In vivo imaging of immune rejection in transplanted pancreatic islets

As islet transplantation becomes an acceptable clinical modality for restoring normoglycemia in type 1 diabetic patients, there is a crucial need for noninvasive assessment of the fate of the grafts. In spite of the success of the Edmonton Protocol, a significant graft loss occurs due to immunological and nonimmunological events immediately after transplantation. Allogeneic rejection in graft recipients is one of the major reasons for islet death and graft failure. Therefore, monitoring the islet rejection using reliable noninvasive methods would significantly aid in clinical assessment of graft success. We have previously developed a method to detect transplanted islets noninvasively using magnetic resonance imaging (MRI). For this procedure, human pancreatic islets are labeled with an MRI contrast agent that enables their visualization on magnetic resonance images. In our present study, we not only detected labeled human islets in a preclinical intrahepatic model of human islet transplantation in mice but also showed that islet rejection can be monitored noninvasively and repeatedly in real time by MRI. In addition, in this study, we have adapted, for islet cell labeling, a Food and Drug Administration-approved commercially available contrast agent, Feridex, that is used clinically for liver imaging. We believe that this agent, in combination with our preclinical model of islet transplantation, will facilitate the transition of imaging immune rejection to clinical trials.     

In Vivo Molecular Imaging Characterizes Pulmonary Gene Expression During Experimental Lung Transplantation

Experimental gene therapy is a promising strategy to prevent ischemia-reperfusion (I/R) injury and allograft rejection after lung transplantation, and methods will eventually be needed to characterize pulmonary transgene expression in vivo in humans. Therefore, we studied positron emission tomography (PET) as a means of performing in vivo molecular imaging in rodent models of lung transplantation. Rats were transfected endotracheally with adenovirus encoding a fusion gene of a mutant Herpes simplex virus-1 thymidine kinase and the green fluorescent protein gene (the former serving as an imaging reporter gene). Twenty-four hours after transfection, lungs were transplanted in groups representing normal transplantation, I/R injury and acute allograft rejection. Imaging was obtained either 24 h after transplantation to study reperfusion injury or 4 days after transplantation to study graft rejection. After imaging, lungs were excised and analyzed for thymidine kinase activity. Imaging detected transgene expression in transplanted lungs even in the presence of acute rejection or I/R injury. The PET imaging signal correlated with in vitro lung tissue assays of thymidine kinase activity (r(2) = 0.534). Thus, noninvasive molecular imaging with PET is a feasible, sensitive and quantitative method for characterizing pulmonary transgene expression in experimental lung transplantation.     

Molecular imaging using labeled donor tissues reveals patterns of engraftment, rejection, and survival in transplantation

Tissue regeneration and transplantation of solid organs involve complex processes that can only be studied in the context of the living organism, and methods of analyzing these processes in vivo are essential for development of effective transplantation and regeneration procedures. We utilized in vivo bioluminescence imaging (BLI) to noninvasively visualize engraftment, survival, and rejection of transplanted tissues from a transgenic donor mouse that constitutively expresses luciferase. Dynamic early events of hematopoietic reconstitution were accessible and engraftment from as few as 200 transplanted whole bone marrow (BM) cells resulted in bioluminescent foci in lethally irradiated, syngeneic recipients. The transplantation of autologous pancreatic Langerhans islets and of allogeneic heart revealed the tempo of transplant degeneration or immune rejection over time. This imaging approach is sensitive and reproducible, permits study of the dynamic range of the entire process of transplantation, and will greatly enhance studies across various disciplines involving transplantation.     

Cytomegalovirus infection after organ transplantation: an update with special emphasis on renal transplantation

Abstract. Cytomegalovirus infections are still the most important infectious complications after organ transplantation. Besides historical notes this review will deal with new aspects concerning the epidemiology of the CMV, diagnostic modalities of CMV infection, the delicate counterbalance between the immune system and the CMV, as well as the symptomatology of this infection. Furthermore, aspects like prophylaxis and new, promising therapeutic regimes for treatment of infection will be dealt with. Although this update is applicable for all types of solid organ transplantation, emphasis will be on renal transplantation.     

Cytomegalovirus infection after organ transplantation: an update with special emphasis on renal transplantation

Cytomegalovirus infections are still the most important infectious complications after organ transplantation. Besides historical notes this review will deal with new aspects concerning the epidemiology of the CMV, diagnostic modalities of CMV infection, the delicate counterbalance between the immune system and the CMV, as well as the symptomatology of this infection. Furthermore, aspects like prophylaxis and new, promising therapeutic regimes for treatment of infection will be dealt with. Although this update is applicable for all types of solid organ transplantation, emphasis will be on renal transplantation.     

