Conventional and novel approaches to immunosuppression

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

Sequelae of organ transplantation

Transplant medicine has significantly changed the prognosis of diseases leading to terminal organ failure. It has evolved from an experimental procedure to standard therapy for liver, kidney and cardio-vascular diseases. Transplant medicine combines operative organ replacement with the management of severely ill patients before transplantation, as well as life-long follow-up of organ graft recipients. Ten year survival rates of 65% to over 90% have led to a steady increase of transplanted patients seen by general medical care providers which represents a challenge for practicing internists. Apart from organ-specific conditions, infectious, immunosuppressant-associated and metabolic consequences determine long-term survival. These include virus reactivation, graft rejection, anastomotic problems but more importantly general mortality determining factors such as diabetes, renal insufficiency and hypertension, which are often a consequence of immunosuppressant administration. They directly impact long-term survival. The awareness and treatment of these secondary conditions of organ transplantation in routine medical practice contributes significantly to secure the long term success of transplant medicine.     

Folgeerkrankungen nach Organtransplantation

Transplant medicine has significantly changed the prognosis of diseases leading to terminal organ failure. It has evolved from an experimental procedure to standard therapy for liver, kidney and cardio-vascular diseases. Transplant medicine combines operative organ replacement with the management of severely ill patients before transplantation, as well as life-long follow-up of organ graft recipients. Ten year survival rates of 65% to over 90% have led to a steady increase of transplanted patients seen by general medical care providers which represents a challenge for practicing internists. Apart from organ-specific conditions, infectious, immunosuppressant-associated and metabolic consequences determine long-term survival. These include virus reactivation, graft rejection, anastomotic problems but more importantly general mortality determining factors such as diabetes, renal insufficiency and hypertension, which are often a consequence of immunosuppressant administration. They directly impact long-term survival. The awareness and treatment of these secondary conditions of organ transplantation in routine medical practice contributes significantly to secure the long term success of transplant medicine.     

In situ labeling of immune cells with iron oxide particles: an approach to detect organ rejection by cellular MRI

In vivo cell tracking by MRI can provide means to observe biological processes and monitor cell therapy directly. Immune cells, e.g., macrophages, play crucial roles in many pathophysiological processes, including organ rejection, inflammation, autoimmune diseases, cancer, atherosclerotic plaque formation, numerous neurological disorders, etc. The current gold standard for diagnosing and staging rejection after organ transplantation is biopsy, which is not only invasive, but also prone to sampling errors. Here, we report a noninvasive approach using MRI to detect graft rejection after solid organ transplantation. In addition, we present the feasibility of imaging individual macrophages in vivo by MRI in a rodent heterotopic working-heart transplantation model using a more sensitive contrast agent, the micrometer-sized paramagnetic iron oxide particle, as a methodology to detect acute cardiac rejection.     

Bone marrow transplantation for severe aplastic anaemia a review of the Westminster experience of 24 cases

Summary Twenty-four patients have received bone marrow transplantation for severe aplastic anaemia at the Westminster Hospitals since 1974. Twelve patients are long term survivors. Infectious complications in association with graft rejection, graft versus host disease or prolonged neutropenia were the major cause of death. In the last 18 months the introduction of more effective conditioning regimes and Cyclosporin A as graft versus host disease prophylaxis has improved the survival rate to 85%. One patient has required regrafting for late graft failure without evidence of graft rejection.     

Bone marrow transplantation for severe aplastic anaemia. A review of the Westminster experience of 24 cases

Twenty-four patients have received bone marrow transplantation for severe aplastic anaemia at the Westminster Hospitals since 1974. Twelve patients are long term survivors. Infectious complications in association with graft rejection, graft versus host disease or prolonged neutropenia were the major cause of death. In the last 18 months the introduction of more effective conditioning regimes and Cyclosporin A as graft versus host disease prophylaxis has improved the survival rate to 85%. One patient has required regrafting for late graft failure without evidence of graft rejection.     

Economic impact of cytomegalovirus in solid organ transplantation

Cytomegalovirus (CMV) infection has a direct effect on morbidity in solid organ transplantation patients, and indirect effects related to the development of opportunistic infections, allograft rejection, and patient mortality. Although intuitively it follows that costs attributable to CMV infections would be increased, direct proof has remained elusive. Accumulating evidence suggests, however, that CMV infection has a significant impact on the costs to transplantation programs, particularly in seronegative recipients of seropositive allografts (D+/R–), and additional costs may be incurred through the effects on CMV potentiating the risks of various opportunistic infections leading to graft rejection.     

