appropriate treatment before the involvement of the underlying viscera. However, the signs of graft rejection are nonspecific and can overlap with other entities. We present a case of a patient who received a multivisceral and abdominal wall transplant from 2 different donors, who presented with acute and eventually chronic graft rejection of the abdominal wall graft. Serial biopsies performed during the course of her treatment demonstrated progressive sclerotic changes in the dermis. Because these changes were confined to the abdominal wall graft, they could represent either chronic graft rejection or graft-versus-graft disease. To date, graft-versus-graft disease has not been documented in these patients. This case illustrates the possibility that patients with multidonor transplants may be at an increased risk for graft failure secondary to multiple potential etiologies.

Resumen Desde los primeros estudios en inmunologia, ha sido evidente la necesidad de entender como, en condiciones normales, el sistema inmune tolera los antigenos propios y ataca algunos antigenos extranos que percibe como potencialmente peligrosos, y como, bajo ciertas circunstancias, la perdida de la tolerancia desencadena enfermedades autoinmunes. Ha pasado mas de medio siglo desde que Billingham, Medawar y Brent demostraron en un modelo experimental algunos eventos involucrados en el desarrollo de la tolerancia inmunologica. Desde entonces, los inmunologos de trasplante han centrado sus esfuerzos en dilucidar los mecanismos que conllevan al mantenimiento de la tolerancia, con la esperanza de eludir las complicaciones de la inmunosupresion no especifica y conseguir la prevencion del rechazo cronico. Medawar (1953) argumentaba que durante el trasplante el sistema inmune del individuo se hacia tolerante al tejido trasplantado, manteniendose la respuesta a otros antigenos. Estudios recientes han demostrado que la perdida de la tolerancia al trasplante esta asociada con una hiperrespuesta a los antigenos del tejido trasplantado, hecho que ha atormentado a los inmunologos clinicos, quienes han encaminado sus esfuerzos a desarrollar sistemas de medicion precisos que les permita evaluar que tan tolerante podria ser un individuo al trasplante. Los intentos por inducir tolerancia en el individuo, se basan en la comprension de los mecanismos basicos de tolerancia, cuyo conocimiento se ha desarrollado paralelamente con una mejor apreciacion de la complejidad de la tolerancia inmune. En particular, se ha avanzado mucho en la comprension del papel esencial de las celulas dendriticas tolerogenicas (CDT) y del mantenimiento de la tolerancia por celulas T reguladoras.

TRANSPLANTEX, a French "investment for the future" initiated consortium of leading transplant units and research laboratories across France and a number of European countries aims to unravel, through mainly high-throughput genomics (and other omics) analyses of donor and recipients, novel (a) non-HLA, histocompatibility antigens, whether inside, or outside the MHC; (b) pre/post transplantation biomarkers. This shall lead to our better understanding of the pathophysiology of (and eventually designing better therapeutics for) the graft-versus-host disease in hematopoietic cell transplants and that of chronic graft rejection after kidney transplant. Industrial developments as well as innovative teaching initiatives are also integral part of this program. The present issue of Human Immunology aims to present a first snapshot of some of the research performed by TRANPLANTEX partners. editorial 2016 Nov imported

Transplantation is often the only choice many patients have when suffering from end-stage organ failure. Although the quality of life improves after transplantation, challenges, such as organ shortages, necessary immunosuppression with associated complications, and chronic graft rejection, limit its wide clinical application. Nanotechnology has emerged in the past 2 decades as a field with the potential to satisfy clinical needs in the area of targeted and sustained drug delivery, noninvasive imaging, and tissue engineering. In this article, we provide an overview of popular nanotechnologies and a summary of the current and potential uses of nanotechnology in cell and organ transplantation.

Immunosuppressive therapy has contributed significantly to improved survival after solid organ transplantation. Nevertheless, treatment-related adverse events and persistently high risk of chronic graft rejection remain major obstacles to long-term survival after lung transplantation. The development of new agents, refinements in techniques to monitor immunosuppression, and enhanced understanding of transplant immunobiology are essential for further improvements in outcome. In this article, conventional immunosuppressive regimens, novel approaches to preventing graft rejection, and investigational agents for solid organ transplantation are reviewed.