Pharmacokinetic Principles of Immunosuppressive Drugs

A basic tenet of clinical pharmacology is that the pharmacologic activity of an exogenously administered agent is related to the free drug concentration available at its receptor or ligand-binding site. The discipline of pharmacokinetics can be defined as the study of the processes that lead to the availability of an agent to its site of action. In this review we will discuss basic principles of pharmacokinetics that govern the absorption, distribution, metabolism, elimination and binding of immunosuppressive drugs commonly utilized in whole organ transplantation. In a discipline such as organ transplantation, where the agents utilized carry significant toxicity and where failure of efficacy can have dire consequences, knowledge of the pharmacokinetics of the agents utilized has become a basic skill for all transplant professionals. In this review we describe some of the underlying principles that govern the disposition of the agents commonly utilized in solid organ transplantation. In addition, we hope this review will help in understanding some of the basic drug interactions encountered in transplant practice.     

Multiphoton Intravital Microscopy of the Transplanted Mouse Kidney

Graft outcomes after kidney transplantation continue to be adversely affected by ischemia‐reperfusion injury and rejection. High‐resolution, real‐time imaging of the transplanted kidney could shed valuable insights into these dynamic processes, but such methodology has not been established. Here we describe a technique for intravital imaging of the transplanted mouse kidney using multiphoton fluorescence microscopy. The technique enabled real‐time, high‐resolution imaging and quantitation of renal filtration, cell death, leukocyte adhesion and capillary blood flow after transplantation. Using this technique, we found that brief graft ischemia associated with the transplantation procedure led to a rapid decline in renal filtration accompanied by a significant increase in microvascular leakage and renal tubular epithelial cell death within the first 3 h after transplantation. No significant changes in leukocyte adhesion or capillary blood flow were observed during the same time period. This report establishes multiphoton fluorescence microscopy as a sensitive tool for simultaneously studying functional and structural perturbations that occur in the mouse kidney after transplantation and for investigating the migration of leukocytes to the graft.     

成人活体肝移植术后肝静脉狭窄的诊断与介入治疗:2例报道并文献复习

肝静脉狭窄是肝移植术后的一种严重并发症,在活体肝移植术后发生率较高。本文通过回顾性分析2例成人活体肝移植术后肝静脉狭窄患者的相关资料,结合国内外相关文献,探讨肝移植术后肝静脉狭窄的诊断方法及介入治疗效果。经皮肝静脉造影术可确诊肝静脉流出道梗阻,经皮经肝球囊、支架成形术是治疗活体肝移植术后早期肝静脉狭窄的一种安全、简便、有效的方法。     

Utility of Intravenous Immune Globulin in Kidney Transplantation: Efficacy, Safety, and Cost Implications

Intravenous immunoglobulin preparations (IVIG) are known to be effective in the treatment of various autoimmune and inflammatory disorders into their immunomodulatory, immunoregulatory, and anti-inflammatory properties. Recently, IVIG has been utilized in the management of highly sensitized patients awaiting renal transplantation. The mechanisms of suppression of panel reactive antibodies (PRA) in patients awaiting transplantation are currently under investigation and appear to be related to anti-idiotypic antibodies present in IVIG preparations. In this review, the various immunomodulatory mechanisms attributable to IVIG and their efficacy in reducing PRAs will be described. In addition, the use of IVIG in solid organ transplant recipients will be reviewed. The adverse events, safety considerations, and economic impact of IVIG protocols for patients awaiting solid organ transplantation will be discussed.     

Glomerular adaptation after kidney transplantation

In renal transplantation, surrogate variables of low nephron endowment are associated with a decreased allograft survival. However, total glomerular number can only be precisely estimated in experimental models or autopsy studies because the whole kidney is necessary for this purpose. The combination of magnetic resonance imaging of the kidney and a renal biopsy allows estimating total glomerular number in vivo, and the application of this approach to stable renal allografts has shown that total glomerular number is a major determinant of graft function.Protocol biopsies performed in stable grafts have allowed the characterization of subclinical rejection (SCR) and chronic allograft nephropathy as well as their predictive value on graft outcome. However, glomerular adaptation after transplantation has not captured the interest of the transplant community despite only one kidney is transplanted and a large proportion of transplant recipients will receive an insufficient nephron number for their metabolic demand.Using protocol biopsies, it has been shown that glomeruli enlarge after transplantation to provide an adequate filtration surface area to the recipient metabolic demand. Glomerular size increases during the first year and this adaptation process is necessary to achieve an adequate renal function. This adaptation is impaired in patients with SCR and/or chronic allograft nephropathy. Furthermore, glomerulosclerosis is also increased in patients with impaired glomerular adaptation. Taken together, these data suggest that the primary target of SCR is the tubulointerstitial compartment leading to interstitial fibrosis/tubular atrophy and to impaired glomerular adaptation/glomerulosclerosis thereafter.     