Lungentransplantation

Since the early days of lung transplantation the demand for donor organs has outstripped donor organ availability. Consequently waiting times continue to increase with patients of highest priority often waiting several weeks or even months until a suitable donor organ becomes available resulting in considerable mortality on the waiting list. These issues have led to renewed interest in bridging strategies for patients with end-stage lung disease. The use of endotracheal intubation and mechanical ventilation (MV) has been viewed as a last resort as the majority of intubated patients fail to reach transplantation and those who do tend to have a poor postoperative outcome. New bridging strategies with awake extracorporeal membrane oxygenation (ECMO) seem to be hopeful alternatives in some patients. In the early intensive care unit (ICU) phase primary graft dysfunction, acute rejection, infections and surgical complications are common problems. Later, rejection, infection and sepsis, special airway complications and pulmonary bleeding may be reasons for ICU treatment.     

Immunosuppression without immunosuppression? How to be a tolerant individual in a dangerous world

The field of transplantation has developed based on two principles: allografts are rejected because they express foreign antigens, and the immune system must be suppressed to prevent rejection. Recently, in vitro and in vivo experimental evidence has accumulated that calls both of these beliefs into question. This article reviews an alternative approach to transplantation that focuses on tissue injury as the instigator of graft rejection and employs physiological mechanisms of tolerance to avoid graft loss. Methods that allow for defense against infectious microbes while at the same time allowing for graft survival are proposed. In particular, the rationale behind the use of anti-CD154 antibody treatment is highlighted. A model is introduced that takes into consideration the experimental successes seen with anti-CD154 therapies ^{1 1} Editor's comment: Infection and cancer are the main complications of the long-term immunosuppression currently used to prevent allograft rejection. Strategies aimed at the induction of tolerance have as a central goal the preservation of the host's antimicrobial responses with the loss of immune reactivity to transplanted tissue antigens. Dr. Kirk takes up this challenge by summarizing the theoretical arguments favoring a strategy based on costimulatory blockade aimed at CD154 (CD40-ligand) in the absence of nonspecific immune suppression. Thus far, the absence of opportunistic infection is a striking feature of primates with long-term allograft survival. This approach provides an important new theme in basic transplantation research. Jay A. Fishman, M.D.
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Th1/Th2细胞因子与移植免疫耐受的研究进展

免疫排斥反应是影响器官移植术后存活率的最重要的因素,应用免疫抑制剂具有很多的不良反应,诱导免疫耐受是解决移植术后排斥反应的最佳方法。Th1/Th2细胞因子的动态平衡在移植耐受中起重要作用,Th1向Th2偏离是移植耐受的机制之一。现对Th1与Th2之间的关系及其在移植免疫、免疫耐受中的最新进展进行综述。     

Spontaneous clearance of hepatitis C after liver and renal transplantation

Spontaneous clearance of hepatitis C virus (HCV) is rare in immunocompromised patients, such as those who have undergone organ transplantation. It has been recognized that patients receiving liver transplantation for HCV-related disease have decreased graft and patient survival compared with those transplanted for other etiologies. There is a growing trend toward treating HCV recurrence aggressively after liver transplantation. For other organ transplant recipients with concurrent HCV, treatment is not often an option, given the high rates of graft rejection and loss secondary to interferon and its immunomodulatory effects. Although spontaneous clearance of HCV has been reported in recipients of solitary liver and renal transplants, a common factor arising in these cases has been previous exposure to interferon. To date, no reports of spontaneous clearance of HCV RNA have been reported in a multiorgan transplant recipient. A case of spontaneous clearance of HCV RNA in an immunocompromised patient, within five months of simultaneous liver and kidney retransplantation is described. Importantly, this patient had no previous exposure to interferon.     

