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Background and Aims: The European Liver Transplant Registry (ELTR) has collected data on liver transplant procedures performed in Europe since 1968., Approach and Results: Over a 50-year period (1968-2017), clinical and laboratory data were collected from 133 transplant centers and analyzed retrospectively (16,641 liver transplants in 14,515 children). Data were analyzed according to three successive periods (A, before 2000; B, 2000-2009; and C, since 2010), studying donor and graft characteristics and graft outcome. The use of living donors steadily increased from A to C (A, n = 296 [7%]; B, n = 1131 [23%]; and C, n = 1985 [39%]; p = 0.0001). Overall, the 5-year graft survival rate has improved from 65% in group A to 75% in group B (p < 0.0001) and to 79% in group C (B versus C, p < 0.0001). Graft half-life was 31 years, overall; it was 41 years for children who survived the first year after transplant. The late annual graft loss rate in teenagers is higher than that in children aged <12 years and similar to that of young adults. No evidence for accelerated graft loss after age 18 years was found., Conclusions: Pediatric liver transplantation has reached a high efficacy as a cure or treatment for severe liver disease in infants and children. Grafts that survived the first year had a half-life similar to standard human half-life. Transplantation before or after puberty may be the pivot-point for lower long-term outcome in children. Further studies are necessary to revisit some old concepts regarding transplant benefit (survival time) for small children, the role of recipient pathophysiology versus graft aging, and risk at transition to adult age., (© 2021 American Association for the Study of Liver Diseases.)

Organ transplantation is an effective way to treat many end-stage diseases. In order to overcome post-transplant rejection, immunosuppressive agents have been widely used, but the long-term survival of transplanted organs still has not been achieved in the clinic. For decades, tolerance is the "holy grail" that transplant immunologists have longed for. The well-known approaches to induce immune tolerance are through adoptively transferred regulatory T cells and achieving chimeric states. In addition, there are a variety of promising potential strategies, including costimulatory blockade, regulating differentiation of immune cell subgroups, adoptive infusion of immunoregulatory cells, using apoptotic cells to induce tolerance, stem cell regenerative medicine to reconstitute tissue and organs, helminthic therapy, using exosomes carrying phagocytic antigen and phagocytic vesicles to induce tolerance, and blocking CD3 and targeted clearance of memory T cells. In this paper, we review the current developments and the potential of these strategies to achieve transplantation tolerance., (Copyright © 2019. Published by Elsevier B.V.)

Background: Scleroderma is a chronic connective tissue disease that results in fibrosis of the skin and internal organs. Although internal organ involvement corresponds with poor prognosis, systemic agents are effective at improving the effects of scleroderma on internal organs. In contrast, skin manifestations are universally present in all patients diagnosed with scleroderma, yet no systemic agents have been shown to be successful. Fat grafting has been shown to improve skin quality and improve contour irregularities and may be helpful in the treatment of patients with scleroderma., Methods: The authors performed a thorough review of the pathophysiology of scleroderma and the current treatment options for scleroderma. The efficacy of fat grafting for the treatment of scleroderma and the mechanism by which fat grafting improves outcomes was also discussed., Results: Scleroderma is characterized by chronic inflammation and vascular compromise that leads to fibrosis of the skin and internal organs. Fat grafting has recently been the focus of significant basic science research. It has been shown to reduce inflammation, reduce fibrosis by limiting extracellular matrix proteins and increasing collagenase activity, and provide structural support through stem cell proliferation and differentiation. The adipocytes, adipose stem cells, endothelial cells, and vascular smooth muscle cells in the processed fat likely contribute to the effectiveness of this treatment., Conclusions: Fat grafting in scleroderma patients likely improves skin manifestations by recreating fullness, correcting contour deformities, and improving skin quality. The injected fat provides a mixture of cells that influences the recipient site, resulting in improved outcomes.

In the past decade, novel lamellar keratoplasty techniques such as Deep Anterior Lamellar Keratoplasty (DALK) for anterior keratoplasty and Descemet stripping automated endothelial keratoplasty (DSAEK)/Descemet membrane endothelial keratoplasty (DMEK) for posterior keratoplasty have been developed. DALK eliminates the possibility of endothelial allograft rejection, which is the main reason for graft failure after penetrating keratoplasty (PK). Compared to PK, the risk of endothelial graft rejection is significantly reduced after DSAEK/DMEK. Thus, with modern lamellar techniques, the clinical problem of endothelial graft rejection seems to be nearly solved in the low-risk situation. However, even with lamellar grafts there are epithelial, subepithelial and stromal immune reactions in DALK and endothelial immune reactions in DSAEK/DMEK, and not all keratoplasties can be performed in a lamellar fashion. Therefore, endothelial graft rejection in PK is still highly relevant, especially in the "high-risk" setting, where the cornea's (lymph)angiogenic and immune privilege is lost due to severe inflammation and pathological neovascularization. For these eyes, currently available treatment options are still unsatisfactory. In this review, we will describe currently used keratoplasty techniques, namely PK, DALK, DSAEK, and DMEK. We will summarize their indications, provide surgical descriptions, and comment on their complications and outcomes. Furthermore, we will give an overview on corneal transplant immunology. A specific focus will be placed on endothelial graft rejection and we will report on its incidence, clinical presentation, and current/future treatment and prevention options. Finally, we will speculate how the field of keratoplasty and prevention of corneal allograft rejection will develop in the future., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The field of vascularized composite allotransplantation (VCA) has moved from a highly experimental procedure to, at least for some patients, one of the best treatment alternatives for catastrophic tissue loss or dysfunction. Although the worldwide experience is still limited, progress has been made in translation to the clinic, and hand transplantation was recently designated standard of care and is now covered in full by the British Health System. This progress is tempered by the long-term challenges of systemic immunosuppression, and the rapidly evolving indications for VCA such as urogenital transplantation. This update will cover the state of and recent changes in the field, and an update of the Louisville VCA program as our initial recipient, the first person to receive a hand transplant in the United States celebrates the 20th anniversary of his transplant. The achievements and complications encountered over the last two decades will be reviewed. In addition, potential directions for research and collaboration as well as practical issues of how third party payers and funding are affecting growth of the field are presented.

