Tolerance and pancreatic islet transplantation

Islet transplantation holds renewed promise as a cure for type I diabetes mellitus. Results of recent clinical trials have shown remarkable success, and have reignited universal optimism for this procedure. In spite of this success, the need for life-long immunosuppression of the recipient still limits islet transplantation to patients with poorly controlled diabetes or to those requiring kidney transplantation. It is obvious that the achievement of immunological tolerance would broaden the indication for islet transplantation to a much larger cohort of patients with type I diabetes mellitus, most likely preventing long-term complications and contributing to a much improved quality of life. Increased understanding of the basic mechanisms of tolerance induction has resulted in the implementation of numerous experimental approaches to achieve long-term survival of islet grafts in the absence of chronic immunosuppression. In this brief review we will attempt to summarize the current status of research and knowledge.     

Promoting islet cell function after transplantation

Engraftment (i.e., the adaptation of transplanted pancreatic islets to their new surroundings with regard to revascularization, reinnervation, and reorganization of other stromal compartments) is of crucial importance for the survival and function of the endocrine cells. Previous studies suggest that transplantation induces both vascular and stromal dysfunctions in the implanted islets when compared with endogenous islets. Thus the vascular density and the blood perfusion of islet grafts is decreased and accompanied with a capillary hypertension. This leads to hypoxic conditions, with an associated shift toward anaerobic metabolism in grafted islets. An improved engraftment will prevent or compensate for the vascular/stromal dysfunction seen in transplanted islets and thereby augment survival of the islet implant. By such means the number of islets needed to cure the recipient will be lessened. This will increase the number of patients that can be transplanted with the limited material available.     

In vivo imaging of islet transplantation

Type 1 diabetes mellitus is characterized by the selective destruction of insulin-producing beta cells, which leads to a deficiency in insulin secretion and, as a result, to hyperglycemia. At present, transplantation of pancreatic islets is an emerging and promising clinical modality, which can render individuals with type 1 diabetes insulin independent without increasing the incidence of hypoglycemic events. To monitor transplantation efficiency and graft survival, reliable noninvasive imaging methods are needed. If such methods were introduced into the clinic, essential information could be obtained repeatedly and noninvasively. Here we report on the in vivo detection of transplanted human pancreatic islets using magnetic resonance imaging (MRI) that allowed noninvasive monitoring of islet grafts in diabetic mice in real time. We anticipate that the information obtained in this study would ultimately result in the ability to detect and monitor islet engraftment in humans, which would greatly aid the clinical management of this disease.     

Isolated islet transplantation in experimental diabetes.

Pancreatic islets have been isolated from the exocrine pancreas of inbred rats by the collagenase digestion method. Transplantation of isolated islets into the portal venous system of streptozotocin diabetic recipients resulted in complete abrogation of the diabetic state as measured by non-fasting serum glucose level, 24 h urinary output, rate of weight gain and glucose tolerance test. Transplantation to other sites resulted in less than optimal survival and function of islets. Allogeneic islets, transplanted across weak histocompatibility barriers, can survive and function for prolonged periods of time when transplanted recipients are immunosuppressed with antilymphocyte serum (ALS). Recipients of allogeneic islets, after a period of immunosuppression with ALS, become permanently tolerant to the allografted islets and to subsequent skin grafts from similar allogeneic donors. Allografted islets are able to prevent the occurrence of diabetic renal and ophthalmic changes that occur in control diabetic animals which had not undergone transplantation.     

The role of endothelial cells on islet function and revascularization after islet transplantation

Islet transplantation has become a widely accepted therapeutic option for selected patients with type 1 diabetes mellitus. However, in order to achieve insulin independence a great number of islets are often pooled from 2 to 4 pancreata donors. Mostly, it is due to the massive loss of islets immediately after transplant. The endothelium plays a key role in the function of native islets and during the revascularization process after islet transplantation. However, if a delayed revascularization occurs, even the remaining islets will also undergo to cell death and late graft dysfunction. Therefore, it is essential to understand how the signals are released from endothelial cells, which might regulate both differentiation of pancreatic progenitors and thereby maintenance of the graft function. New strategies to facilitate islet engraftment and a prompt revascularization could be designed to intervene and might lead to improve future results of islet transplantation.     

The SPORTCOR registry: a national databank for sports cardiology

Being physically active is generally regarded as the best buy to prevent (cardiovascular) disease. Although the positive effects of regular exercise prevail, negative aspects of sports activity, particularly sportsrelated injuries, should not be ignored. Sudden cardiac death can be regarded as the most tragic sports-related injury.     

Adiponectin gene therapy prevents islet loss after transplantation

Significant pancreatic islet dysfunction and loss shortly after transplantation to the liver limit the widespread implementation of this procedure in the clinic. Nonimmune factors such as reactive oxygen species and inflammation have been considered as the primary driving force for graft failure. The adipokine adiponectin plays potent roles against inflammation and oxidative stress. Previous studies have demonstrated that systemic administration of adiponectin significantly prevented islet loss and enhanced islet function at post‐transplantation period. In vitro studies indicate that adiponectin protects islets from hypoxia/reoxygenation injury, oxidative stress as well as TNF‐α‐induced injury. By applying adenovirus mediated transfection, we now engineered islet cells to express exogenous adiponectin gene prior to islet transplantation. Adenovirus‐mediated adiponectin transfer to a syngeneic suboptimal islet graft transplanted under kidney capsule markedly prevented inflammation, preserved islet graft mass and improved islet transplant outcomes. These results suggest that adenovirus‐mediated adiponectin gene therapy would be a beneficial clinical engineering approach for islet preservation in islet transplantation.     

Molecular and cellular key players in human islet transplantation

Human islet transplantation could represent an attractive alternative to insulin injections for the treatment of diabetes type 1. However, such an approach requires a better understanding of the molecular and cellular switches controlling β-cell function in general as well as after transplantation into the liver. Although much research has been done into the suitability of stem or progenitor cells to generate a limitless supply of human β-cells, a reproducible and efficient protocol for the differentiation of such cells into stably insulin-secreting β-cells suitable for transplantation has yet to be reported. Fueled by recent findings showing that mature β-cells are able to regenerate, many efforts have been undertaken to expand this cell pool. Unfortunately, also these approaches had problems to yield sufficiently differentiated human islet cells. The aim of this review is to summarize recent findings describing some of the molecular and cellular key players of islet biology. A more complete understanding of their orchestration and the use of new methods such as real time confocal imaging for the assessment of islet quality may yield the necessary advancements for more successful human islet transplantation.