Clinical significance of donor-specific human leukocyte antigen antibodies in liver transplantation

Antibody-mediated rejection(AMR) caused by donorspecific anti-human leukocyte antigen antibodies(DSA) is widely accepted to be a risk factor for decreased graft survival after kidney transplantation. This entity also plays a pathogenic role in other solid organ transplants as it appears to be an increasingly common cause of heart graft dysfunction and an emerging issue in lung transplantation. In contrast, the liver appears relatively resistant to DSA-mediated injury. This "immune-tolerance" liver property has been sustained by a low rate of liver graft loss in patients with preformed DSA and by the intrinsic liver characteristics that favor the absorption and elimination of DSA; however, alloantibody-mediated adverse consequences are increasingly being recognized, and several cases of acute AMR after ABO-compatible liver transplant(LT) have been reported. Furthermore, the availability of new solid-phase assays, allowing the detection of low titers of DSA and the refinement of objective diagnostic criteria for AMR in solid organ transplants and particularly in LT, have improved the recognition and management of this entity. A cost-effective strategy of DSA monitoring, avoidance of class Ⅱ human leukocyte antigen mismatching, judicious immunosuppression attached to a higher level of clinical suspicion of AMR, particularly in cases unresponsive to conventional antirejection therapy, can allow a rational approach to this threat.     

Lungentransplantation

Lung transplantation has become the standard therapy for selected patients with end-stage pulmonary disease who have no other available therapeutic options. Due to the broadening of indications for lung transplantation and a less restrictive selection of candidates, there is an imbalance between the large number of candidates waiting for an organ and the limited donor pool. This fact was addressed by the extension of donor selection criteria and by the development of new strategies for organ management. Because of the high risk of acute and chronic rejection, lung recipients require intensive immunosuppression, which increases the risk of infections. During the 30 years follow-up after the first successful lung transplant, perioperative mortality has been reduced due to the improvement of surgical techniques, organ preservation and medicinal therapy. Whereas infections represent the main cause of death during the first year after transplantation, chronic graft failure is the main problem of long-term survival.     

Immunological analysis in xenogeneic fetal porcine liver transplantation into a beagle

BACKGROUND/AIMS: While allogeneic organ transplantation has been performed safely, a major barrier in xenogeneic transplantation is how to inhibit hyperacute rejection. METHODOLOGY: We challenged xenogeneic fetal liver transplantation from pig to dog. The graft was investigated by immunohistochemical analysis on recipient's IgG, IgM and C3. RESULTS: In 1 of 4 cases, the graft escaped hyperacute rejection for about 4 hours after transplantation, however, the recipient died next day due to hemorrhage from the torn capsule of the liver due to the arterial blood pressure of the recipient. Histologically, the parenchyma showed good countenance and no congestion nor hemorrhage was shown in the vessels. On immunohistochemical analysis, canine IgG, IgM and C3 were deposited on the sinusoidal epithelium of the fetal liver more moderately than that of adult control. Fetal porcine liver showed less expression of major histocompatability complex class I antigen than that of the adult one. CONCLUSIONS: We consider that the hyperacute rejection occurred more slowly in xenogeneic fetal liver transplantation than in the adult one due to not only less expression of major histocompatability complex class I, but also lower expression of the epitope recognized by a natural antibody of the recipient.     

Isolated intestinal transplantation for intestinal failure

OBJECTIVE: Parenteral nutrition sustains life in patients with intestinal failure. However, some experience life-threatening complications from parenteral nutrition, and in these individuals intestinal transplantation may be lifesaving. METHODS: This is a retrospective review of 28 consecutive isolated small bowel transplants performed in eight adults and 20 children between December 1993 and June 1998 at the University of Nebraska Medical Center. RESULTS: The 1-yr patient and graft survivals were 93% and 71%, respectively. The causes of graft loss were hyperacute rejection (n = 1), acute rejection (n = 5), vascular thrombosis (n = 1), and patient death (n = 1). The median length of time required until full enteral nutrition was 27 days. All 28 patients have experienced acute rejection of their small bowel grafts and rejection led to graft failure in five. Jaundice and/or hepatic fibrosis was present preoperatively in 17 of the 28 recipients and hyperbilirubinemia was completely reversed in all patients with functional grafts within 4 months of transplantation. Three patients developed post-transplant lymphoproliferative disease (11%). Three recipients developed cytomegalovirus enteritis and all were successfully treated. CONCLUSIONS: Patient survival after intestinal transplantation is comparable to parenteral nutrition for patients with intestinal failure. Better immunosuppressive regimens are needed to decrease the risk of graft loss from acute rejection. The incidence of posttransplant lymphoproliferative disorder is higher after intestinal transplantation than after other solid organ transplants and the risk of cytomegalovirus enteritis is low with the use of cytomegalovirus seronegative donors. Liver dysfunction in the absence of established cirrhosis can be reversed.     