Invasive fungal infections constitute an important cause of morbidity and mortality in solid organ transplantation recipients. Since solid organ transplantation is an effective therapy for many patients with end-stage organ failure, prevention and treatment of fungal infections are of vital importance. Diagnosis and management of these infections, however, remain difficult due to the variety of clinical symptoms in addition to the lack of accurate diagnostic methods. The use of fungal biomarkers can lead to an increased diagnostic accuracy, resulting in improved clinical outcomes. The evidence for optimal prophylactic approaches remains inconclusive, which results in considerable variation in the administration of prophylaxis. The implementation of a standard protocol for prophylaxis remains difficult as previous treatment regimens, which can alter the distribution of different pathogens, affect the outcome of antifungal susceptibility testing. Furthermore, the increasing use of antifungals also contributes to incremental costs and the risk of development of drug resistance. This review will highlight risk factors, clinical manifestations and timing of fungal infections and will focus predominately on the current evidence for diagnosis and management of fungal infections., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Since the 1960s, skin has been considered to be the most allogenic tissue in humans. This tenet has remained unquestioned in the reconstructive transplant arena, which has led to skin serving as the sole monitor for early rejection in vascularized composite allotransplantation. In this article, the authors question the validity of this belief. The authors' hypothesis is that skin is not always an accurate monitor of rejection in the deep tissues, thus questioning the positive and negative predictive value of the punch biopsy for suspected vascularized composite allotransplantation rejection. A search was carried out identifying vascularized composite allotransplantation publications where the allogenicity of transplanted skin was evaluated. Eighteen publications claimed skin was found to be the most allogenic tissue in humans, justifying its use as a superior monitor for rejection. Eight publications demonstrated skin to be a poor monitor of rejection deeper to the skin. Two vascularized composite allotransplantation animal studies reported skin rejecting simultaneously with the deeper tissues. Finally, three publications discussed a skin and kidney allograft, transplanted simultaneously, indicating skin allogenicity was equivalent to the that of the kidney allograft. Much of the literature in human vascularized composite allotransplantation claims skin to be an excellent monitor of the deep tissues. The conclusion from this study is that skin does not always function as a good monitor for what could be rejecting in the deep tissues. The authors believe continued research is necessary to focus on expanding novel monitoring techniques and technologies to accurately diagnose vascularized composite allotransplantation rejection without tissue destruction.

Antibodies of non-human mammals are glycosylated with carbohydrate antigens, such as galactose-α-1-3-galactose (α-Gal) and N-glycolylneuraminic acid (Neu5Gc). These non-human carbohydrate antigens are highly immunogenic in humans due to loss-of-function mutations of the key genes involved in their synthesis. Such immunogenic carbohydrates are expressed on therapeutic polyclonal rabbit anti-human T-cell IgGs (anti-thymocyte globulin; ATG), the most popular induction treatment in allograft recipients. To decipher the quantitative and qualitative response against these antigens in immunosuppressed patients, particularly against Neu5Gc, which may induce endothelial inflammation in both the graft and the host. We report a prospective study of the antibody response against α-Gal and Neu5Gc-containing glycans following rabbit ATG induction compared to controls. We show a drop in the overall levels of anti-Neu5Gc antibodies at 6 and 12 months post-graft compared to the pre-existing levels due to the major early immunosuppression. However, in contrast, in a cross-sectional study there was a highly significant increase in anti-Neu5Gc IgGs levels at 6 months post-graft in the ATG-treated compared to non-treated patients(P = 0.007), with a clear hierarchy favouring anti-Neu5Gc over anti-Gal response. A sialoglycan microarray analysis revealed that the increased anti-Neu5Gc IgG response was still highly diverse against multiple different Neu5Gc-containing glycans. Furthermore, some of the ATG-treated patients developed a shift in their anti-Neu5Gc IgG repertoire compared with the baseline, recognizing different patterns of Neu5Gc-glycans. In contrast to Gal, Neu5Gc epitopes remain antigenic in severely immunosuppressed patients, who also develop an anti-Neu5Gc repertoire shift. The clinical implications of these observations are discussed., (© 2019 Stichting European Society for Clinical Investigation Journal Foundation.)

Despite improvements in graft survival, solid organ transplantation is still associated with considerable infection induced morbidity and mortality. If we were able to show that serious infection risk was associated with excessive suppression of immune capacity, we would be justified in "personalizing" the extent of immunosuppression by carefully monitored reduction to see if we can improve immune compromize without increasing the risk of rejection. Reliable biomarkers are needed to identify this patients at an increased risk of infection. This review focuses on the currently available evidence in solid organ transplant recipients for immune non-pathogen specific biomarkers to predict severe infections with the susceptibility to particular pathogens according to the component of the immune system that is suppressed. This review is categorized into immune biomarkers representative of the humoral, cellular, phagocytic, natural killer cell and complement system. Biomarkers humoral and cellular systems of the that have demonstrated an association with infections include immunoglobulins, lymphocyte number, lymphocyte subsets, intracellular concentrations of adenosine triphosphate in stimulated CD4 + cells and soluble CD30. Biomarkers of the innate immune system that have demonstrated an association with infections include natural killer cell numbers, complement and mannose binding lectin. Emerging evidence shows that quantification of viral nucleic acid (such as Epstein Barr Virus) can act as a biomarker to predict all-cause infections. Studies that show the most promise are those in which several immune biomarkers are assessed in combination. Ongoing research is required to validate non-pathogen specific immune biomarkers in multi-centre studies using standardized study designs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

B cells play a crucial role in alloreactivity of organ transplant rejection and graft versus host diseases (GVHD). Over the past decade, it has been well recognized that B-cell infiltration in allografts and de novo donor-specific antibodies (DSA) were strongly associated with severe graft rejection and loss, as well as glucocorticoid resistance. Emerging evidence has demonstrated that Follicular T helper (Tfh) cells are key effectors to promote the proliferation and differentiation of B cells into antibody-producing plasmablasts and memory B cells. T-follicular regulatory (Tfr) cells are a recently recognized cell population that has a negative regulatory role on Tfh cells in the follicle, preventing incessant antibody production. It is still less clear how those humoral immunoreactive cells affect transplant rejection and allograft loss. This review focuses on the production and function of Tfr/Tfh cells in the transplant environment. Better understanding of the functions and mechanisms of Tfr/Tfh cells will help to design new strategies to prevent allograft rejection and prolong graft survival., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Rapid changes in tissue-typing technology, including the widespread availability of highly specific molecular typing methods and solid-phase assays for the detection of allele-specific anti-HLA antibodies, make it increasingly challenging to remain up to date with developments in organ matching. Terms such as epitopes and eplets abound in the transplantation literature, but often it can be difficult to see what they might mean for the patient awaiting transplantation. In this review, we provide the historical context for current practice in tissue typing and explore the potential role of HLA epitopes in kidney transplantation. Despite impressive gains in preventing and managing T-cell-mediated rejection and the associated improvements in graft survival, the challenge of the humoral alloresponse remains largely unmet and is the major cause of late graft loss. Describing HLA antigens as a series of antibody targets, or epitopes, rather than based on broad seroreactivity patterns or precise amino acid sequences may provide a more practical and clinically relevant system to help avoid antibody-mediated rejection, reduce sensitization, and select the most appropriate organs in the setting of pre-existing alloantibodies. We explain the systems proposed to define HLA epitopes, summarize the evidence to date for their role in transplantation, and explore the potential benefits of incorporating HLA epitopes into clinical practice as this field continues to evolve toward everyday practice., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

This was a nationwide cohort study to investigate the impact of anti-A/B and donor-specific anti-HLA (HLA-DSA) antibodies on the clinical outcomes in kidney transplant recipients (KTRs). We classified a total of 1964 KTRs into four groups: transplants from ABO-incompatible donors (ABOi, n = 248); transplants in recipients with HLA-DSA (HLAi, n = 144); transplants from combined ABOi and HLAi donors (ABOi + HLAi, n = 31); and a control group for whom neither ABOi nor HLAi was applicable (CONT, n = 1541). We compared the incidence of biopsy-proven acute rejection (BPAR), allograft and patient survival rates. The incidence of BPAR was higher in the HLAi and ABOi + HLAi groups relative to the CONT group; in contrast, it was not higher in the ABOi group. Death-censored graft survival rates did not differ across the four groups. However, relative to the CONT group, patient survival rate was reduced in the ABOi and ABOi + HLAi groups, and with infection being the most common cause of death. Further, multivariable analysis revealed that desensitization therapy because of ABOi or HLAi was independent risk factors for patient mortality. HLAi was a more important risk factor for BPAR compared with ABOi. However, pretransplant desensitization therapy for either ABOi or HLAi significantly increased the risk of infection-related mortality., (© 2017 Steunstichting ESOT.)