Central pontine myelinolysis after living donor liver transplantation

Central pontine myelinolysis (CPM) is the most serious central nervous system complication that could be seen after liver transplantation and represents an important source of mortality early after liver transplantation. CPM following liver transplantation was reported more and more in literatures, but the true incidence of CPM after living related liver transplantation (LDLT) remains unknown. However, with the introduction of magnetic resonance imaging (MRI), early recognition has become possible. In this report, we present a case of rapid resolution of CPM followed by MRI examinations.     

Osteoporosis after solid organ and bone marrow transplantation

Organ transplantation has become increasingly common as a therapy for end-stage renal, liver, cardiac and pulmonary disease. The population of patients who have survived organ transplantation has grown dramatically over the last 2 decades. Although organ transplant recipients now benefit from greatly improved survival, long-term complications of organ transplantation, such as osteoporosis, adversely affect quality of life and must be addressed. In the early post-transplantation period, the effects of high dose glucocorticoids, combined with other immunosuppressive drugs such as cycosporine A and tacrolimus, cause rapid bone loss particularly at the spine and proximal femur. In this setting, fracture incidence rates as high as 25-65% have been reported. Treatment and prevention strategies must target this early post-transplant period, as well as the patient awaiting transplantation and the long-term transplant recipient. This review will discuss the clinical features of transplantation osteoporosis, the pathophysiology of post-transplantation bone loss and prevention and therapy of this unique bone disease.     

Islet Transplantation a Decade Later and Strategies for Filling a Half-Full Glass

Alloislet transplantation for the treatment of type 1 diabetes enjoyed highly favorable status in the first half of the last decade but declined in favor during the second half. In this Perspective, I will briefly review the literature published in this area from 2000 to 2010 for the purposes of extracting lessons we have learned, considering whether the procedure should be deemed a partial success or a partial failure, and offering several strategies to improve alloislet transplantation outcomes in the future. In the end, I hope to strike a positive note about where this procedure is going, and how it will be applied to establish insulin independence in patients with type 1 diabetes.Successful pancreatic islet transplantation was established using rodents in 1972 and became a reality for humans in 1980. The application of this technology to patients with type 1 diabetes proved to be difficult and, for various reasons, lagged as a successful procedure until 2000. That year, the seminal publication by Shapiro et al. (1) from the University of Alberta, Edmonton, appeared and caused a huge wave of excitement and optimism about a cure for type 1 diabetes. A solution to insulin-induced hypoglycemia, perhaps the most vexing complication to insulin-based therapy, appeared to be at hand. Now, a decade later, a more circumspect attitude of reflection and retooling pervades the picture. This is an archetypical scenario for research findings that make a big splash in the scientific and lay press. Nonetheless, the facts remain. Seven consecutive type 1 diabetic patients were rendered insulin independent and free of hypoglycemia by islet transplantation, a remarkable accomplishment that spawned many research programs world-wide focused on curing diabetes with this procedure.In this Perspective I will briefly review the recent history of successful islet transplantation and point out some of the lessons we have learned from this intensive experience. This will be followed by a consideration of whether this technology is more success or failure. The final section will look to the future, i.e., how do we apply the lessons we have learned to modify islet transplantation so that it will come closer to the expectations it elicited in 2000?     

Current views on chronic rejection after lung transplantation

Chronic lung allograft dysfunction (CLAD) was recently introduced as an overarching term mainly to classify patients with chronic rejection after lung transplantation, although other conditions may also qualify for CLAD. Initially, only the development of a persistent and obstructive pulmonary function defect, clinically identified as bronchiolitis obliterans syndrome (BOS), was considered as chronic rejection, if no other cause could be identified. It became clear in recent years that some patients do not qualify for this definition, although they developed a chronic and persistent decrease in FEV₁, without another identifiable cause. As the pulmonary function decline in these patients was rather restrictive, this was called restrictive allograft syndrome (RAS). In the present review, we will further elaborate on these two CLAD phenotypes, with specific attention to the diagnostic criteria, the role of pathology and imaging, the risk factors, outcome, and the possible treatment options.     

