Clinical relevance of GSTT1 mismatch in solid organ and hematopoietic stem cell transplantation

Since 2001, year in which Glutathione S-transferase theta class 1 (GSTT1) gene appeared to be related to the occurrence of de novo immune hepatitis after liver transplantation, this gene with two allelic variants, GSTT1^∗A (wild type copy) and GSTT1^∗0 (deletion copy), has emerged as a potent histocompatibility antigen. Namely, a donor-recipient liver graft combination of a GSTT1-negative recipient (homozygous for GSTT1^∗0) and a GSTT1-positive donor results, very frequently, in the appearance of a severe immune-related graft hepatitis with production of IgG anti-GSTT1 antibodies. In kidney transplantation, GSTT1 donor-recipient mismatch is also associated with production of anti-GSTT1 antibodies and antibody-related rejection episodes with C4d deposition in graft biopsy. The more recent discovery of anti-GSTT1 antibodies in hematopoietic stem cell transplantation, clearly confirms a role of GSTT1 as histocompatibility antigen in this setting. Interestingly, the consequences of GSTT1 mismatch might be either rejection or graft-versus-host disease, depending on the GSTT1 mismatch’s sense of direction. The involvement of GSTT1 in immunological allo-recognition is unquestionable although there are still many aspects that remain to be explored.     

Clinical relevance of lung-restricted antibodies in lung transplantation

Lung transplant is a definitive treatment for several end-stage lung diseases. However, the high incidence of allograft rejection limits the overall survival following lung transplantation. Traditionally, alloimmunity directed against human leukocyte antigens (HLA) has been implicated in transplant rejection. Recently, the clinical impact of non-HLA lung-restricted antibodies (LRA) has been recognized and extensive research has demonstrated that they may play a dominant role in the development of lung allograft rejection. The immunogenic lung-restricted antigens that have been identified include amongst others, collagen type I, collagen type V, and k-alpha 1 tubulin. Pre-existing antibodies against these lung-restricted antigens are prevalent in patients undergoing lung transplantation and have emerged as one of the predominant risk factors for primary graft dysfunction which limits short-term survival following lung transplantation. Additionally, LRA have been shown to predispose to chronic lung allograft rejection, the predominant cause of poor long-term survival. This review will discuss ongoing research into the mechanisms of development of LRA as well as the pathogenesis of associated lung allograft injury.     

Role of angiotensin II type 1 receptor-activating antibodies in solid organ transplantation

Angiotensin type I receptor (AT₁R) mediates physiologic and pathophysiologic actions of its ligand, angiotensin II. Overactivity of the AT₁R and angiotensin II interaction results in hypertension and vascular remodeling. Antibodies to AT₁R have been implicated in several vascular pathologies. In renal transplantation, elevated levels of anti-AT₁R antibodies have been associated with antibody mediated rejection (AMR) in the absence of donor HLA specific antibodies. In heart transplantation, increased levels of anti-AT₁R antibodies have been associated with cellular and AMR as well as an early onset of microvasculopathy. This review summarizes the current investigations regarding the impact of anti-AT₁R antibodies in solid organ transplantation and provides insight into the humoral response in the presence of non-HLA and HLA specific antibodies.     

Regulation of immunity and inflammation by intravenous immunoglobulin: relevance to solid organ transplantation

Intravenous immunoglobulin (IVIg) products are derived from pooled human plasma from thousands of donors and have been used for the treatment of primary immunodeficiency disorders for more than 30 years. IVIg products are also effective in the treatment of autoimmune and inflammatory disorders, however, the precise mechanism(s) of action are not known. Recent data suggest that IVIg has a much broader ability to regulate cellular immunity, including innate and adaptive components. IVIg-induced upregulation of Fcγ receptor IIB on B cells appears to be an important mode of action in suppression of antigen-presenting cell activity and antibody production. IVIg is also a recently recognized modifier of complement activation and injury. Analysis of clinical studies examining the use of IVIg in desensitization protocols and for treatment of antibody-mediated rejection in transplant recipients are supportive. Here, we discuss these important advancements and their relevance to transplant medicine.     