Regenerative medicine promises to meet two of the most urgent needs of modern organ transplantation, namely immunosuppression-free transplantation and an inexhaustible source of organs. Ideally, bioengineered organs would be manufactured from a patient's own biomaterials-both cells and the supporting scaffolding materials in which cells would be embedded and allowed to mature to eventually regenerate the organ in question. While some groups are focusing on the feasibility of this approach, few are focusing on the immunogenicity of the scaffolds that are being developed for organ bioengineering purposes. This review will succinctly discuss progress in the understanding of immunological characteristics and behavior of different scaffolds currently under development, with emphasis on the extracellular matrix scaffolds obtained decellularized animal or human organs which seem to provide the ideal template for bioengineering purposes., (© 2017 Steunstichting ESOT.)

The diagnostic criteria for antibody-mediated rejection (ABMR) are constantly evolving in light of the evidence. Inclusion of C4d-negative ABMR has been one of the major advances in the Banff Classification in recent years. Currently Banff 2015 classification requires evidence of donor specific antibodies (DSA), interaction between DSA and the endothelium, and acute tissue injury (in the form of microvasculature injury (MVI); acute thrombotic microangiopathy; or acute tubular injury in the absence of other apparent cause). In this article we review not only the ABMR phenotypes acknowledged in the most recent Banff classification, but also the phenotypes related to novel pathogenic antibodies (non-HLA DSA, antibody isoforms and subclasses, complement-binding functionality) and molecular diagnostic tools (gene transcripts, metabolites, small proteins, cytokines, and donor-derived cell-free DNA). These novel tools are also being considered for the prognosis and monitoring of treatment response. We propose that improved classification of ABMR based on underlying pathogenic mechanisms and outcomes will be an important step in identifying patient-centered therapies to extend graft survival., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Sarcoidosis is a systemic granulomatous disorder of unknown cause. Apparition or flare of previously diagnosed sarcoidosis following hematopoietic stem cell transplantation (HSCT) has rarely been reported., Observation: We report a 62-year-old woman who presented a radiological flare of sarcoidosis post-autologous stem cell transplantation for a POEMS syndrome. Imaging findings and lymph node histology, which revealed non-caseating granuloma, were consistent with the sarcoidosis diagnosis. The patient was asymptomatic and was kept free of treatment., Conclusion: Sarcoidosis must be considered ahead of compatible clinicoradiological presentation occurring after HSCT. Sarcoidosis can mimic metastatic cancer or lymphatic relapse. Tissue biopsies and exclusion of differential diagnosis of granuloma diseases are warranted to confirm sarcoidosis diagnosis., (Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Compelling data suggest that lymphocyte depletion following T cell depleting therapy may induce prolonged CD4 T cell lymphopenia and trigger lymphocyte activation in some patients. These profound and non-reversible immune changes in T cell pool subsets are the consequence of both impaired thymic renewal and peripheral homeostatic proliferation. Chronic viral challenges by CMV play a major role in these immune alterations. Even when the consequences of CD4 T cell lymphopenia have been now well described, recent studies shed new light on the clinical consequences of immune activation. In this review, we will first focus on the mechanisms involved in T cell pool reconstitution after T cell depletion and further consider the clinical consequences of ATG-induced T cell activation and senescence in renal transplant recipients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Transplantation of sensitized recipients has been associated with increased risk of post-transplant complications. In 2010, the Canadian Cardiac Transplant Network (CCTN) created a unique status listing for highly sensitized heart transplant candidates. Status 4S listing requires calculated panel-reactive antibody (cPRA) level >80% as the sole listing criteria and enables geographic expansion of the donor pool by providing national access. In this study, we describe patient characteristics and outcomes of those transplanted as Status 4S in Canada., Methods: Patients' characteristics and clinical outcomes were retrospectively collected from all 11 adult heart transplant centers in Canada., Results: Ninety-six patients were listed Status 4S from January 2010 to September 2015. Fifty-two were transplanted as Status 4S. Of these 52 transplants, mean cPRA level was 93.4%, mean age was 47 years, 46% were male, 44% had dilated cardiomyopathy and 17% were re-transplanted for cardiac allograft vasculopathy (CAV). Blood group O comprised 42% and 53% had a left ventricular assist device as a bridge to transplant. Desensitization therapy occurred in 9 patients (17%). Over a mean follow-up period of 28 months (1 week to 5.3 years), 9 patients died (17%). Kaplan-Meier 1-year year survival is 86%. Two patients were treated for antibody-mediated rejection (AMR) in the first year post-transplant and 33% of patients had at least 1 ISHLT Grade ≥2R cellular rejection in the first year. Twenty-nine percent of patients developed de novo door-specific antibodies and demonstrated no correlation with AMR. Freedom from CAV at 1 year is 88.5% and at 5 years is 81.0%. Fifty-two percent of donor hearts originated from outside the recipients' geographic and organ donation organization., Conclusions: A national strategy of prioritizing highly sensitized heart transplant recipients has demonstrated effective expansion of the donor pool, acceptable short-term survival, freedom from CAV and low rates of clinically relevant AMR. However, we observed significantly higher rates of cellular rejection and de novo donor-specific antibody development in this population. It is currently unknown whether this will translate into poorer long-term outcome., (Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Donor-specific anti-HLA antibodies (DSA) are common after heart transplantation and are associated with rejection, cardiac allograft vasculopathy, and mortality. A noninvasive diagnostic test for pathologic antibody-mediated rejection (pAMR) does not exist., Methods: From January 1, 2010, through August 31, 2013, 221 consecutive adult patients underwent heart transplantation and were followed through October 1, 2015. The primary objective was to determine whether the presence of DSA could detect AMR at the time of pathologic diagnosis. Secondary analyses included association of DSA (stratified by major histocompatibility complex class and de novo status) during AMR with new graft dysfunction, graft loss (mortality or retransplantation), and development of cardiac allograft vasculopathy., Results: During the study period, 69 patients (31.2%) had DSA (24% had de novo DSA), and there were 74 episodes of pAMR in 38 patients. Sensitivity of DSA at any mean fluorescence intensity to detect concurrent pAMR was only 54.3%. The presence of any DSA during pAMR increased the odds of graft dysfunction (odds ratio = 5.37; 95% confidence interval [CI], 1.34-21.47; p = 0.018), adjusting for age, sex, and timing of AMR. Circulating class II DSA after transplantation increased risk of future pAMR (hazard ratio = 2.97; 95% CI, 1.31-6.73; p = 0.009). Patients who developed de novo class II DSA had 151% increased risk of graft loss (contingent on 30-day survival) compared with patients who did not have DSA (95% CI, 1.11-5.69; p = 0.027)., Conclusions: DSA were inadequate to diagnose pAMR. Class II DSA provided prognostic information regarding future pAMR, graft dysfunction with pAMR, and graft loss., (Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: After lung transplantation, bronchial complications are one of the major concerns for surgeons and physicians. In the era of evolving immunosuppressive regimens and surgical approaches, we have reassessed risk factors for bronchial complications after lung transplantation., Methods: We undertook a retrospective study of all consecutive lung transplantations performed at a single center from 2004 to 2014. We monitored the incidence of symptomatic bronchial complications. Demographic data of donors and recipients were also studied. Our objective was to evaluate the impact of 3 subsequent immunosuppressive regimens (including the use of induction therapy), and of a technical modification of bronchial anastomosis on the incidence of airway complications., Results: We performed 270 consecutive lung transplantations during the study period. On multivariate analysis, bronchial complications were not directly associated with the different immunosuppressive regimens. In subgroup analysis, when comparing different immunosuppressive regimens, primary graft dysfunction within 72 hours (odds ratio [OR] = 2.55; p = 0.08), lung infection within the first month (OR = 2.96; p = 0.039), diabetes before transplantation (OR = 2.66; p = 0.11) and chronic obstructive pulmonary disease (OR = 2.20; p = 0.04) appeared as major risk factors (c-index = 0.77 on multivariate analysis). The use of a modified bronchial suture technique was associated with fewer bronchial complications (OR = 0.47; p = 0.059) (c-index = 0.71 on multivariate analysis)., Conclusions: The mode of immunosuppression had no influence on airway complications. We were able to reproduce the beneficial effect of a modified suture technique., (Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Achieving long-term cardiac allograft survival without continuous immunosuppression is highly desired in organ transplantation. Studies have shown that Salvia miltiorrhiza, an herb also known as danshen, improves microcirculation and is highly effective in treating coronary heart disease. Our objective is to determine whether tanshinol, an ingredient of danshen, improves cardiac allograft survival., Methods: Fully vascularized heterotopic heart transplantation was performed using BALB/c mice as donors and C57BL/6 mice as recipients, which were then treated with tanshinol and rapamycin. CD4 + FoxP3 + regulatory T cells (Tregs) were quantified by flow analyses, whereas CCL22 was measured by real-time polymerase chain reaction and Western blotting., Results: We found that tanshinol significantly delayed cardiac allograft rejection. It promoted long-term allograft survival induced by rapamycin, a mammalian target-of-rapamycin (mTOR) inhibitor. Tanshinol increased CD4 + FoxP3 + Treg numbers in cardiac allografts, but not spleens and lymph nodes, of recipient mice by enhancing chemokine CCL22 expression in cardiac allografts, especially cardiac dendritic cells. In contrast, rapamycin increased Treg numbers in both lymphoid organs and allografts, suggesting that it generally expands Tregs. Moreover, Tregs induced by rapamycin plus tanshinol were more potent in suppressing T-cell proliferation in vitro than those from untreated recipients. Neutralizing CCL22 hindered CD4 + FoxP3 + Treg migration to cardiac allografts and reversed long-term allograft survival induced by tanshinol plus rapamycin., Conclusions: Tanshinol suppresses cardiac allograft rejection by recruiting CD4 + FoxP3 + Tregs to the graft, whereas rapamycin does so via expanding the Tregs. Thus, tanshinol cooperates with rapamycin to further extend cardiac allograft survival., (Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

