Does autoantigen administration inhibit recurrence of type 1 diabetes in transplanted islets?

Type 1 diabetes is a chronic disease with a subclinical prodromal period resulting from autoimmune destruction of pancreatic beta-cells. At the time of clinical symptoms of diabetes, the majority of islets have irreversibly been destroyed. Thus, the only cure for type 1 diabetes is pancreas (or islet) transplantation. To reach this goal, both allograft rejection and recurrent autoimmunity must be overcome. These have partly been achieved at the cost of lifelong immunosuppression, however, the risk to benefit ratio for immunosuppressive drugs to insulin usage remains obscure. To eliminate the need for immunosuppression, several tolerance induction protocols have been developed which particularly target alloimmune responses, whereas no tolerance induction protocol that particularly prevents the recurrence of autoimmunity has been suggested. It is hypothesized that autoantigen-based interventions may inhibit the recurrence of type 1 diabetes in transplanted pancreas (or islets) through the induction of specific tolerance to beta-cell autoantigens.     

Clinical islet transplant: current and future directions towards tolerance

Summary:  The ultimate goal of islet transplantation is to completely correct the diabetic state from an unlimited donor source, without the need for chronic immunosuppressive drug therapy. Although islet transplantation provides an opportunity to develop innovative strategies for tolerance in the clinic, both alloimmune and autoimmune barriers must be controlled, if stable graft function is to be maintained long-term. After islet extraction from the pancreas, the cellular graft may be stored in tissue culture or cryopreserved for banking, providing an opportunity not only to optimally condition the recipient but also to allow in vitro immunologic manipulation of the graft before transplantation, unlike solid organ grafts. As such, islets may be considered a 'special case.' Remarkable progress has occurred in the last three years, with dramatic improvements in outcomes after clinical islet transplantation. The introduction of a steroid-free, sirolimus-based, anti-rejection protocol and islets prepared from two (or rarely three) donors led to high rates of insulin independence. The 'Edmonton Protocol' has been successfully replicated by other centers in an international multicenter trial. A number of key refinements in pancreas transportation, processing, purification on non-ficoll-based media, storage of islets in culture for two days and newer immunological conditioning and induction therapies have led to continued advancement through extensive collaboration between key centers. This review outlines the historical development of islet transplantation over the past 30 years, provides an update on current clinical outcomes, and summarizes a series of unique opportunities for development and early testing of tolerance protocols in patients.     

Treatment of type 1 diabetics by transplantation of isolated pancreatic islets

Type 1 diabetes is an autoimmune disease with selective destruction of insulin-producing pancreatic beta cells. Since insulin plays pivotal roles in energy homeostasis by transferring glucose into cells, type 1 diabetic patients can not survive without insulin replacement. Insulin secretion is precisely controlled by ingested glucose as well as hormones and neural factors, therefore it is impossible to reproduce the physiological secretory pattern of insulin via exogenous insulin, even by multiple or continuous delivery by injection. Transplantation of beta cells has long been expected as the fundamental treatment to cure type 1 diabetics, and transplantation of the whole pancreas, both exocrine pancreas and islets, has been applied with success, resulting insulin independence. However, the exocrine pancreas, which releases amylase and trypsin to the digestive tract, is not indispensable for insulin replacement, so the interest in islet transplantation has increased enormously. In the past 20 years, the techniques for isolating large numbers of human islets have been advanced and more potent immunosuppressive agents have also been introduced, permitting newer attempts at islet transplantation. In 2000, insulin independence was first achieved in Canada using the Edmonton protocol. The success rates have increased gradually using this protocol, and 5 institutes in Japan have started to prepare human islet transplantation under the control of the Japan Pancreas and Islet Transplant Society. In 2004, insulin independence by islet transplantation was first achieved at Kyoto University Hospital and the number of islet transplantations has increased, though very slowly. By the end of 2005, approximately 100 patients were on the waiting list for islet transplantation in Japan. Many problems remain unsolved in islet transplantation to meet clinical practice: these are the shortage of insulin-producing cells, further progress in immunosuppressive agents that do not interfere with insulin secretion, strategies for protecting islets against hypoxia, and/or non-immunological damage such as mechanical damage soon after transplantation, and the destruction of islet cells by innate immunity. We investigated the role of neutrophil leucocytes infiltrating the liver using natural killer cell-knock-out mice and proposed a new strategy for protecting transplanted islets from non-specific damage, which occurs within one day after transplantation.     

Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen

BACKGROUND: Registry data on patients with type 1 diabetes mellitus who undergo pancreatic islet transplantation indicate that only 8 percent are free of the need for insulin therapy at one year. METHODS: Seven consecutive patients with type 1 diabetes and a history of severe hypoglycemia and metabolic instability underwent islet transplantation in conjunction with a glucocorticoid-free immunosuppressive regimen consisting of sirolimus, tacrolimus, and daclizumab. Islets were isolated by ductal perfusion with cold, purified collagenase, digested and purified in xenoprotein-free medium, and transplanted immediately by means of a percutaneous transhepatic portal embolization. RESULTS: All seven patients quickly attained sustained insulin independence after transplantation of a mean (+/-SD) islet mass of 11,547+/-1604 islet equivalents per kilogram of body weight (median follow-up, 11.9 months; range, 4.4 to 14.9). All recipients required islets from two donor pancreases, and one required a third transplant from two donors to achieve sustained insulin independence. The mean glycosylated hemoglobin values were normal after transplantation in all recipients. The mean amplitude of glycemic excursions (a measure of fluctuations in blood glucose concentrations) was significantly decreased after the attainment of insulin independence (from 198+/-32 mg per deciliter [11.1+/-1.8 mmol per liter] before transplantation to 119+/-37 mg per deciliter [6.7+/-2.1 mmol per liter] after the first transplantation and 51+/-30 mg per deciliter [2.8+/-1.7 mmol per liter] after the attainment of insulin independence; P<0.001). There were no further episodes of hypoglycemic coma. Complications were minor, and there were no significant increases in lipid concentrations during follow-up. CONCLUSIONS: Our observations in patients with type 1 diabetes indicate that islet transplantation can result in insulin independence with excellent metabolic control when glucocorticoid-free immunosuppression is combined with the infusion of an adequate islet mass.     

Role of ICOS pathway in autoimmune and alloimmune responses in NOD mice

Islet allografts are subject to alloimmune and autoimmune destruction when transplanted into autoimmune prone animals or humans. The ICOS-B7h pathway plays a role in alloimmune responses, but its function in autoimmunity against islet cells is controversial. We investigated the role of ICOS signaling in autoimmune and alloimmune responses in NOD mice. ICOS blockade prevents development of spontaneous disease in pre-diabetic NOD mice. Furthermore, while ICOS blockade prolongs graft survival in a fully mismatched non-autoimmune islet allograft model in C57BL/6 recipients, it has no beneficial effect in reversing diabetes in models of islet transplantation in NOD mice involving autoimmunity alone or both allo- and autoimmunity. Interestingly, ICOS blockade is effective in prolonging heart allograft (not subject to tissue-specific autoimmunity) survival in NOD mice. We conclude that in islet transplantation and autoimmune diabetes, ICOS blockade can be effective in inhibiting alloimmunity and preventing autoimmunity but is ineffective in inhibiting recurrence of autoimmunity.     

An important role for autoimmunity in the immunopathogenesis of chronic allograft rejection

Organ transplantation is the treatment of choice for patients with end-stage organ dysfunction. In spite of advances in understanding of donor and recipient physiology, organ preservation, operative techniques and immunosuppression, long-term graft survival still remains a major problem primarily due to chronic rejection. Alloimmune responses to mismatched major histocompatibility antigens have been implicated as an important factor leading to rejection. However, there is increasing evidence pointing towards cross-talk between the alloimmune and autoimmune responses creating a local inflammatory milieu, which eventually leads to fibrosis and occlusion of the lumen in the transplanted organ i.e. chronic rejection. In this review, we will discuss recent studies and emerging concepts for the interdependence of alloimmune and autoimmune responses in the immunopathogenesis of chronic allograft rejection. The role of autoimmunity in the development of chronic rejection is an intriguing and exciting area of research in the field of solid-organ transplantation with a significant potential to develop novel therapeutic strategies towards preventing chronic allograft rejection.     