A 43 year-old female, who underwent bilateral lung transplantation for Eisenmenger syndrome 10 years previously, visited our hospital complaining of progressive severe dyspnea. She was diagnosed as having bronchiolitis obliterans syndrome, which was presumably caused by chronic graft rejection following lung transplantation. Due to the aggravated dyspnea despite medical treatment, she required ventilator care and then she underwent lung retransplantation. We report here on a case of lung retransplantation for treating chronic graft rejection following the previous lung transplantation for the first time in Korea.

Biliary atresia (BA) is a neonatal progressive cholangiopathy of unknown etiology and one of the most common reasons for liver transplantation (LT) in children. Kasai portoenterostomy (KP) improves survival of the native liver, although LT remains the only ultimate treatment. In some cases KP makes it possible to defer the ultimate LT until adulthood. We report our experience regarding 5 cases of BA treated with LT during adulthood. KP was performed in all patients at an average age of 176 days (range, 60–280), which allowed an average survival of the native liver of 19.01 years (range, 14.06–22.32). Five-year survival rate was 100%. Ten-year survival rate did not reach 100% because of a death 9.55 years after LT due to chronic graft rejection, in a patient who was already prepared for a new LT. Our results corroborate that KP remains the first-line treatment of BA. Early performance of the KP provides children with the best chance of survival, allowing the delay of the LT to adulthood. LT during adulthood in these patients achieves good post-LT survival rate; we have not found any data regarding this group of patients in the literature.

Objectives: Pneumonia is an important cause of morbidity and mortality in recipients of solid-organ transplant. We aimed to determine risk factors for development of pneumonia and associated deaths in kidney transplant recipients. Materials and Methods: A retrospective review of medical records was performed for all kidney transplant recipients from December 1988, to April 2011. The diagnosis of community-acquired pneumonia was made from symptoms, clinical findings, and chest radiography. The diagnosis of nosocomial pneumonia was made according to published criteria. Laboratory and serologic tests, radiographic findings, cultures of respiratory specimens, and tissue biopsies were reviewed. Results: In 406 kidney transplant recipients, there were 82 patients (20%) who had 111 episodes of pneumonia, including 49 nosocomial episodes of pneumonia (44%). Bacterial infections were the most common cause (34 episodes [31%]). In multivariate analysis, significant risk factors associated with pneumonia episodes were older age, hypertension, cardiac disease, history of acute graft rejection, and not using everolimus/mycophenolate mofetil/prednisolone protocol. There were 28 episodes that resulted in death (25%), including 20 nosocomial episodes (71%). In multivariate analysis, significant risk factors associated with death from pneumonia episodes were antibiotic use in the previous 3 months, high C-reactive protein, and low albumin. Cutoff values for increased risk of death from pneumonia included C-reactive protein > 10 mg/dL and procalcitonin > 8.8 ng/mL. Conclusions: Recipients of kidney transplant may be at risk for pneumonia and associated death. Nosocomial pulmonary infections may be associated with marked morbidity and mortality in kidney transplant recipients.

Previous studies on pathophysiological mechanisms of chronic graft rejection demonstrated the impact of both alloresponsiveness and nonspecific immunological events on the process. To study the role of alloantigen-specific factors further, we hypothesized an acceleration of chronic graft rejection after presensitization. Chronically rejected renal allografts in the established Fischer 344 --> Lewis rat model were replaced sequentially by native allografts of donor origin. Grafting of second allografts was performed 2, 4, 8, and 12 weeks after the original transplantation and followed long term. Second allografts demonstrated significantly ameliorated functional and structural alterations with few cellular infiltrates. These changes were independent from the time interval between first and second engraftment (2-12 weeks); immunosuppressive treatment after the second engraftment was not influential. The nonresponsiveness was not restricted to the second kidney allografts, as heart allografts of donor origin in these recipients also functioned indefinitely, whereas third-party grafts (Lewis x Brown Norway F1) and Fischer 344 heart grafts in untreated Lewis control rats were acutely rejected. Thus, donor-specific and tissue-nonspecific graft acceptance is achieved by second engraftment of donor-specific allografts in a model of chronic graft rejection. Those observations demonstrate the synergistic effects of alloresponsiveness and of the injured graft itself for the development of chronic graft failure.