Indirect allorecognition in solid organ transplantation

Recipient T cell recognition of donor major histocompatibility complex (MHC) alloantigens plays a central role in both acute and chronic rejection of human organ allografts. Two different pathways of T cell recognition of donor MHC alloantigens have been described. The direct pathway involves T cell recognition of intact MHC molecules expressed by donor antigen-presenting cells (APCs). The second, or indirect pathway, operates via T helper cell recognition of peptides derived from the processing and presentation of allogeneic MHC molecules on self-APCs. At the onset of primary acute rejection, recipient CD4+ T cell responses to donor HLA-DR alloantigens are limited to a single dominant determinant present on one of the disparate alloantigens and restricted by one of the responder's HLA-DR molecules. In allograft recipients with recurring episodes of rejection, and/or at the onset of chronic rejection, recipient T cell reactivity may spread to other epitopes within the allogeneic MHC molecule, as well as to other alloantigens expressed by graft tissue. Both quantitative and qualitative alterations in T cell allopeptide reactivity are associated with increased risk of cellular and/or humoral rejection. These studies provide a basis for the design of new therapeutic strategies and for immunologic monitoring of transplant recipients.     

Impact and production of Non‐HLA‐specific antibodies in solid organ transplantation

Organ transplantation is an effective way to treat end‐stage organ disease. Extending the graft survival is one of the major goals in the modern era of organ transplantation. However, long‐term graft survival has not significantly improved in recent years despite the improvement of patient management and advancement of immunosuppression regimen. Antibody‐mediated rejection is a major obstacle for long‐term graft survival. Donor human leucocyte antigen (HLA)‐specific antibodies were initially identified as a major cause for antibody‐mediated rejection. Recently, with the development of solid‐phase‐based assay reagents, the contribution of non‐HLA antibodies in organ transplantation starts to be appreciated. Here, we review the role of most studied non‐HLA antibodies, including angiotensin II type 1 receptor (AT₁R), K‐α‐tubulin and vimentin antibodies, in the solid organ transplant, and discuss the possible mechanism by which these antibodies are stimulated.     

HLA and Kaposi's sarcoma in solid organ transplantation

Of 188 cases of Kaposi's sarcoma arising de novo after transplantation, HLA-A, -B typing was available for 135 and HLA-DR typing available for 67. Compared to the reported HLA phenotype frequencies of renal transplant recipients in the Southeast Organ Procurement Foundation (SEOPF), there is a significantly decreased frequency of HLA-A1 and HLA-B7, and increased frequency of HLA-B5, -B8, -B18, and -DR5. The most striking characteristic of the Kaposi's sarcoma group was its ethnic background. Fifty-six percent of patients were Italian, Greek, Jewish, or Arabic. When this ethnic background is considered, the expected HLA phenotype frequencies are almost exactly the same as in the Kaposi's sarcoma population. The quality of donor-recipient HLA match was evaluable for 106 patients. Only 22% had four or more mismatches, and 59% had at least two antigens matched. This argues against poor donor-recipient matching as a risk factor for developing Kaposi's sarcoma after transplantation.     

Innate immune receptors in solid organ transplantation

The discovery of Pattern Recognition Receptors (PRRs) followed by that of their role in the early detection of pathogens and the ignition of the innate immune response has been a formidable progress for immunological research in the past 15 years. This has massively fueled investigations aiming at developing better strategies to fight off infectious diseases and/or to prevent their occurrence. However, infected individuals are for most part outliers in a given population and therefore, the primary function of these receptors should be considered in pathogen-free conditions. Our current understanding indicates that an important physiological function of PRRs resides in their capacity to maintain epithelial homeostasis in response to colonizing commensals. In addition, endogenous host-derived ligands, expressed under stressed, albeit sterile, conditions (called DAMPs for Danger-Associated Molecular Patterns) are also able to trigger PRR signaling. Solid organ transplantation represents a unique situation where both contributions of PRRs signaling can be studied. Indeed, dysbiosis (either caused by antibiotherapy preceding organ transplantation or simply due to the microbiota differences between the transplanted organ and the recipient host) is a characteristic feature of this situation, which is also marked by a massive synthesis and liberation of DAMPs as a result of hypoxia/reperfusion injury. Therefore, in the transplanted organ, at least two compartments (epithelial and that composed of immune cells) participate in graft rejection/acceptance depending on the activation status of expressed PRRs.     