Different islet protein expression profiles during spontaneous diabetes development vs. allograft rejection in BB-DP rats

Type 1 diabetes (T1D) is characterized by selective autoimmune destruction of the insulin producing beta-cells in the islets of Langerhans. When the beta-cells are destroyed exogenous administration of insulin is necessary for maintenance of glucose homeostasis. Allogeneic islet transplantation has been used as a means to circumvent the need for insulin administration and has in some cases been able to restore endogenous insulin production for years. However, long life immunosuppression is needed to prevent the graft from being rejected and destroyed. Changes in protein expression pattern during spontaneous diabetes development in the diabetes prone BioBreeding rat (BB-DP) have previously been described. In the present study, we have investigated if any of the changes seen in the protein expression pattern during spontaneous diabetes development are also present during allograft rejection of BB-DP rat islets. Two hundred neonatal islets were syngeneically transplanted under the kidney capsule of 30 day old BB-DP rats and removed prior to and at onset of diabetes. Allogeneically transplanted islets from BB-DP rats were removed before onset of allograft rejection and at maximal islet graft inflammation (rejection). The protein expression profiles of the transplants were visualised by two-dimensional gel (2-DG) electrophoresis, analysed and compared. In total, 2590 protein spots were visualised and of these 310 changed expression (p < 0.01) in syngeneic islet transplants in the BB-DP rats from 7 days after transplantation until onset of diabetes. In BB-DP islets transplanted to WK rats 53 protein spots (p < 0.01) showed changes in expression when comparing islet grafts removed 7 days after transplantation with islet grafts removed 12 days after transplantation where mononuclear cell infiltration is at its maximum. Only four protein spots (1%) were significantly changed in both syngeneic (autoimmune) and allogeneic islet destruction. When comparing protein expression changes in syngeneic BB-DP islet transplants from 37 days after transplantation to onset of diabetes with protein expression changes in allografts from day 7 to 12 after transplantation only three spot were found to commonly change expression in both situations. In conclusion, a large number of protein expression changes were detected in both autoimmune islet destruction and allogeneic islet rejection, only two overlaps were detected, suggesting that autoimmune islet destruction and allogeneic islet rejection may result from different target cell responses to signals induced by the cellular infiltrate. Whether this reflects activation of distinct signalling pathways in islet cells is currently unknown and need to be further investigated.     

Harnessing the immunomodulatory properties of Sertoli cells to enable xenotransplantation in type I diabetes

Islet transplantation has emerged as a viable long-term means of treating type I diabetes. This is largely due to the success of the “Edmonton protocol” which has produced insulin independence in 85% of patients 1 year after transplantation of allogeneic islets together with a non-steroid immunosuppressive regimen. While these data provide a clear and unequivocal demonstration that islet transplantation is a viable treatment strategy, the shortage of suitable donor tissue together with the debilitating consequences of life-long immunosuppression necessitate the development of novel means to enable transplantation of all type 1 diabetics including the young juvenile diabetics. One potential means of enabling islet transplantation takes advantage of the ability of Sertoli cells to provide local immunoprotection to co-grafted islets, including those from xenogeneic sources. Sertoli cells are normally found in the testes where one of their functions is to provide local immunologic protection to developing germ cells. In animal models, allogeneic and xenogeneic islets survive and function for extended periods of time when grafted into the testes. Moreover, isolated Sertoli cells protect co-grafted allogeneic and xenogeneic islets from immune destruction and reverse diabetes in immunocompetent and autoimmune animals. These benefits are discussed in the context of several potential underlying biological mechanisms.     