I n the earlier years of clinical transplantation, there was a tendency among clinicians and investigators to focus on the immediate problem of acute graft rejection, which occurred soon arter transplantation in a large number or transplant recipients and was a major cause ofgraft loss. In the current clinical era, acute rejection can be pharmacologically controlled in most patients, and clinical concerns have begun to focus on the less immediate problem of chronic graft rejection. This phenomenon occurs in about half of all transplant patients, and is a majot cause of late graft loss. Chronic rejection is generally unresponsive to therapies that are effective against acute rejection, and to date, there is no accepted clinical therapy for chronic graft rejection. As a result, chronic rejection now claims more grafts than acute rejection. Chronic rejection is not simply delayed acute rejection. Indeed, acute and chronic rejection are diKerent in many ways. Acute rejection is histologically characterized by a rapid, intense and destructive leukocytic inliltration of graft tissues, and generally represents a pathologic inflammatory response.‘” In contrast, chronic rejection is characterized by a slower development within the graft or interstitial librosis and neointimal formation within the large1 vessels, and seems to represent a pathologic tissue remodeling response .+a For some time, these disparate characteristics led clinicians and investigators to consider acute and chronic rejection as separate and unrelated entities. However, there is developing cvidence that the two pathologies are closely related manifestations of post-transplant cellular and humoral sensitization to graft alloantigens. provided by several investigators,‘* who indcpendently showed that long-term (5-10 year) graft survival decreases signilicantly in direct relation to the number of acute rejection episodes experienced by the patients. For esample, Matas et al” have calculated that the half-life of kidney allografts in patients with no clinical acute rejection episodes is 733 years, compared with 5 1 years in patients with one rejection episode, and 6 years in patients with more than one acute rejection episode. Conversely, these data indicate that late graft loss due to chronic rejection is relatively rare among patients who do not esperience an early acute rejection episode. This suggests that the two types of graft rejection are somehow related. It also suggests that control of chronic rejection in transplant patients might be achieved by developing immunosuppressive strategies that efTectively avoid, rather than reverse, acute rejection episodes. Indeed, the current clinical tendency to accept acute rejection, because it is treatable, may indirectly promote chronic rejection development. The purpose of this discussion is to review some current concepts regarding the related mechanisms of acute and chronic grart rejection in the light of some key observations in experimental transplant models. This is not meant to be a comprehensive review of the subject, and many interesting studies will not be cited for the sake of clarity and brevity. What should emerge from this discussion is a broadened view of transplant biology, and a working model of the continuum of pathologic events associated with acute and chronic graft rejection.

Since the first studies in immunology, there has been a clear need to understand how, under normal conditions, the immune system tolerates its own antigens and attacks some foreign antigens that it perceives as potentially dangerous and how, in certain circumstances, the loss of tolerance triggers autoimmune diseases. It has been over half a century since Billingham, Brent and Medawar demonstrated, in an experimental model, the mechanisms involved in the development of immunological tolerance. Since then transplant immunologists have intensively investigated the mechanisms involved in maintaining tolerance, in the hope of avoiding the complications of non-specific immunosuppression, as well as the prevention of chronic rejection. An important characteristic was observed by Medawar, who argued that during transplantation an individual's immune system is tolerant to transplanted tissue, maintaining the response to other antigens. Recent studies have shown that loss of tolerance to transplantation is associated with a hyper-response to antigens of the transplanted tissue; a problem that has plagued clinical immunologists, who have focused their efforts on developing accurate measurement systems to enable them to measure how an individual could be tolerant to transplant. Attempts to induce tolerance in the individual are based on understanding the basic mechanisms of tolerance, in which there has been significant progress. This growth in knowledge has been in parallel with a better appreciation of the complexity of immune tolerance. In particular, progress has been made in understanding the essential role of tolerogenic dendritic cells (CDS) and the maintenance of tolerance by regulatory T cells. © 2013 Asociación Colombiana de Reumatología. Published by Elsevier España, S.L. All rights reserved.

Cardiac transplantation displays a well established therapeutic procedure for different end-stage heart diseases. Effective immunosuppressive drugs, progress in operative techniques, modern perioperative intensive care, and application of increasingly potent antibiotics in case of postoperative infections led to an improvement in short term outcome of organ transplantation. Nevertheless, achievements in long term transplant results are rare due to rejection of allografts. Chronic graft rejection is the major cause of late transplant failure.