With organs in short supply, only a limited number of kidney transplants can be performed a year. Live donor donation accounts for 1/3rd of all kidney transplants performed in the United States. Unfortunately, not every donor recipient pair is feasible because of Human leukocyte antigen (HLA) sensitization and ABO incompatibility. To overcome these barriers to transplant, strategies such as kidney paired donation (KPD) and desensitization have been developed. KPD is the exchange of donors between at least two incompatible donor-recipient pairs such that they are now compatible. Desensitization is the removal of circulating donor specific antibodies to prevent graft rejection. Regardless of the treatment strategy, highly sensitized patients whose calculated panel reactive antibody (cPRA) is ≥95% remain difficult to transplant with match rates as low as 15% in KPD pools. Desensitization has proved to be difficult in those with high antibody titers. A novel approach is the combination of both KPD and desensitization to facilitate compatible and successful transplantation. A highly sensitized patient can be paired with a better immunological match in the KPD pool and subsequently desensitized to a lesser degree. This article reviews the current progress in KPD and desensitization and their use as a combined therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Antibody-mediated rejection has now been recognized as one of the most important causes of graft loss. Transplantation across HLA barriers and nonadherence can result in acute antibody-mediated rejection, which is associated with particularly worse graft outcomes. New technologies, including genomic studies and assays to detect and define donor-specific antibodies, have provided important insights into the pathophysiology and diagnosis of acute antibody-mediated rejection but have engendered many questions about the clinical application of these tests in the prognosis and prevention of this protean disease process. In this article, we review the pathophysiology of acute antibody-mediated rejection, the evolving diagnostic criteria, and specific challenges related to its prognosis, treatment, and prevention., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Along with death engraftment, in recent years, antibody-mediated damage has been identified as the leading cause of loss of kidney transplants. Despite the recognition of the role of the B-lymphocyte subpopulation in the development of both tolerance and rejection, little is known about the trigger mechanisms and effectors of this humoral response., Background: We analyzed the relationship between B lymphocyte subpopulations and levels of B-cell-activating factor (BAFF) with the histological findings in biopsies of renal transplantation., Material and Methods: We selected 35 patients whose kidney transplant biopsy was performed between January and November 2015. The biopsy specimens were classified according to Banff criteria. At the moment of the biopsy BAFF levels and B-lymphocyte subpopulations in blood were measured using enzyme-linked immunosorbent assay (ELISA) and using flow cytometry, respectively., Results: Mean BAFF levels were 493 ± 245 pg/mL. The median performance of biopsy post-transplantation was 12.9 (11.7-23.9) months. BAFF levels correlated with pretransplantation antibodies (r = 0.523; P = .002) but not with kidney function. In biopsies performed more than 1 year after transplantation BAFF levels correlated with the severity of chronic glomerular (cg) involvement (r = 0.625; P = .003). Histological variables related to antibody-mediated injury selected by principal component analysis (glomerulitis, peritubular capillary, and chronic glomerulopathy) related to BAFF levels (B factor, 116; 95% confidence interval [CI], 12-220; P = .029). Biopsy specimens with transplant glomerulopathy (TG) showed lower levels of circulating naive CD19 + subpopulation, IgD+, and CD27- (32.7 ± 28.1 vs 87.9 ± 79.1; P = .017) compared with biopsy specimens without TG., Conclusions: Elevated levels of BAFF are associated with increased presence and severity of TG and a set of variables related to antibody-mediated histological damage. TG is associated with changes in circulating B-lymphocyte subpopulations that could contribute to its pathogenesis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Kidney transplant (KT) is the optimal renal replacement therapy for patients with end-stage renal disease (ESRD). The demand for kidneys, however, continues to exceed the supply. To overcome this problem, efforts to extend the donor pool by including human leukocyte antigen (HLA)- and ABO-incompatible (ABOi) KTs are increasing. The aim of this article was to retrospectively review data on recipients, donor profiles, and clinical outcomes in 4000 cases of KT. In addition, we analyzed clinical outcomes in ABOi and flow-cytometric crossmatch (FCXM) positive KT in a subgroup analysis.This was a retrospective, observational study using data extracted from medical records. A total of 4000 consecutive patients who underwent KT at our institution from January 1990 to February 2015 were included in this study. KTs across immunological barriers such as ABO incompatible (276 cases, 6.9%), FCXM positive (97 cases, 2.4%), and positive complement-dependent cytotoxicity (CDC) XM KT (16 cases, 0.4%) were included.From a Kaplan-Meier analysis, overall patient survival (PS) rates after KT at 1, 5, 10, and 20 years were 96.9%, 95.1%, 92.0%, and 88.9%, respectively. The overall graft survival (GS) rates after KT at 1, 5, 10, and 20 years were 96.3%, 88.9%, 81.2%, and 67.4%, respectively. Our subgroup analysis suggested that overall PS, GS, death-censored GS, and rejection-free GS in ABOi KT showed no significant differences in comparison with ABO-compatible KT if adequate immunosuppressive treatment was performed. The overall PS rate in patients who underwent FCXM positive KT did not differ significantly from that of the control group during the 3-year follow-up (P = 0.34). The overall GS, death-censored GS, and rejection-free GS also did not differ significantly between the FCXM KT and control groups (P = 0.99, 0.42, and 88).The outcomes of KTs continually improved during the study period, while the annual number of KTs increased. ABO or FCXM positive KTs can be performed safely with successful graft outcomes.