Harnessing the Immunomodulatory Properties of Sertoli Cells to Enable Xenotransplantation in Type I Diabetes

Islet transplantation has emerged as a viable long‐term means of treating type I diabetes. This is largely due to the success of the “Edmonton protocol” which has produced insulin independence in 85% of patients 1 year after transplantation of allogeneic islets together with a non‐steroid immunosuppressive regimen. While these data provide a clear and unequivocal demonstration that islet transplantation is a viable treatment strategy, the shortage of suitable donor tissue together with the debilitating consequences of life‐long immunosuppression necessitate the development of novel means to enable transplantation of all type 1 diabetics including the young juvenile diabetics. One potential means of enabling islet transplantation takes advantage of the ability of Sertoli cells to provide local immunoprotection to co‐grafted islets, including those from xenogeneic sources. Sertoli cells are normally found in the testes where one of their functions is to provide local immunologic protection to developing germ cells. In animal models, allogeneic and xenogeneic islets survive and function for extended periods of time when grafted into the testes. Moreover, isolated Sertoli cells protect co‐grafted allogeneic and xenogeneic islets from immune destruction and reverse diabetes in immunocompetent and autoimmune animals. These benefits are discussed in the context of several potential underlying biological mechanisms.     

Different islet protein expression profiles during spontaneous diabetes development vs. allograft rejection in BB-DP rats

Type 1 diabetes (T1D) is characterized by selective autoimmune destruction of the insulin producing β-cells in the islets of Langerhans. When the β-cells are destroyed exogenous administration of insulin is necessary for maintenance of glucose homeostasis. Allogeneic islet transplantation has been used as a means to circumvent the need for insulin administration and has in some cases been able to restore endogenous insulin production for years. However, long life immunosuppression is needed to prevent the graft from being rejected and destroyed. Changes in protein expression pattern during spontaneous diabetes development in the diabetes prone BioBreeding rat (BB-DP) have previously been described. In the present study, we have investigated if any of the changes seen in the protein expression pattern during spontaneous diabetes development are also present during allograft rejection of BB-DP rat islets.

Two hundred neonatal islets were syngeneically transplanted under the kidney capsule of 30 day old BB-DP rats and removed prior to and at onset of diabetes. Allogeneically transplanted islets from BB-DP rats were removed before onset of allograft rejection and at maximal islet graft inflammation (rejection). The protein expression profiles of the transplants were visualised by two-dimensional gel (2-DG) electrophoresis, analysed and compared.

In total, 2590 protein spots were visualised and of these 310 changed expression (p < 0.01) in syngeneic islet transplants in the BB-DP rats from 7 days after transplantation until onset of diabetes. In BB-DP islets transplanted to WK rats 53 protein spots (p < 0.01) showed changes in expression when comparing islet grafts removed 7 days after transplantation with islet grafts removed 12 days after transplantation where mononuclear cell infiltration is at its maximum. Only four protein spots (1%) were significantly changed in both syngeneic (autoimmune) and allogeneic islet destruction. When comparing protein expression changes in syngeneic BB-DP islet transplants from 37 days after transplantation to onset of diabetes with protein expression changes in allografts from day 7 to 12 after transplantation only three spot were found to commonly change expression in both situations.

In conclusion, a large number of protein expression changes were detected in both autoimmune islet destruction and allogeneic islet rejection, only two overlaps were detected, suggesting that autoimmune islet destruction and allogeneic islet rejection may result from different target cell responses to signals induced by the cellular infiltrate. Whether this reflects activation of distinct signalling pathways in islet cells is currently unknown and need to be further investigated.     

The role of autoimmunity in the pathogenesis of lung allograft rejection

For many patients, lung transplantation is the only definitive treatment modality for different forms of end-stage lung disease. However, the lung is rejected more often than any other type of solid organ allografts, and the 5-year survival rate is less than that of other transplanted organs. While alloimmunity directed against donor transplantation antigens is believed to be the key mechanism that mediates rejection responses, newer immunosuppressive regimens designed to abrogate alloimmune activation have not improved survival. Accordingly, these data suggest that other antigens are involved in rejection. Autoimmune responses, reported to occur during allograft rejection, could participate in graft destruction. This review article discusses the role of autoimmune responses to type V collagen, a minor collagen in the lung, in the pathogenesis of lung allograft rejection. By recognizing that lung transplant rejection involves both alloimmune and autoimmune responses, scientific investigation may uncover novel targets for therapeutic intervention that could prolong the life of the lung transplant recipient.     