Ischemia reperfusion injury (IRI) is an inevitable clinical consequence in organ transplantation. It can lead to early graft nonfunction and contribute to acute and chronic graft rejection. Advanced molecular biology has revealed the highly complex nature of this phenomenon and few definitive therapies exist. This paper reviews factors involved in the pathophysiology of IRI and potential ways to attenuate it. In recent years, inhaled nitric oxide, carbon monoxide, and hydrogen sulfide have been increasingly explored as plausible novel medical gases that can attenuate IRI via multiple mechanisms, including microvascular vasorelaxation, reduced inflammation, and mitochondrial modulation. Here, we review recent advances in research utilizing inhaled nitric oxide, carbon monoxide, and hydrogen sulfide in animal and human studies of IRI and postulate on its future applications specific to solid organ transplantation.

Chronic rejection currently limits the long-term efficacy of clinical transplantation. Although B cells have recently been shown to play a pivotal role in the induction of alloimmunity and are being targeted in other transplant contexts, the efficacy of preemptive B cell depletion to modulate alloimmunity or attenuate cardiac allograft vasculopathy (CAV) (classic chronic rejection lesions found in transplanted hearts) in a translational model has not previously been described. We report here that the CD20-specific antibody (alphaCD20) rituximab depleted CD20+ B cells in peripheral blood, secondary lymphoid organs, and the graft in cynomolgus monkey recipients of heterotopic cardiac allografts. Furthermore, CD20+ B cell depletion therapy combined with the calcineurin inhibitor cyclosporine A (CsA) prolonged median primary graft survival relative to treatment with alphaCD20 or CsA alone. In animals treated with both alphaCD20 and CsA that achieved efficient B cell depletion, alloantibody production was substantially inhibited and the CAV severity score was markedly reduced. We conclude therefore that efficient preemptive depletion of CD20+ B cells is effective in a preclinical model to modulate pathogenic alloimmunity and to attenuate chronic rejection when used in conjunction with a conventional clinical immunosuppressant. This study suggests that use of this treatment combination may improve the efficacy of transplantation in the clinic.

Plasma exchange has been used in our renal transplantation programme for over ten years to treat 86 patients divided into four groups. Five patients had preformed cytotoxic antibodies before transplantation (group A); 13 sensitized patients (>60% PRA) underwent prophylactic plasma exchange in the immediate postoperative period (group B); 62 patients were treated for acute vascular rejection (group C); six patients had chronic graft rejection (group D). Plasma exchange is a valid tool for the treatment of acute vascular rejection, provided that it is started before irreversible graft damage occurs: 75% rejection crises were reversed by plasma exchange and the actuarial graft survival from the rejection episode was 75% at one year, 66% at two and 50% at five years. Serum creatinine before treatment and glomerular thrombosis at graft biopsy correlated with the response to plasma exchange. In sensitized patients and in those with chronic rejection the results were disappointing and suggest that in these clinical conditions plasma exchange should be used only in selected cases.

Mechanical circulatory support has been used to treat graft failure after heart transplantation, but in patients who needed mechanical circulatory support because of chronic rejection, we have suffered from the treatment because its outcome was catastrophic. Multiple organ failure was often caused by the addition of or increase in immunosuppressive medications, and it is known as a cause of the poor outcomes. The CardioWest total artificial heart was implanted for a case of chronic heart transplant rejection to enable complete withdrawal of immunosuppressive medication. The patient underwent re-heart transplantation, with a good result. This is a new therapeutic technique for chronic graft rejection.

BACKGROUND Lumen loss in graft arteriosclerosis is the consequence of the development of a thick neointima and constrictive arterial remodeling. The latter is due to adventitial chronic inflammation and excessive perivascular collagen deposition. We reasoned that blockade of the portal of entry of inflammatory effectors may constitute a strategy to prevent constrictive arterial remodeling. METHODS AND RESULTS We found that an anti-angiogenic therapy (ABT-510 nonapeptide), devoid of direct immunomodulatory properties, dramatically reduced adventitial angiogenesis by 66% (P\textless0.0001) in the rat aortic interposition model of graft arteriosclerosis. The associated decreased entry of inflammatory cells (44%; P\textless0.00001) resulted in drastic reduction of collagen deposition (57%; P\textless0.0001) thereby preventing subsequent adventitial constrictive remodeling and reduction of lumen surface area (5.26+/-0.74 vs. 8.58+/-2.48 microm2; Control vs. ABT-510-treated rats; P\textless0.0001). ABT-510 had no effect on the development of the neointima. CONCLUSION This work supports the idea that targeting angiogenesis may act synergistically with conventional immunosuppressive therapy in preventing graft arteriosclerosis, a crucial feature of chronic graft rejection.