Invasive mycosis in solid organ transplantation]

Invasive mycosis in solid organ transplantation is mainly caused by Candida and Aspergillus, and its risk is higher in small bowel, liver, pancreas, and lung transplantation. Although limited analyses propose not a few risk factors for invasive mycosis in respective transplanted organs, the efficacy of prophylactic use of antifungal agents or preemptive treatments based on the information is not fully supported by prospective randomized controlled clinical data. The final guideline should be helpful for tailor-made evidence-based management based on the stratification of patients by pretransplant, surgical, immunosuppressive and organ specific characteristics. The process of repeated proposals and verification in a large number of patients is necessary.     

源自供者实体器官移植的受者感染

背景：目前,器官移植受者所面临的最大危险来自移植后感染。随着实体器官移植的广泛开展,器官来源严重短缺,大量边缘供者器官被采用,通过移植过程将供者的感染性疾病传播给受者的病例时有报道,其中包括一些罕见疾病的传播。2009年美国传染性疾病咨询委员会提出包括肿瘤在内的源自供者的传染性疾病的等级评判标准,为源自供者的受者感染性疾病的诊断提供了统一的标准。 目的：综述国内外关于源自供者的实体器官移植受者感染性事件的研究概况。 方法：应用计算机检索PubMed数据库、中国生物医学文献数据库、CNKI数据库及万方数据库2000-01/2010-01有关源自供者的实体器官移植受者感染性事件的文章,英文检索词为“transmission, organ transplantation”。中文检索词为“器官移植,供者,传染”。同时根据所获得的文献进行引文检索并对部分疾病进行补充检索。排除组织移植、不切题、重复或陈旧性文献。 结果与结论：共保留48篇文献进一步分析。近10年来,源自供者的实体器官移植受者感染性事件的报道涉及细菌、病毒以及寄生虫传染,但绝大部分为罕见疾病的报道。源自供者的受者感染性事件的发生,无疑对目前广泛适用的供者筛查标准提出了挑战,但其毕竟只是小概率事件,并不影响器官移植的开展。     

Graft microvascular disease in solid organ transplantation

Alloimmune inflammation damages the microvasculature of solid organ transplants during acute rejection. Although immunosuppressive drugs diminish the inflammatory response, they do not directly promote vascular repair. Repetitive microvascular injury with insufficient regeneration results in prolonged tissue hypoxia and fibrotic remodeling. While clinical studies show that a loss of the microvascular circulation precedes and may act as an initiating factor for the development of chronic rejection, preclinical studies demonstrate that improved microvascular perfusion during acute rejection delays and attenuates tissue fibrosis. Therefore, preservation of a functional microvasculature may represent an effective therapeutic strategy for preventing chronic rejection. Here, we review recent advances in our understanding of the role of the microvasculature in the long-term survival of transplanted solid organs. We also highlight microvessel-centered therapeutic strategies for prolonging the survival of solid organ transplants.     

Fungal infections in solid organ transplantation.

Fungal infections in solid organ transplant recipients continue to be a significant cause of morbidity and mortality. Candida spp. and Aspergillus spp. account for most invasive fungal infections. The incidence of fungal infection varies with type of solid organ transplant. Liver transplant recipients have highest reported incidence of candida infections while lung transplant recipients have highest rate of Aspergillus infections. Recent epidemiological studies suggest the emergence of resistant strains of candida as well as mycelial fungi other than Aspergillus in these patients. The current review incorporates the recent changes in the epidemiology of fungal infections in solid organ transplant recipients and highlights the newer data on the diagnosis, prophylaxis and treatment of fungal infections in these patients.     