Molecular Imaging in Breast Cancer - Potential Future Aspects

SUMMARY: Molecular imaging aims to visualize and quantify biological, physiological, and pathological processes at cellular and molecular levels. Recently, molecular imaging has been introduced into breast cancer imaging. In this review, we will present a survey of the molecular imaging techniques that are either clinically available or are being introduced into clinical imaging. We will discuss nuclear imaging and multiparametric magnetic resonance imaging as well as the combined application of molecular imaging in the assessment of breast lesions. In addition, we will briefly discuss other evolving molecular imaging techniques, such as phosphorus magnetic resonance spectroscopic imaging and sodium imaging.     

Noninvasive monitoring and tracking of muscle stem cell transplants

BACKGROUND: Efficient techniques to noninvasively monitor stem cell transplants will accelerate the development of stem cell therapies. Magnetic resonance (MR) imaging of labeled stem cells is a noninvasive approach that can provide images with high spatial resolution. In this report, we have evaluated the ability of a commercially available, FDA-approved contrast agent to allow for the monitoring of therapeutic stem cell transplants in murine dystrophic muscle. METHODS: Multipotent, muscle-derived stem cells were labeled by incubation with ferumoxide:polycation complexes. Labeled stem cells were evaluated for the ability to differentiate into mature myotubes and be detected by high resolution MR images in vitro and in vivo. RESULTS: Endosomal accumulation of superparamagnetic iron-oxide resulted in changes in the MR contrast T(2) and T(2)*, allowing for three dimensional, noninvasive detection of labeled cells. Relaxivity measurements on cell phantoms indicate that less than eight labeled cells could be detected by MR imaging. Furthermore, therapeutic cellular grafts transplanted into dystrophic muscle could be imaged sequentially and these noninvasive images correlated with histological images obtained by conventional microscopy. Additional studies revealed that MR imaging is applicable to tracking the migration of a small number of labeled cells following arterial delivery. CONCLUSIONS: MR monitoring is a highly sensitive technique that is applicable to muscle stem cell transplantation. We anticipate that it will enhance stem cell investigations by reducing the need for invasive tissue harvests and biopsies.     

活体肝移植进展与展望（2000-2020）

活体肝移植比公民逝世后器官捐献肝移植操作更为复杂，围手术期评估及技术实施直接影响供体安全和受体预后。目前，行活体肝移植时，供体选择应遵循“自愿、知情、无害”伦理原则，利用影像学评估供肝质量、解剖结构及残肝体积；受体选择时优先考虑良性终末期肝病病人，而选择肝癌病人应考虑肿瘤分期；移植物选择应满足不同受体的“移植物-受体重量比”标准，对于<3岁的儿童，其比值在2%~4%为宜；在传统开放手术供肝获取经验基础上，腹腔镜供肝获取技术发展与挑战并存；术中各管道重建时，管道条件、匹配程度及通畅性是移植技术的关键；供受体血型不相容时，应用利妥昔单抗可起到减少并发症及改善预后作用；术后精细化管理，尽量减少免疫抑制剂用量以期减少其药物相关副反应。尽管存在诸多问题，相信随着外科技术的进步，医生对肝脏解剖认识的加深及移植物再生血流动力学的理解，活体肝移植技术会更加完备、更加安全。作为公民逝世后器官捐献肝移植的重要补充，活体肝移植将为更多终末期肝病病人提供有效治疗手段。     

Ultrasonography in kidney transplantation: values and new developments

Renal transplant is performed on patients with end-stage renal disease. Gray-scale renal sonography combined with color Doppler has become the main noninvasive imaging method for evaluating a kidney transplant, as it provides information about the kidney anatomy and its vascular flow.In this article, we discuss the utility of sonography in renal transplants and describe the ultrasound findings in early and chronic graft pathology. Also, we explain new developments in ultrasound imaging with contrast media and its utility in renal transplantation, proposing that contrast-enhanced sonography be incorporated as a method to evaluate graft status because of its capability to evaluate cortical capillary blood flow.     

肝移植时代的门静脉高压治疗

胃食管静脉曲张出血是门静脉高压的常见并发症。药物和内窥镜治疗是静脉曲张的基础治疗。经颈静脉肝内门体静脉分流被推荐用于处理难治性或复发性胃食管静脉曲张出血。当患者存在危及生命的出血风险,而传统治疗风险较高、存在禁忌或效果不理想时,应选择肝移植治疗。传统治疗可以获得短期疗效,甚至可以较长时间稳定病情,但如果这些治疗导致门静...