Extracorporeal photopheresis (ECP), originally used to treat cutaneous T-cell lymphoma, also has been applied to the therapy of transplant rejection. Our aim was to investigate the biologic response in two children who underwent kidney transplantation with ECP as prophylactic treatment. They received conventional immunosuppressive therapy and ECP immediately after transplantation: six applications over the course of 3 weeks. During a 12-month follow-up, the clinical course was favorable in both patients; renal histology was normal 6 months after transplantation. When compared with four transplanted controls, the ECP-treated patients showed lower tumor necrosis factor-alpha serum levels in the short-term and a marked increase of Foxp3-positive T-regulatory cells. T-regulatory cells were still higher than in the controls 1 year after transplantation. These preliminary results suggest that the addition of ECP to standard immunosuppressive therapy induces a tolerogenic shift in the immune system of kidney transplanted patients and may pave the way to preventing chronic rejection.

Since the first lung transplantation was attempted in 1963, the use of the procedure has gradually increased. The first successful operation was performed in 1983, and during the past decade the number of lung transplantations and heart-lung transplantations has increased rapidly, with 75% of recipients surviving past the first year. Chronic rejection is the greatest obstacle to long-term survival. In this article, a brief history of lung transplantation is provided. Recipient selection criteria are reviewed, together with the listing process and donor organ criteria. Recommendations for care of patients before and after lung transplantation are outlined, with a description of the postoperative course, including complications, pain control, rehabilitation, discharge procedures, and outpatient treatment.

Acute rejection episodes have been cited as a major immunological risk factor for the development of chronic rejection. To examine the influence of a single rejection event on ultimate graft outcome, acutely rejection rat kidney grafts were retransplanted sequentially into syngeneic rats and their functional and structural behavior assessed over time. Early structural changes (days 3 and 4) were completely reversible, while signs of chronic rejection did become obvious during the long-term follow up. More advanced deteriorated grafts (days 5 and 7) were irreversibly damaged and the rats died shortly after retransplantation. Those results indicate the critical impact of acute rejection episodes on chronic graft rejection. Immediate and aggressive treatment of acute rejection episodes may remove this event as a risk factor for late deteriorating changes.

Following a successful orthotopic liver transplantation (OLT) various graft syndromes may beset an uneventful follow-up. The major syndromes include episodes of acute graft rejection, viral infection with graft involvement, bacterial infection with liver abcess formation or bacterial cholangitis, obstructed bile flow in the large bile ducts, an impaired blood supply of the graft, drug reactions in the graft and chronic graft rejection. Rejection phenomena and infections of the graft being the main topics in this chapter, the other conditions will only be mentioned in relation to differential diagnostic and pathogenetic problems.

Four patients underwent liver transplantation in the Cambridge/King's College Hospital programme for malignant primary and secondary apudomas, secreting various peptide hormones and uncontrollable by standard treatment techniques. After transplantation all patients had excellent symptomatic relief and specific peptide hormone levels fell to normal ranges. Two patients remain alive and well after 38 and 22 months, the latter with recurrence of slight tumour-related symptoms and elevation of the specific secretory product. The other two patients died from chronic graft rejection 7 and 8 months after transplantation.

Hypertension after renal homotransplantation occurs in from 30% to 50% of cases. Hypertension during the posttransplant period can be caused by many factors: the presence of the patient's own kidneys, acute or chronic graft rejection, renal artery stenosis in the homograft, acute ureteral obstruction, recurrence of the original renal disease, persistence of essential hypertension, a genetic predisposition for hypertension, and the effect of corticosteroids. From this list, it can be appreciated that pinpointing the cause and understanding the mechanisms for hypertension of transplant recipients can be difficult, especially because many of the potential causes with differing mechanisms may coexist in the same patient. In this issue of theArchives, Rao and collaborators have reported their experience with hypertension in a large transplant population (p 1236). They limited their study to patients who had had a functioning renal homograft for at least six months. Several of their observations provoke comment. They