If pig hearts could be transplanted successfully into patients with end-stage cardiac failure, the critical shortage of hearts from deceased human donors would be overcome. The several attempts at cardiac xenotransplantation carried out in the 20th century, usually with hearts from nonhuman primates (NHPs), are reviewed, as are the surgical techniques used in experimental heart transplantation in animals. For a number of reasons, the pig has been selected as the potential source of organs for clinical transplantation. The major pathobiological barriers that the pig presents, and progress in overcoming these barriers either by genetic engineering of the pig or by the administration of novel immunosuppressive agents, are described. Currently, non-life-supporting pig heterotopic heart transplantation in NHPs has extended to more than 2 years in 1 case, with life-supporting orthotopic heart transplantation of almost 2 months. Future approaches to resolve the remaining problems and the selection of patients for the initial clinical trials are briefly discussed., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

There is a critical shortage in the number of deceased human organs that become available for the purposes of clinical transplantation. This problem might be resolved by the transplantation of organs from pigs genetically engineered to protect them from the human immune response. The pathobiological barriers to successful pig organ transplantation in primates include activation of the innate and adaptive immune systems, coagulation dysregulation and inflammation. Genetic engineering of the pig as an organ source has increased the survival of the transplanted pig heart, kidney, islet and corneal graft in non-human primates (NHPs) from minutes to months or occasionally years. Genetic engineering may also contribute to any physiological barriers that might be identified, as well as to reducing the risks of transfer of a potentially infectious micro-organism with the organ. There are now an estimated 40 or more genetic alterations that have been carried out in pigs, with some pigs expressing five or six manipulations. With the new technology now available, it will become increasingly common for a pig to express even more genetic manipulations, and these could be tested in the pig-to-NHP models to assess their efficacy and benefit. It is therefore likely that clinical trials of pig kidney, heart and islet transplantation will become feasible in the near future., (Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Solid organ transplantation is the treatment of choice for patients with end-stage organ failure. To prevent rejection of the transplanted organ continuous treatment with immunosuppressive medication is needed. Immunosuppression may be harmful to the transplant recipient, increasing the risk of cancer, infections and cardiovascular disease. To improve transplant and patient survival, there is a need for an immune-modulatory regimen that is not only potent in preventing rejection of the transplanted organ, but has less side effects compared to current immunosuppressive regimens. Increasingly, transplantation research focusses on regulatory T cell (Treg) therapy to achieve this aim, in which Treg are used as a strategy to allow reduction of immunosuppression. Currently, the first clinical trials are underway investigating the safety and feasibility of Treg therapy in renal transplantation. This review gives an overview of the rationale of using Treg therapy in transplantation, previous experience with Treg therapy in humans, and the expected safety, potential efficacy and cost-effectiveness of Treg therapy in solid organ transplantation., (© 2015 Steunstichting ESOT.)

Solid-phase assays (SPA) have facilitated detection and definition of antibodies to human leukocyte antigens (HLA) and major histocompatibility complex class I chain-related antigen A (MICA). However, clinical consequences of pretransplant SPA results in heart transplantation have been studied insufficiently in the current era of immunosuppression and rejection surveillance. Pretransplant sera, panel-reactive antibodies (PRA), pretransplant crossmatch, and clinical data were retrospectively analyzed in 264 adult heart transplant recipients. The specificity of HLA and MICA antibodies and C1q-binding activity of donor-specific antibodies (DSA) were defined using SPA. Pretransplant HLA antibodies were detected in 57 (22%) individuals, in 28 individuals (11%); these antibodies were DSA after transplant. Preformed DSA and elevated peak PRA were independent predictors of pathologic AMR, which occurred in 19 individuals (7%). The increasing number of DSA and the cumulative mean fluorescence intensity of DSA were associated with AMR. C1q-binding assay was a suboptimal predictor of AMR in our cohort. Pretransplant allosensitization and MICA antibodies were related neither to impaired graft survival nor to other adverse clinical events during a median follow-up of 39 months. Identification of preformed DSA by SPA, in addition to PRA monitoring, may predict AMR in the contemporary era of heart transplantation., (© 2015 Steunstichting ESOT.)