The anatomic pathologist and solid organ transplantation

Pathologists continue to play important roles in the management of solid organ allografts. These organs experience the same diseases in the corresponding non-transplant organs, but the added context of immunosuppression and alloimmunity introduces several unique factors that the pathologist has to take into context while evaluating biopsies from this group of patients. This introduction to the current miniseries highlights these special considerations and discusses the factors that differentiate transplant biopsy from other scenarios, with a view to emphasizing their importance as they enhance the pathologist's ability to obtain and provide optimum information from allograft biopsies.     

Clinical relevance of antiprothrombin antibodies

Antiprotrombin antibodies belong to the family of antiphospholipid antibodies (aPLs). The clinical relevance of antiprothrombin antibodies has not been established and it depends on the applied detection method. Antibodies against phosphatidylserine-prothrombin complex (aPS/PT) are closely associated with clinical features of antiphospholipid syndrome (APS) and lupus anticoagulant rather than antibodies against prothrombin alone. The determination of aPS/PT in routine clinical practice should be done in conjunction with other aPLs detection to improve the likelihood of recognising the APS, which would ultimately facilitate the management of the disease.     

Humoral immunity and antibody-mediated rejection in solid organ transplantation

The humoral arm of the immune system provides robust protection against extracellular pathogens via the production of antibody molecules that neutralize or facilitate the destruction of microorganisms. However, the humoral immune system also provides a significant barrier to solid organ transplantation due to the antibody-mediated recognition of non-self proteins and carbohydrates expressed on transplanted organs. Historically, the presence of donor-specific antibodies (DSA) that recognize donor HLA molecules, incompatible ABO blood group antigens and other endothelial or xenogeneic antigens was considered a contraindication to transplantation. However, recent advances in antibody testing and immunosuppressive therapies have made it possible to cross certain antibody barriers successfully. In this article, we review our current understanding of antibody-mediated processes in solid organ transplantation and discuss the clinically available treatment options for preventing and treating antibody-mediated rejection.     

Multidrug-resistant Enterobacterales infections in abdominal solid organ transplantation

BackgroundTransplant recipients are highly susceptible to multidrug-resistant (MDR) related infections. The lack of early appropriate antimicrobial treatment may contribute to the high mortality due to MDR-related infections in transplant recipients especially in case of metallo-β-lactamases.ObjectivesIn this review, we present the current state of knowledge concerning multidrug-resistant Gram negative bacilli's risk management in the care of solid-organ transplant recipients and suggest control strategies.SourcesWe searched for studies treating MDR g-negative bacilli related infections in the renal and hepatic transplant patient population. We included randomized and observational studies.ContentSolid-organ transplant is the best therapeutic option for patients diagnosed with end-stage organ disease. While the incidence of opportunistic infections is decreasing due to better prevention, the burden of “classical” infections related to MDR bacteria especially related to Gram-negative bacteria is constantly increasing.Over the last two decades, various MDR pathogens have emerged as a relevant cause of infection in this specific population associated with significant mortality. Several factors related to the management of transplant donor candidates and recipients increase the risk of MDR infections in transplant recipients. The awareness of this high susceptibility of transplant recipients to MDR-related infections challenges the choice of empirical therapy, while its appropriateness can only be validated a posteriori. Indeed, the lack of early appropriate antimicrobial treatment may contribute to the high mortality due to MDR-related infections in transplant recipients especially in case of metallo-β-lactamases.ImplicationsMultidrug-resistant Gram-negative bacteria are associated with high morbidity and mortality in solid organ transplant recipients. It seems important to identify patients at risk of colonization/MDR bacteria to evaluate strategies to limit the risk of secondary infections and to minimize the inappropriate use of broad-spectrum antibiotics.