Glutamic acid decarboxylase antibodies are more frequent than islet cell antibodies in islet transplanted IDDM patients and persist or occur despite immunosuppression

Pancreatic islet grafts transplanted into patients with autoimmune diabetes are potentially threatened by two immune responses, allograft rejection and the recurrence of autoimmune insulitis. In the present study we investigated the humoral autoimmune response directed to islet autoantigens by studying islet cell antibodies and glutamic acid decarboxylase (GAD 65) antibodies in twenty-one insulin-dependent diabetes-mellitus (IDDM) patients undergoing intraportal islet allotransplantation. Islet transplantation was performed according to the following recipient categories: Islet after kidney transplantation (n=10), simultaneous islet and kidney transplantation (n=6) and islet transplant alone (n=5). GAD 65 antibodies were detected in a radioligand GAD 65 antibody assay using recombinant, in vitro translated, human ³⁵S-methionin labelled GAD 65 as tracer. Islet cell antibodies were determined by indirect immunofluorescence technique on human pancreas. In six out of twenty-one patients we observed GAD 65 antibodies before islet transplantation and the GAD 65 antibodies persisted despite immunosuppression. In contrast only two subjects were concordantly islet cell antibody positive and the titre decreased post transplantation. In addition we observed occurrence of GAD 65 antibodies in five subjects that were shown to be antibody negative before islet transplantation with three of them subsequently becoming positive for islet cell antibodies. The remaining ten patients were GAD 65 antibody and islet cell antibody negative before islet transplantation and remained negative thereafter. Interestingly none of the patients was exclusively positive for islet cell antibodies without being positive for GAD 65 antibodies. In summary we have demonstrated in twenty-one islet grafted individuals that humoral autoimmunity to islet antigens can persist or occur despite immunosuppression. Islet cell antibodies appear to be less frequent (5 out of 21, 23%) compared to GAD 65 antibodies (11 out of 21, 52%) suggesting that they are more affected by immunosuppressive therapy. We conclude that GAD 65 antibodies are a useful tool to further evaluate a possible link between persistent autoimmunity and early or late graft failure after islet transplantation.     

Heterologous immunity: an overlooked barrier to tolerance

Summary:  In less than 50 years the field of organ transplantation has transitioned from an experimental concept to clinical commonplace. Notwithstanding the dramatic improvements in patient and allograft outcomes, chronic rejection and the complications from life-long immunosuppressive therapy remain significant problems. The induction of transplantation tolerance, indefinite allograft acceptance independent of chronic immunosuppressive therapy, remains the ultimate objective in transplantation. Many strategies have achieved tolerance to transplanted tissue in rodents; however, few, if any, have shown equal efficacy when tested in non-human primate transplant models or human patients. A critical distinction between specific pathogen-free mice and primates or human patients is the exposure of the latter to environmental pathogens and the resultant-acquired immune history. Recent data has shown that virally induced, alloreactive immune responses can provide a potent barrier to tolerance. In this review, we discuss one of the most robust methods for tolerance, the induction of hematopoietic chimerism as well as the influence of viral infections on the alloimmune response.     

Chronic rejection: a significant role for Th17-mediated autoimmune responses to self-antigens

Despite progress in the field of organ transplantation for improvement in graft survival and function, long-term graft function is still limited by the development of chronic allograft rejection. Various immune-mediated and nonimmune-mediated processes have been postulated in the pathogenesis of chronic rejection. In this review, the authors discuss the important role of alloimmune responses to donor-specific antigens and autoimmune responses to tissue restricted self-antigens in the immunopathogenesis of chronic rejection following solid organ transplantation. In particular, the authors discuss the role of induction of Th17-type autoimmune responses and the crosstalk between autoimmune and alloimmune responses. These self-perpetuate each other leading to activation of profibrotic and proinflammatory cascades that ultimately result in the development of chronic rejection.     