Research reports presented at the American Transplant Congress 2015 provided an array of basic science findings of relevance to the transplant community. Among key themes is the concept that ischemia-reperfusion injury and early posttransplantation inflammation is linked to adaptive alloimmunity and transplant injury. Molecular and cellular mechanisms contributing to these interactions were highlighted. The relevance of understanding how blocking costimulation, including CD40/CD154 interactions, affects various aspects of the alloimmune response was enhanced by the description of preclinical studies demonstrating efficacy of a unique, blocking anti-CD40 monoclonal antibody that could potentially be used in humans. The identification of mechanisms underlying interactions among T cell subsets and B cells, including follicular helper T cells, regulatory T cells, effector B cells, and regulatory B cells, provides multiple previously unrecognized targets for future therapeutic interventions. Additional reports of interest include novel insights into effects of the gut microbiome on graft survival and the ability to differentiate insulin-secreting, islet-like cells from induced pluripotent stem cells. Overall, the reported basic science findings from American Transplant Congress 2015 add to the fundamental understanding of innate and adaptive alloimmunity and provide novel and testable hypotheses that have the potential to be translated into improved clinical care of transplant patients., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Chronic rejection leading to allograft loss remains a significant concern after facial allotransplantation. Chronic rejection may occur without clinical signs or symptoms. The current means of monitoring is histologic analyses of allograft biopsy specimens, which is both invasive and impractical. Prior data suggest that chronic rejection is associated with changes in intima and media thickness of vessels in arms and solid organ allografts; such data have not been published for face transplant recipients., Methods: The authors used a 48-MHz transducer to acquire images of the bilateral facial, radial, dorsalis pedis and, if applicable, sentinel flap arteries in five face transplant recipients (8 months to 4.5 years after transplantation) and five control subjects. The authors assessed the intima, media, and adventitia thickness plus lumen and the total vessel diameter and area., Results: Face transplant recipients had thicker intima in all sites compared with controls, but the ratio of the intimal thickness of facial and radial arteries was similar in face transplant recipients compared with controls (1.00 versus 0.95; p = 0.742). Intraobserver correlation showed reliable reproducibility of the measurements (r = 0.935, p ≤ 0.001). Interobserver correlation demonstrated reproducibility of intima measurements (r = 0.422, p ≤ 0.001)., Conclusion: The authors demonstrate that ultrasound biomicroscopy is feasible for postsurgical monitoring, and have developed a new benchmark parameter, the facial artery-to-radial artery intimal thickness ratio, to be used in future testing in the setting of chronic rejection., Clinical Question/level of Evidence: Diagnostic, IV.

CD40-CD154 pathway blockade prolongs renal allograft survival in nonhuman primates (NHPs). However, antibodies targeting CD154 were associated with an increased incidence of thromboembolic complications. Antibodies targeting CD40 prolong renal allograft survival in NHPs without thromboembolic events but with accompanying B cell depletion, raising the question of the relative contribution of B cell depletion to the efficacy of anti-CD40 blockade. Here, we investigated whether fully silencing Fc effector functions of an anti-CD40 antibody can still promote graft survival. The parent anti-CD40 monoclonal antibody HCD122 prolonged allograft survival in MHC-mismatched cynomolgus monkey renal allograft transplantation (52, 22, and 24 days) with accompanying B cell depletion. Fc-silencing yielded CFZ533, an antibody incapable of B cell depletion but still able to potently inhibit CD40 pathway activation. CFZ533 prolonged allograft survival and function up to a defined protocol endpoint of 98-100 days (100, 100, 100, 98, and 76 days) in the absence of B cell depletion and preservation of good histological graft morphology. CFZ533 was well-tolerated, with no evidence of thromboembolic events or CD40 pathway activation and suppressed a gene signature associated with acute rejection. Thus, use of the Fc-silent anti-CD40 antibody CFZ533 appears to be an attractive approach for preventing solid organ transplant rejection., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Innate lymphoid cells (ILC) are lymphocytes lacking rearranged antigen receptors such as those expressed by T and B cells. ILC are important effector and regulatory cells of the innate immune system, controlling lymphoid organogenesis, tissue inflammation, and homeostasis. The family of ILC consists of cytotoxic NK cells and the more recently described noncytotoxic group 1, 2, and 3 ILC. The classification of noncytotoxic ILC-in many aspects-mirrors that of T helper cells, which is based on the expression of master transcription factors and signature cytokines specific for each subset. The IL-22 producing RORγt(+) ILC3 subset was recently found to be critical in the prevention of intestinal graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (HCT) via strengthening the intestinal mucosal barrier. In this review, we summarize the current view of the immunological functions of human noncytotoxic ILC subsets and discuss the potentially beneficial features of IL-22 producing ILC3 in improving allo-HCT efficacy by attenuating susceptibility to GVHD. In addition, we explore the possibility of other ILC subsets playing a role in GVHD., (© 2015 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons.)

Background: Acute cellular rejection (ACR) is still a relevant complication after orthotopic heart transplantation. The diagnosis of ACR is based on endomyocardial biopsy (EMB). Recent advances in two-dimensional strain imaging may allow early noninvasive detection of ACR. The objective of this study was to analyze the usefulness of conventional and new echocardiographic parameters to exclude ACR after orthotopic heart transplantation., Methods: Thirty-four consecutive adult heart transplant recipients admitted to a single center between January 2010 and December 2012 for orthotopic heart transplantation were prospectively included. A total of 235 pairs of EMB and echocardiographic examination were performed. A median of seven studies per patient (interquartile range, six to eight studies per patient) were performed during the first year of follow-up. Classic echocardiographic parameters; speckle-tracking-derived left ventricular (LV) longitudinal, radial, and circumferential strain; and global and free wall right ventricular (RV) longitudinal strain were analyzed., Results: ACR was detected in 26.4% of EMB samples (n = 62); 5.1% (n = 12) required specific treatment (ACR degree ≥ 2R). Lower absolute values of global LV longitudinal strain and free wall RV longitudinal strain were present in patients with ACR degree ≥ 2R compared with those without ACR (13.7 ± 2.7% vs 17.8 ± 3.4% and 16.6 ± 3.6% vs 23.3 ± 5.2%, respectively). An average LV longitudinal strain < 15.5% had 85.7% sensitivity, 81.4% specificity, 98.8% negative predictive value, 25.0% positive predictive value, and 81.7% accuracy for the presence of ACR degree ≥ 2R. Free wall RV longitudinal strain < 17% had 85.7% sensitivity, 91.1% specificity, 98.8% negative predictive value, 42.9% positive predictive value, and 90.7% accuracy for ACR degree ≥ 2R. Both variables were normal in 106 echocardiograms (57.6%); none of these patients presented with ACR degree ≥ 2R., Conclusions: The combination of two new echocardiographic measures, global LV and RV free wall longitudinal strain, may be able to identify a group of heart transplant patients who are unlikely to have ACR. If these findings are confirmed independently, it may be possible to use LV and RV strain measures as reliable tools to exclude ACR and to reduce the burden of repeated EMB., (Copyright © 2015 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Liver tolerance was initially recognized by the spontaneous acceptance of liver allografts in many species. The underlying mechanisms are not completely understood. However, liver transplant (LT) tolerance absolutely requires interferon (IFN)-γ, a rejection-associated inflammatory cytokine. In this study, we investigated the rejection of liver allografts deficient in the IFN-γ receptor and reveal that the liver graft is equipped with machineries capable of counterattacking the host immune response through a mesenchyme-mediated immune control (MMIC) mechanism. MMIC is triggered by T effector (Tef) cell-derived IFN-γ that drives expression of B7-H1 on graft mesenchymal cells leading to Tef cell apoptosis. We describe the negative feedback loop between graft mesenchymal and Tef cells that ultimately results in LT tolerance. Comparable elevations of T-regulatory cells and myeloid-derived suppressor cells were observed in both rejection and tolerance groups and were not dependent on IFN-γ stimulation, suggesting a critical role of Tef cell elimination in tolerance induction. We identify potent MMIC activity in hepatic stellate cells and liver sinusoidal endothelial cells. MMIC is unlikely exclusive to the liver, given that spontaneous acceptance of kidney allografts has been reported, although less commonly, probably reflecting variance in MMIC activity., Conclusion: MMIC may represent an important homeostatic mechanism that supports peripheral tolerance and could be a target for the prevention and treatment of transplant rejection. This study highlights that the graft is an active participant in the equipoise between tolerance and rejection and warrants more attention in the search for tolerance biomarkers., (© 2015 by the American Association for the Study of Liver Diseases.)

