Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 6, Issue 2, 2006

Ever since Paul Langerhans described characteristic cell clusters in the pancreas in 1869, they have been the subject of a vast amount of research, mainly focusing on finding a cure for diabetes. Since the number of patients with diabetes is rapidly increasing and is estimated to reach 150-220 million worldwide by the year 2010, this topic is becoming increasingly important. Over the last few years, the transplantation of islets has become a realistic option for the treatment of selected patients with type 1 diabetes mellitus. However, even though progress has been made, there are still hurdles to overcome before a definite cure for every individual suffering from type 1 diabetes can be provided. Inadequate supplies of insulin producing cells, poor post-transplantation performance of the islets, and the requirement of life-long treatment of patients with immunosuppressive drugs are some of the challenges that clinicians and researchers face. In view of this, I am very honoured and pleased to have some of the leading research groups in the field of diabetes research contributing to this themed issue of islet transplantation; hopes and hurdles. The latest news on a diverse range of topics including fascinating articles regarding islet isolation, clinical islet transplantation, stem cells and angiogenesis are published in this special issue. At last, I sincerely hope that you enjoy the articles provided in this themed issue and that we can someday say that we have won the battle against diabetes mellitus.

Mammalian cell encapsulation is under investigation for the treatment of a wide variety of diseases, since it allows for transplantation of endocrine cells in the absence of undesired immunosuppression. The technology is based on the principle that transplanted tissue is protected for the host immune system by an artificial membrane. In spite of the simplicity of the concept, progress in the field of immuno-isolation has been hampered. During the past two decades, three major approaches of encapsulation have been studied. These include (i) intravascular macrocapsules, which are anastomosed to the vascular system as AV shunt, (ii) extravascular macrocapsules, which are mostly diffusion chambers transplanted at different sites, and (iii) extravascular microcapsules transplanted in the peritoneal cavity. The advantages and pitfalls of the three approaches are discussed and compared in view of applicability in clinical islet transplantation. At present, microcapsules, due to their spatial characteristics, offer better diffusion capacity than macrocapsules. During the past five years, important advances have been made in the knowledge of the characteristics and requirements capsules have to meet in order to provide optimal biocompatibility and survival of the enveloped tissue. Novel insight shows that islet-cells themselves and not the capsule materials should be held responsible for loss of a significant portion of the immuno-isolated islet cells and, thus, failure of the grafts on the long term. New approaches in which newly discovered inflammatory responses are silenced bring the technology of transplantation of immunoisolated cells close to clinical application.

Successful islet transplantation depends on the infusion of sufficiently large quantities of islets, requiring multiple pancreas donors per recipient. Unfortunately, more than 70% of functional islet mass are lost in the early posttransplantation phase. Unlike whole-organ transplantation by which grafts are implanted as vascularized tissue, islets are transplanted as single islets or islet clusters that are considered avascular. As a result, microvascular perfusion to newly transplanted islets does not resume immediately after transplantation and can take up to weeks until the reestablishment of a functional microvasculature within islet grafts. Delayed and insufficient islet revascularization can deprive newly transplanted islets of oxygen and nutrients, resulting in islet cell death and contributing to early graft failure. There is mounting evidence that impaired islet revascularization constitutes an independent factor that reduces the viability and compromises the function of transplanted islets, thereby limiting the success rate of islet transplantation. In this article, we will review the most recent advances made in deciphering the underlying mechanism of islet revascularization and exploring therapeutic strategies for enhancing islet revascularization and preserving functional islet mass in diabetic recipients.

Pancreatic islet transplantation is a tempting strategy to treat patients with type 1 diabetes mellitus, since if successful it could provide a cure for the disease. At present, there is, however, a poor long-term outcome of such transplantations compared to the results for whole pancreas transplantation. One explanation for this may be inadequate engraftment of the transplanted cells in the new microenvironment. The engraftment process includes immediate survival in the post transplantation phase. There is likely extensive cell death immediately following transplantation mainly due to inflammatory responses triggered by e.g. hypoxia. Also the long-term survival and function of the transplanted islets is encompassed by the term engraftment. This is influenced by the cellular turn-over rate, and the degree of revascularization and reinnervation of the islet tissue. To regain optimal function in surviving cells, new vascular and nervous systems similar to those in endogenous islets need to form. Both qualitative and quantitative changes compared to endogenous islets have, however, been described in the new vascular system that develops following transplantation, and these changes seem to have consequences for islet blood perfusion, metabolism and function. Comparatively little is known regarding the extent of functional re-growth of nerves that occurs, and its influence on graft function. This review also discusses the challenges of engraftment that seem specific for intraportally transplanted islets, e.g. the instant blood mediated immune reaction, the loss of glucagon response to hypoglycemia, and the lower β-cell proliferation rate in intraportally transplanted islets than in islets grafted to the kidney.