Approaches for the cure of type 1 diabetes by cellular and gene therapy

Type 1 diabetes results from insulin deficiency caused by autoimmune destruction of insulin-producing pancreatic beta cells. Islet transplantation, beta cell regeneration, and insulin gene therapy have been explored in an attempt to cure type 1 diabetes. Major progress on islet transplantation includes substantial improvements in islet isolation technology to obtain viable and functionally intact islets and less toxic immunosuppressive drug regimes to prevent islet graft failure. However, the availability of human islets from cadaveric pancreata is limited. Regeneration of pancreatic beta cells from embryonic or adult stem cells may overcome the limited source of islets and transplant rejection if beta cells are regenerated from endogenous stem cells. However, it is difficult to overcome the persisting hostile beta cell-specific autoimmune response that may destroy the regenerated beta cells. Insulin gene therapy might overcome the weakness of islet transplantation and beta cell regeneration with respect to their vulnerability to autoimmune attack. This method replaces the function of beta cells by introducing various components of the insulin synthetic and secretory machinery into non- beta cells, which are not targets of beta cell-specific autoimmune responses. However, there is no regulatory system that results in the expression and release of insulin in response to glucose with satisfactory kinetics. Although there is no perfect solution for the cure of type 1 diabetes at the present time, research on a variety of potential approaches will offer the best choices for the cure of human type 1 diabetes.     

骨髓间充质干细胞体外诱导分化为胰岛样细胞的降血糖作用

背景：移植胰岛及胰岛细胞治疗糖尿病已初见成效,但由于胰岛来源匮乏和免疫排斥反应而研究受阻。 目的：移植将大鼠骨髓间充质干细胞在体外诱导分化为胰岛样细胞,观察其对糖尿病大鼠的治疗作用。 方法：将大鼠骨髓间充质干细胞用碱性成纤维细胞生长因子、肝细胞生长因子等诱导,免疫细胞染色等检测诱导情况。SD大鼠腹腔注射链脲佐菌素建立糖尿病模型,建模成功后,随机分为对照组移植诱导胰岛样细胞的实验组,实验组经肾包囊移植诱导后的胰岛样细胞,对照组移植相同体积生理盐水,观察移植后糖尿病大鼠血糖和体质量变化。 结果与结论：大鼠骨髓间充质干细胞体外经肝细胞生长因子、碱性成纤维细胞生长因子等因子诱导后可以向胰岛样细胞转化。细胞移植后,对照组大鼠血糖无明显变化(P > 0.05),实验组大鼠血糖与对照组和移植前相比较,明显降低(P < 0.05)。大鼠骨髓间充质干细胞经含肝细胞生长因子、碱性成纤维细胞生长因子等的诱导体系可诱导成胰岛样细胞,经诱导的细胞有一定胰岛素分泌能力,将诱导后细胞通过肾包囊途径移植入糖尿病大鼠体内,可降低大鼠血糖水平。     

De novo cancers and post-transplant lymphoproliferative disorder in adult liver transplantation

De novo cancer is one of the most serious complications after organ transplantation. Chronic immunosuppression, viral agents, pretransplant chronic alcohol-induced and other addictive behavior-induced injury are important conditions associated with the development of de novo cancers in solid organ transplants. The aim of the study was to evaluate types and clinical course of de novo cancers in adult liver transplant recipients. Data regarding 502 adult patients who underwent to 554 liver transplantations have been collected. Sex, age at transplantation, immunosuppressive regimen, time from transplantation to diagnosis of cancer, cancer type, surgical and non-surgical treatments and follow-up time have been analyzed as well as acute rejection episodes and viral status. Thirty patients developed 31 de novo cancers. The predominant tumors were carcinoma of the skin, lymphomas and Kaposi's sarcoma. Kaposi's sarcoma and lung cancer were associated with greater mortality. In lymphomas and Kaposi's sarcoma, a high rate of graft involvement was observed. In liver transplant recipients, de novo cancers demand strategies focusing on prophylactic and careful long-term screening protocols. Lymphomas and Kaposi's sarcoma should be ruled out in all patients with clinical manifestations of chronic biliary obstruction.     