Dendritic cells (DCs) are a family of antigen presenting cells that play a paramount role in bridging innate and adaptive immunity. In murine models several subtypes of DCs have been identified, including classical DCs, monocyte-derived DCs, and plasmacytoid DCs. Quiescent, immature DCs and some subtypes of plasmacytoid cells favor the expression of regulatory T cells, but in an inflammatory milieu DCs become mature and after intercepting the antigen migrate to lymphatic system where they present the antigen to naïve T cells. Transplant rejection largely depends on the phenotype and maturation of DCs. The ischemia-reperfusion injury causes the release of endogenous molecules that are recognized as danger signals by the pattern recognition receptor of the innate immunity with subsequent activation of inflammatory cells and mediators. In this environment DCs become mature and migrate to lymphonodes where they present the alloantigen to T cells and direct their differentiation towards Th1 and Th17 effector cells. On the other hand, manipulation of DCs may favor T cell differentiation towards tolerant Th2 and T regulators (Treg). Experimental studies in murine models showed the possibility of inducing an operational tolerance by injecting immature tolerogenic DCs. Recently, such a possibility has been also confirmed in primates. Although manipulation of DCs may represent an important step ahead in kidney transplantation, a number of technical and ethical issues should be solved before its clinical application., (Copyright © 2015 Elsevier Inc. All rights reserved.)

HLA antigens are polymorphic proteins expressed on donor kidney allograft endothelium and are critical targets for recipient immune recognition. HLA antibodies are risk factors for acute and chronic rejection and allograft loss. Solid-phase immunoassays for HLA antibody detection represent a major advance in sensitivity and specificity over cell-based methods and are widely used in organ allocation and pretransplant risk assessment. Post-transplant, development of de novo donor-specific HLA antibodies and/or increase in donor-specific antibodies from pretransplant levels are associated with adverse outcomes. Although single antigen bead assays have allowed sensitive detection of recipient HLA antibodies and their specificities, a number of interpretive considerations must be appreciated to understand test results in clinical and research contexts. This review, which is especially relevant for clinicians caring for transplant patients, discusses the technical aspects of single antigen bead assays, emphasizes their quantitative limitations, and explores the utility of HLA antibody testing in identifying and managing important pre- and post-transplant clinical outcomes., (Copyright © 2015 by the American Society of Nephrology.)

A joint meeting organized by the European (ESOT) and The Transplantation (TTS) Societies for basic science research was organized in Paris, France, on November 7-9, 2013. Focused on new ideas and concepts in translational transplantation, the meeting served as a venue for state-of-the-art developments in basic transplantation immunology, such as the potential for tolerance induction through regulation of T-cell signaling. This meeting report summarizes important insights which were presented in Paris. It not only offers an overview of established aspects, such as the role of Tregs in transplantation, presented by Nobel laureate Rolf Zinkernagel, but also highlights novel facets in the field of transplantation, that is cell-therapy-based immunosuppression or composite tissue transplantation as presented by the emotional story given by Vasyly Rohovyy, who received two hand transplants. The ESOT/TTS joint meeting was an overall productive and enjoyable platform for basic science research in translational transplantation and fulfilled all expectations by giving a promising outlook for the future of research in the field of immunological transplantation research., (© 2014 Steunstichting ESOT.)

One of the main concerns associated with renal transplantation in HIV-infected patients is the high risk of acute rejection, which makes physicians reluctant to use steroid-free immunosuppressive therapy in this subset of patients. However, steroid therapy increases cardiovascular morbidity and mortality. The aim of this study was to define the efficacy of a steroid-sparing regimen in HIV-infected renal transplant recipients. Thirteen HIV-infected patients were consecutively transplanted. The induction therapy consisted of basiliximab and methylprednisolone for 5 days followed by a calcineurin inhibitor plus mycophenolate acid. The mean follow-up was 50 ± 22 months. Eight patients (61.5%) experienced acute rejection, and 75% of the first episodes occurred within 2 months after transplantation. The probability of first acute rejection was 58% after 1 year and 69% after 4 years. Seven of eight patients recovered or maintained their kidney function after antirejection therapy and steroid resumption. At the last follow-up, seven of 13 patients (54%) had resumed steroid therapy. The 4-year patient and graft survivals were 100% and 88.9%, respectively. The benefits of this steroid-free regimen in HIV-infected renal recipients must be reconsidered because of the high rate of acute rejection. New immunosuppressive steroid-free strategies should be identi-fied in this set of patients., (© 2014 Steunstichting ESOT.)

New nucleos(t)ide agents (NAs) [entecavir (ETV) and tenofovir (TDF)] have made hepatitis B immunoglobulin (HBIG)-sparing protocols an attractive approach against hepatitis B virus (HBV) recurrence after liver transplantation (LT). Twenty-eight patients transplanted for HBV cirrhosis in our centre were prospectively evaluated. After LT, each patient received HBIG (1000 IU IM/day for 7 days and then monthly for 6 months) plus ETV or TDF and then continued with ETV or TDF monoprophylaxis. All patients had undetectable HBV DNA at the time of LT, and they were followed up with laboratory tests including glomerular filtration rate (GFR) after LT. All patients (11 under ETV and 17 under TDF) remained HBsAg/HBV DNA negative during the follow-up period [median: 21 (range 9-43) months]. GFR was not different between TDF and ETV groups of patients at 6 and 12 months and last follow-up (P value >0.05 for all comparisons). The two groups of patients were similar regarding their ratio of maximum rate of tubular phosphate reabsorption to the GFR (TmP/GFR). In conclusion, in this prospective study, we showed for the first time that maintenance therapy with ETV or TDF monoprophylaxis after 6 months of low-dose HBIG plus ETV or TDF after LT is highly effective and safe., (© 2014 Steunstichting ESOT.)