A review of split liver transplantation with full right/left hemi-liver grafts for 2 adult recipients

Liver transplantation has become a routine operation in many transplantation centers worldwide. However, liver graft availability fails to meet patient demands. Split liver transplantation (SPLT), which divides a deceased donor liver into 2 partial liver grafts, is a promising strategy for increasing graft availability for transplantation and ameliorating organ shortage to a certain degree. However, the transplantation community has not yet reached a consensus on SPLT because of the variable results. Specifically, SPLT for 2 adult recipients using full right/left hemi-liver grafts is clinically more challenging in terms of surgical technique and potential postoperative complications. Therefore, this review summarizes the current status of SPLT, focusing on the transplantation of adult recipients. Furthermore, the initiation of the SPLT program, donor allocation, surgical aspects, recipient outcomes, and obstacles to developing this procedure will be thoroughly discussed. This information might help provide an optimal strategy for implementing SPLT for 2 adult recipients among current transplantation societies. Meanwhile, potential obstacles to SPLT might be overcome in the near future with growing knowledge, experience, and refinement of surgical techniques. Ultimately, the widespread diffusion of SPLT may increase graft availability and mitigate organ donation shortages.     

Apheresis in Thoracic Organ Transplantation

The beneficial addition of cyclosporine and tacrolimus to the immunosuppressive armamentarium have unfortunately only partially solved the problems of acute and chronic rejection in thoracic organ transplantation. Apheresis techniques offer creative avenues for modifications of allograft rejection. Plasmapheresis can be used for mechanical reduction of alloantibody burdens in highly sensitized patients and permit transplantation in an otherwise almost hopeless situation and can also be used on a short-term basis for the treatment of acute humoral rejection. Extracorporeal photochemotherapy holds promise as a possibly synergistic adjunct to conventional therapy and may even reduce the severity of graft vasculopathy. The increasing availability of highly specific column immunoadsorption techniques may further increase the applicability of apheresis in transplantation.     

Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogeneic hyperacute organ rejection.

The serious shortage of human organs available for transplantation has engendered a heightened interest in the use of animal organs (xenografts) for transplantation. However, the major barrier to successful discordant xenogeneic organ transplantation is the phenomenon of hyperacute rejection. Hyperacute rejection results from the deposition of high-titer preformed antibodies that activate serum complement on the luminal surface of the vascular endothelium, leading to vessel occlusion and graft failure within minutes to hours. Although endogenous membrane-associated complement inhibitors normally protect endothelial cells from autologous complement, they are species restricted and thus confer limited resistance to activated xenogeneic complement. To address the pathogenesis of hyperacute rejection in xenotransplantation, transgenic mice and a transgenic pig were engineered to express the human terminal complement inhibitor hCD59. High-level cell surface expression of hCD59 was achieved in a variety of murine and porcine cell types, most importantly on both large vessel and capillary endothelium. hCD59-expressing porcine cells were significantly resistant to challenge with high-titer anti-porcine antibody and human complement. These experiments demonstrate a strategy for developing a pig-to-primate xenogeneic transplantation model to test whether the expression of a human complement inhibitor in transgenic pigs could render xenogeneic organs resistant to hyperacute rejection.     

Lung transplant in end-staged chronic obstructive pulmonary disease (COPD) patients: a concise review

Lung transplantation is commonly used for patients with end-stage lung disease. However, there is continuing debate on the optimal operation for patients with chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis. Single-lung transplantation (SLT) provides equivalent short- and medium-term results compared with bilateral lung transplantation (BLT), but long-term survival appears slightly better in BLT recipients (especially in patients with COPD). The number of available organs for lung transplantation also influences the choice of operation. Recent developments suggest that the organ donor shortage is not as severe as previously thought, making BLT a possible alternative for more patients. Among the different complications, re-implantation edema, infection, rejection, and bronchial complications predominate. Chronic rejection, also called obliterative bronchiolitis syndrome, is a later complication which can be observed in about half of the patients. Improvement in graft survival depends greatly in improvement in prevention and management of complications. Despite such complications, graft survival in fibrosis patients is greater than spontaneous survival on the waiting list; idiopathic fibrosis is associated with the highest mortality on the waiting list. Patients should be referred early for the pre-transplantation work-up because individual prognosis is very difficult to predict.