Pancreas Transplantation for Diabetes Mellitus

Between 1966 and 1997, over 10 000 pancreas transplants were performed worldwide, 88% of these being simultaneous kidney-pancreas transplantations (SKPTs). The overall 1-year patient survival rate exceeds 90%, and the graft survival (complete insulin independence) rate is 80%. SKPT should be regarded as the treatment of choice in carefully selected patients with type 1 (insulin-dependent; IDDM) diabetes mellitus and advanced nephropathy, because of its ability to offer superior glycaemic control and an improved quality of life. Studies have shown that the addition of a pancreas transplant does not appear to jeopardise either the patient or the kidney transplant, as many centres report either similar or improved survival rates after SKPT compared with kidney transplantation alone. Indications for solitary pancreas transplantation are based on the presence of early, well defined diabetic complications or glucose hyperlability with poor quality of life. Improvements in quality of life and possible prevention of further morbidity associated with diabetes makes pancreas transplantation an important therapeutic option for selected diabetic patients. According to registry data from the United Network for Organ Sharing (UNOS) Registry, rejection accounts for 32% of graft failures in the first year after pancreas transplantation. Most pancreas transplant centres employ quadruple drug immunosuppression with antilymphocyte induction with either a monoclonal or polyclonal agent. Maintenance immunosuppression involves triple therapy, consisting of a calcineurin inhibitor (cyclosporin or tacrolimus), corticosteroids and an antimetabolite (azathioprine or mycophenolate mofetil). Before 1995, nearly all pancreas transplant recipients were managed with the original formulation of cyclosporin ('Sandimmun'). In the past 2 years, tacrolimus-based therapy has been used in approximately 20% of cases and a new microemulsion formulation of cyclosporin ('Neoral') has replaced the original formulation in contemporary post-transplant immunosuppression. In addition, mycophenolate mofetil is replacing azathioprine as part of the standard immunosuppressive regimen after pancreas transplantation. At present, a number of centres are conducting various trials with new drug combinations including either cyclosporin microemulsion or tacrolimus in combination with corticosteroids and mycophenolate mofetil with or without antibody induction therapy. The current array of new immunosuppressive agents is providing more effective control of rejection and permitting solitary pancreas transplantation to become an accepted treatment option in diabetic patients without advanced complications. Immunosuppressive strategies will continue to evolve to achieve effective control of rejection while minimising injury to the allograft and risk to the patient. In addition, new regimens must not only address the issue of specific drug toxicities but also long term economic, metabolic and quality-of-life outcomes.     

Interleukin-2 receptor blockers in renal transplantation

The last two decades have witnessed significant advances in the renal transplantation immunosuppressive protocols. The introduction of mycophenolate mofetil, tacrolimus, sirolimus and polyclonal antibodies has significantly improved graft survival. However, intensification of immunosuppression results in complications such as malignant diseases, opportunistic infections and metabolic disturbances with consequential increase in cardiovascular mortality. Advances in molecular engineering have made possible the development of monoclonal humanized or chimeric antibodies, which will not induce the host immune response with production of neutralizing antibodies or serum sickness. Antibodies directed against the alpha chain of human IL-2 receptor have recently been introduced into immunosuppressive protocols. Daclizumab is a humanized antibody, and basiliximab is a chimeric antibody, engineered by cloning segments of the murine immunoglobulin sequence into the human-immunoglobulin gene. It decreases immunogenicity while maintaining high specificity for IL-2R alpha chain. The efficacy and safety of both preparations have been reported in large randomized studies. Their use in induction resulted in a significant decrease in acute graft rejections after renal transplantation. The possibility of decreasing the dose or complete withdrawal of certain immunosuppressive agents with the use of IL-2R blockers seems promising for further improvement in the longterm graft survival. Longterm follow-up is necessary to determine their role in solid organ transplantation.     

Islet transplantation in the twenty-first century

Isolated islet transplantation is poised for clinical application to treat insulin-dependent diabetes. Unlike exogenous insulin therapy, islet transplantation has promise for preventing and/or reversing the dismal secondary complications of diabetes. Islet transplants are arguably the most unique type of allografts, and we discuss their properties, limitations, and potential in this overview. The induction of immunologic tolerance to allow islet grafts to endure and prevail, without the hardship of chronic immunosuppressive therapy, is a major goal in this field. In this context, we discuss our successful results in preclinical models of primate allogeneic and xenogeneic islet graft tolerance.