Reduced β-cell numbers and function (β-cell failure) contribute to essentially all forms of diabetes, and must be corrected if established disease is to be cured. Current therapies have been shown not to prevent β-cell failure and the availability of insulin-secreting cells for replacement-based therapies is severely restricted. Researchers have responded to this challenge by aiming to generate new β-cells (or β-like cells) in vitro or potentially in situ, by diverse strategies including manipulation of stem cells, β-cells, or even non- β-cells such as hepatocytes. Which ever approach is ultimately most successful is at present not known, what is certain is that progress will needs to be informed by a deeper understanding of those cellular processes which determine β-cell differentiation, renewal and survival. Interest in this approach has been fuelled by the remarkable capacity for β-cell replication and renewal demonstrated in many model systems. Potential regulatory factors have already been identified and include various proteins required for promoting the G1/S transition of the cell cycle, including c-Myc and downstream transcriptional targets such as cyclin D and E2F family members. It is likely that for these factors to be exploited therapeutically, that we will need to circumvent the inherent tumor suppressor activity associated with aberrant activity of these proteins, including avoidance of apoptosis and growth arrest. Much recent work has begun to unravel the complexity of growth-regulating networks in which these proteins are involved and there is reason for future optimism.

Accelerated developments and improved understanding of the issues that face clinical islet cell transplantation during the last 20 years have led this simple concept to a successful treatment for diabetes. Islet cell transplantation involves the extraction of islets of Langerhans from organ donors through complex digestion and purification processes. After implantation in patients with type-1 diabetes, the treatment can provide near perfect, moment-to-moment control of blood glucose, far more effectively than injected insulin. The procedure offers the benefits of whole pancreas transplantation, but with less risk. Since the introduction of "Edmonton Protocol", significant advances in islet isolation techniques and purification technology, novel immunosuppressants and tolerance strategies have renewed interest in clinical islet transplantation for the treatment of diabetes mellitus. The "Edmonton Protocol" has been successfully replicated by other centers in an international multicenter trial. A number of key refinements in pancreas transportation, islet preparation and newer immunological conditioning and induction therapies have led to continued advancement through extensive collaboration between key centers. This article provides an overview of the history of islet transplantation followed by discussion on current controversies of donor selection, pancreas procurement, hypothermic preservation solutions, current islet isolation technique, islet transplantation procedure, post transplantation immunology, and developments for future.

Pancreatic tissue, processed for subsequent clinical islet transplantation, is exposed to enormous biophysical and biochemical stress causing injury and death in a large number of islets even before they are transplanted. Since several steps within this heterogenous process are associated with non-physiologic and harmful ambient conditions the damaging mechanisms are attributed to four different determinants: 1) brain death in the organ donor, 2) insufficient oxygen supply during pancreas procurement, isolation processing, culture and after intraportal transplantation, 3) destruction of the natural environment during isolation, and 4) exposure to toxic reagents during the isolation process. Potential strategies to ameliorate the detrimental impact of these factors on the quality of subsequently transplanted islets are discussed.

Diabetes affects an estimated 150 million people worldwide, being the most prevalent metabolic disorder. The pathology is characterized by a selective destruction of pancreatic β-cells and is divided into two main types: type 1 and type 2. Type 1 diabetes results from an autoimmune-mediated destruction of insulin-producing β-cells. Type 2 diabetes is a more complex pathology, presenting a progression from insulin resistance in peripheric tissues (muscle and adipose) to a fail use in β-cell function and insulin secretion, culminating in the activation of apoptotic mechanisms and β-cell death. In this context, scientists are proposing novel therapeutic strategies that might allow perfect glycemic control for most patients with diabetes. Embryonic stem cells are pluripotent cells derived from the inner cell mass of blastocysts. Adult stem cells are committed cells present in certain niches located in adult tissues and responsible for tissue repair and regeneration. Recently, the development of appropriate culture conditions for the differentiation of these cells into specific fates has permitted their use as potential therapeutic agents for several diseases. The therapeutic potential of transplantation of insulin-secreting pancreatic β-cells has stimulated the interest in using stem cells as a starting material from which to generate insulin secreting cells in vitro. Insulin-producing cells derived from stem cells have been shown to reverse experimentally induced diabetes in animal models. This review will summarize the different approaches that have been used to obtain insulin-producing cells from stem cells by focussing on key points that will allow in vitro differentiation and subsequent transplantation on the future.