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Regenerative medicine aims to replace a body function or specific cell loss. It includes therapies at the forefront of modem medicine, issuing from translational biomedical research. Transplantation of organs and cells has revolutionized the management of patients for whom medical treatment is a failure. Unfortunately, organ shortage is limiting treatment possibility. As an example, among the 15,000 patients with type I diabetes in Switzerland, only approximately 30 can receive a pancreas or an islet transplant per year. Second example, 500 patients die each year in Switzerland from alcoholic cirrhosis because no treatment is available. Transplantation of islet cells, hepatocytes, mesenchymal stem cells or dopaminergic neurons represents hope fora therapy available for large populations of patients.

Aim: Islet transplantation is gaining recognition as a therapeutic option for selected diabetic patients. The immunosuppressive regimen based on sirolimus/low-dose tacrolimus is considered a major breakthrough that allowed considerable improvement in graft survival. A high incidence of side effects associated with such a regimen has been reported in the literature, but this immunosuppressive protocol is generally considered safe or even protective to the kidney. Herein, we analyze the impact of the sirolimus/low-dose tacrolimus-based protocol on kidney function., Patients and Methods: Five islet-after-kidney and 5 islet-transplant-alone patients were enrolled and followed up. Renal function was assessed by the periodic measurement of serum creatinine and by the presence of albuminuria. Metabolic control markers and graft function were followed, as well as immunosuppressive whole blood trough levels., Results: Kidney function significantly decreased in 6 of 10 patients. Neither metabolic markers nor immunosuppressive drugs levels were significantly associated with the decreased kidney function., Conclusion: Although a specific etiology was not identified, subsets of patients presented a higher risk for decrease of kidney function. The presence of low creatinine clearance, albuminuria, and long-established kidney graft were associated with poorer outcomes.

Background: Cellular immunity plays a major role in rejection of xenografted islets. Depending on the phylogenetical disparity, direct or indirect antigen presentation is predominant. The aim of this study was to analyze in vitro the predominance of direct or indirect presentation, and in vivo the effect of macrophage depletion on concordant and discordant islet xenograft survival., Materials and Methods: In vitro, we performed mouse antirat and mouse antihuman mixed lymphocyte reactions (MLR) after depletion of responder or stimulator antigen-presenting cells. In vivo, streptozotocin-induced diabetic C57BL/6 mice were treated by gadolinium chloride to deplete macrophages and rat or human islets were transplanted under the kidney capsule. Islet function was followed by glycemia and xenografts were analyzed at regular intervals for histology., Results: Mouse antirat MLR showed a predominant direct antigen presentation pathway, whereas in mouse antihuman MLR, direct and indirect pathways were similarly involved. Survival of rat islets was not modified by GdCl therapy. In contrast, survival of human islets was significantly prolonged in GdCl-treated mice. Macrophage infiltration was decreased in concordant and discordant GdCl-treated xenografts at day 4, compared to controls. At day 15, macrophage infiltration was similar in all groups., Discussion: Our results indicate that direct antigen presentation is dominant in rejection of concordant islet xenografts and cannot be influenced by host macrophage depletion. Both direct and indirect antigen presentation are involved in rejection of discordant xenogeneic islets. Macrophage depletion or inhibition should be considered as therapeutic tool for discordant islet xenotransplantation.

Background: Costimulatory blockade has been shown to allow long-term survival of xenogeneic islets. The aim of the present study was to evaluate the role of recipient CD40 and CD154 in the rejection process of concordant and discordant islet xenotransplantation (Tx)., Methods: Diabetic C57BL/6 mice, CD40- or CD154 knockout (KO) mice were transplanted with either concordant rat or discordant human islets., Experimental Design: group 1, control (ie, C57BL/6 mice received islet Tx without therapy); group 2, C57BL/6 mice received islet Tx with anti-CD154 monoclonal Ab (mAb) therapy; group 3, CD40 KO mice; and group 4, CD154 KO mice were used as recipients without therapy. Mouse anti-rat mixed lymphocyte reactions (MLR) were performed using mouse splenocytes obtained from animals transplanted with rat islets in groups 1 to 4., Results: In group 2, short-term anti-CD154 mAb therapy significantly prolonged rat-to-mouse and human-to-mouse xenograft survival, compared to controls. In CD40-KO and CD154-KO recipients, survival of concordant or discordant islets was not prolonged significantly compared to control groups. Mouse anti-donor rat cellular responses were reduced approximately 50% in group 2 but remained unmodified in groups 3 and 4, when compared to group 1., Conclusions: Improved graft survival and reduced MLR responses against donor cells in vitro among the anti-CD154 mAb-treated mice could be explained by specific targeting of activated T cells with subsequent inactivation by anergy and/or elimination by apoptosis, or complement- or cellular-mediated mechanisms. Rejection of xenografts and strong MLR responses against donor cells in vitro in CD40 or CD154 KO animals is possible through efficient activation of alternate pathways of costimulation.

Liver transplantation is a standardized therapy for end-stage liver disease. With current immunosuppressive protocols and patient care, ten-year patient survival rate has reached 60%. Several medical complications may develop during this period, including renal dysfunction, hypertension, diabetes mellitus, hyperlipidemia, and metabolic bone disease. The aim of this article is to analyze long-term results of several clinical trials reporting common medical dysfunctions after liver transplantation and to discuss their management.

Living donor liver transplantation is a relatively new procedure in which the right side of the liver is harvested in a healthy donor and transplanted into a recipient. After the first case in 1994, over 3000 cases have been done worldwide. This review summarizes the reasons why the procedure is needed, describes its main technical aspects, highlights the boundaries in which it can be done safely, summarizes the current experience worldwide and describes the main points of the program in our unit. We argue that living-donor transplantation is a viable alternative to a long time on the waiting list for several patients, and it can be performed safely and successfully provided that all precautions are undertaken to minimize the risks in the donor and to increase the chances of a good outcome in the recipients. If these prerequisites are met, and within the framework of a structured multidisciplinary program, we believe that living-donor liver transplantation should be funded by health insurances as a recognized therapeutic option.

Islet of Langerhans transplantation is gaining recognition as a therapy for type 1 diabetes. The procedure involves enzymatic digestion of the pancreatic tissue, purification of the islets from the exocrine tissue, infusion of the islets into the portal vein and implantation in the liver. Until 1999, and overall rate of insulin independence of 14% at one year was reported in the International Islet Transplant Registry. The results of the "Edmonton protocol" since 2000 were a breakthrough in the field, with reports of 80% insulin independence at 1-year after solitary islet transplantation in non uremic patients with brittle type 1 diabetes. A rapamycin-based, steroid-free, islet-sparing immunosuppressive regimen was designed and the problem of the insufficient islet mass was tackled by sequential infusions of islets isolated from at least two pancreatic. The University of Geneva has been involved in clinical islet transplantation since 1992, and has performed 51 allogeneic and 17 autologous. Twenty-one patients have been transplanted in Geneva since 2002. They were five solitary islet transplants, 14 islet after kidney transplants and two simultaneous islet-kidney (SIK) recipients. Insulin independence was achieved in 67%.