Appropriate recipient selection of simultaneous liver/kidney transplantation (SLKT) remains controversial. In particular, data on liver graft survival in hepatitis C virus-infected (HCV+) SLKT recipients are lacking. We conducted a single-center, retrospective study of HCV+ SLKT recipients (N = 25) in comparison with HCV- SLKT (N = 26) and HCV+ liver transplantation alone (LTA, N = 296). Despite backgrounds of HCV+ and HCV- SLKT being similar, HCV+ SLKT demonstrated significantly impaired 5-year liver graft survival of 35% (HCV- SLKT, 79%, P = 0.004). Compared with HCV+ LTA, induction immunosuppression was more frequently used in HCV+ SLKT. Five-year liver graft survival rate for HCV+ SLKT was significantly lower than that for LTA (35% vs. 74%, respectively, P < 0.001). Adjusted hazard ratio of liver graft loss in HCV+ SLKT was 4.9 (95% confidence interval 2.0-12.1, P = 0.001). HCV+ SLKT recipients were more likely to succumb to recurrent HCV and sepsis compared with LTA (32% vs. 8.8%, P < 0.001 and 24% vs. 8.8%, P = 0.030, respectively). Ten HCV+ SLKT recipients underwent anti-HCV therapy for recurrent HCV; only 1 achieved sustained virological response. HCV+ SLKT is associated with significantly decreased long-term prognosis compared with HCV- SLKT and HCV+ LTA., (© 2014 Steunstichting ESOT.)

There has been significant progress in the field of heart transplantation over the last 45 years. The 1-yr survival rates following heart transplantation have improved from 30% in the 1970s to almost 90% in the 2000s. However, there has been little change in long-term outcomes. This is mainly due to chronic rejection, malignancy, and the detrimental side effects of chronic immunosuppression. In addition, over the last decade, new challenges have arisen such as increasingly complicated recipients and antibody-mediated rejection. Most, if not all, of these obstacles to long-term survival could be prevented or ameliorated by the induction of transplant tolerance wherein the recipient's immune system is persuaded not to mount a damaging immune response against donor antigens, thus eliminating the need for chronic immunosuppression. However, the heart, as opposed to other allografts like kidneys, appears to be a tolerance-resistant organ. Understanding why organs like kidneys and livers are prone to tolerance induction, whereas others like hearts and lungs are tolerance-resistant, could aid in our attempts to achieve long-term, immunosuppression-free survival in human heart transplant recipients. It could also advance the field of pig-to-human xenotransplantation, which, if successful, would eliminate the organ shortage problem. Of course, there are alternative futures to the field of heart transplantation that may include the application of total mechanical support, stem cells, or bioengineered whole organs. Which modality will be the first to reach the ultimate goal of achieving unlimited, long-term, circulatory support with minimal risk to longevity or lifestyle is unknown, but significant progress in being made in each of these areas.

In 1998, the first successful total laryngeal transplant was performed. Outstanding voice quality and swallowing function were achieved, and over the subsequent 14 years, much was learned about tolerance of a transplanted larynx. After approximately a decade, a slowly progressive, chronic rejection process gradually rendered the organ nonfunctional, and the patient and his providers deemed him appropriate for explantation. This is a report of the clinical indications and outcome surrounding the explantation of the first successful total laryngeal transplant.

Vascularized composite allotransplantation (VCA) is a novel therapeutic option for treatment of patients suffering from limb loss or severe facial disfigurement. To date, 72 hand and 19 facial transplantations have been performed worldwide. VCA in hand and facial transplantation is a complex procedure requiring a multidisciplinary team approach and extensive surgical planning. Despite good functional outcome, courses after hand and facial transplantation have been complicated by skin rejection. Long-term immunosuppression remains a necessity in VCA for allograft survival. To widen the scope of these quality-of-life-improving procedures, minimization of immunosuppression to limit risks and side effects is needed.

Today human leukocyte antigen-haploidentical transplantation is a feasible option for patients with high-risk acute leukemia who do not have matched donors. Whether it is T-cell replete or T-cell depleted, it is still, however, associated with issues of transplant-related mortality and posttransplant leukemia relapse. After reports that adoptive immunotherapy with T-regulatory cells controls the alloreactivity of conventional T lymphocytes in animal models, tomorrow's world of haploidentical transplantation will focus on new "designed" grafts. They will contain an appropriate ratio of conventional T lymphocytes and T-regulatory cells, natural killer cells, γ δ T cells, and other accessory cells. Preliminary results of ongoing clinical trials show the approach is feasible. It is associated with better immune reconstitution and a quite powerful graft-versus-leukemia effect with a low incidence of graft-versus-host disease and no need for posttransplant pharmacological prophylaxis. Future strategies will focus on enhancing the clinical benefit of T-regulatory cells by increasing their number and strengthening their function.

The first hand allograft transplantation was performed in 1998 by a French surgeons team and has opened the era of functional allotransfers. In France, the authorized preliminary study included five patients who sustained traumatic amputation of both hands. All patients had bilateral hand allograft transplantation. Long-term results (follow-up ranging from 3 to 12 years) undoubtedly show a useful daily function, a good psychological acceptance and a physiological integration. Despite several obstacles as the need of immunosuppressive therapy for life, hand allograft transplantation is worthy of interest in some outstanding situations., (Copyright © 2013. Published by Elsevier Masson SAS.)

Seminal studies in rabbits and rodent transplantation models by Peter Medawar revealed that cellular processes, rather than humoral antibodies, are central to the acute rejection of transplanted organs, and much of basic transplantation research continues to be focused on the biology and control of these cells, which were subsequently shown to be T cells. However, the success of current immunosuppression at controlling T-cell-mediated rejection has resulted in an increasing awareness of antibody-mediated rejection in the clinic. This, in turn, has fueled an emerging interest in the biology of allospecific antibodies, the B cells that produce these antibodies, and the development of mouse models that allow their investigation. Here we summarize some of the more widely used mouse models that have been developed to study the immunobiology of alloreactivity, transplantation rejection and tolerance, and used to identify therapeutic strategies that modulate these events.

A number of classical pharmacokinetic studies have been conducted in transplant patients. However, they suffer from some limitations, for example, (1) the study design was limited to intense blood sampling in small groups of patients during a certain posttransplant period, (2) patient factors were evaluated one at a time to identify their association with the pharmacokinetic parameters, and (3) mean pharmacokinetic parameters often cannot be precisely estimated due to large intraindividual variability. Population pharmacokinetics provides a potential means of addressing these limitations and is a powerful tool to evaluate the magnitude and consistency of drug exposure. Population pharmacokinetic studies of cyclosporine focused solely on developing limited sampling strategies and Bayesian estimators to estimate drug exposure, have been summarized before, and are, therefore, not a subject of this review. The major focus of this review is to describe factors (demographic factors, hepatic and gastrointestinal functions, drug-drug interactions, genetic polymorphisms of drug metabolizing enzymes and transporters) that have been identified to contribute to the large portion of observed variability in the pharmacokinetics of cyclosporine in transplant patients. This review summarizes and interprets the conclusions as well as the nonlinear mixed-effects modeling methodologies used in such studies. A highly diversified collection of structural models, variability models, and covariate submodels have been evaluated and validated using internal or external validation methods. This review also highlights areas where additional research is warranted to improve the models since a portion of model variability still remains unexplained.