Field Of Islet Transplantation Research Articles

Seeing is believing: How the MIP-luc mouse can advance the field of islet transplantation and β-cell regeneration

In the last five years, bioluminescence has emerged as a vital tool in the non-invasive quantification of beta-cell mass following islet transplantation in murine models. The successes achieved in bioluminescence imaging in islet transplantation has prompted its use in the discipline of beta-cell regeneration. Employing bioluminescence permits quantifying changes in β-cell mass in an individual mouse over time, which can provide valuable insights into the kinetics of beta-cell regeneration.

The in vivo performance of polyvinyl alcohol macro-encapsulated islets

Islet transplantation is a method for the treatment of type 1 diabetes mellitus (DM) and has been widely performed around the world. The long-term cryopreservation of islets shows many advantages in the field of islet transplantation. Previous studies have described the development of sheet-type polyvinyl alcohol (PVA) macro-encapsulated islets (MEI) to treat type 1 DM without any immunotherapy. The present study examined their beneficial effects on islet cryopreservation. PVA MEI of Wistar rats were divided into three groups of 1-day, 7-day and 30-day cryopreservation at −80 °C. The 30-day group showed a lower recovery rate of the islet number and impaired insulin release in comparison to the 1-day group, whereas no significant differences of the in vitro results were observed between the 1-day and 7-day groups. The MEI transplantation recipient mice in the 1-day and 7-day groups reached normoglycemia for a 4-week observation period, and the recipients in 30-day group also showed a significant decrease followed by a slightly higher non-fasting blood glucose level. These results suggest that the PVA MEI are useful for islet long-term cryopreservation, and that the use of cryopreserved PVA MEI may, therefore, be a promising modality for performing DM therapy.

Amyloid Deposition in Transplanted Human Pancreatic Islets: A Conceivable Cause of Their Long-Term Failure

Following the encouraging report of the Edmonton group, there was a rejuvenation of the islet transplantation field. After that, more pessimistic views spread when long-term results of the clinical outcome were published. A progressive loss of the β-cell function meant that almost all patients were back on insulin therapy after 5 years. More than 10 years ago, we demonstrated that amyloid deposits rapidly formed in human islets and in mouse islets transgenic for human IAPP when grafted into nude mice. It is, therefore, conceivable to consider amyloid formation as one potential candidate for the long-term failure. The present paper reviews attempts in our laboratories to elucidate the dynamics of and mechanisms behind the formation of amyloid in transplanted islets with special emphasis on the impact of long-term hyperglycemia.

An Odyssey of Islet Transplantation for Therapy of Type 1 Diabetes

Canadian surgical contributions to the field of islet transplantation have a rich heritage and a promising future. In this article, some seminal Canadian contributions to this field are reviewed, including contributions at the basic research laboratory and translational applications to bedside therapy of type 1 diabetes.

Therapeutic Approaches to Counteract Immediate Blood-Mediated Inflammatory Reaction in Islet Transplantation

Therapeutic Approaches to Counteract Immediate Blood-Mediated Inflammatory Reaction in Islet Transplantation

Islet Transplantation: Steeple Chase and the Next Hurdle

Islet Transplantation: Steeple Chase and the Next Hurdle

Paul Eston Lacy, MD, PhD

It was a wonderful birthday celebration. Because Paul Eston Lacy would turn 80 on 7 February 2005, luminaries in the field of islet transplantation from around the world came to honor him in Philadelphia on 1 December 2004. Lee Ducat of NDRI (National Disease Research Interchange) carefully selected the speakers and artfully managed the affair. Pictures of Paul holding his signature pipe seemed to be everywhere. So did Paul, grinning graciously, enthusiastically greeting his many friends and admirers. The large audience heard scientific presentations, sharp questions, circumspect answers (and a few edgy ones), and enjoyed interactive meals. His old-time friends presented him with a bound volume of personal letters of tribute. The first Paul E. Lacy Medal was awarded to James Shapiro of Edmonton. Paul himself spoke effortlessly and knowingly of the history of islet transplantation and made predictions for the future. His life-long passion and dedication to curing patients of diabetes was never more evident. He was his usual robust, folksy, confident, and humble self. One could not have …

INTERNATIONAL MULTI-CENTER TRIAL OF ISLET TRANSPLANTATION USING THE EDMONTON PROTOCOL IN PATIENTS WITH TYPE 1 DIABETES

O449* The Immune Tolerance network international multicenter trial using the Edmonton Protocol was designed to explore the safety and efficacy of islet-alone transplantation in patients with Type 1 diabetes. Stringent enrollment criteria included metabolic lability, recurrent hypoglycemic or progressive complications of diabetes. Only optimal patients were selected based on strict weight limitation (70kg) and adequate renal reserve (CC>80ml/min/1.73m). The trial involved nine sites in Canada, the US and Europe, with a target enrollment of 36 patients. All 36 participants have been enrolled and have received at least one islet transplant. We anticipate all transplants to be completed in the next several months. Clinical follow-up will continue for three years post final transplant with the primary endpoint assessed at one-year post the patient’s final transplant. Updated information regarding the number of transplants, insulin independence, glucose control, complications related to transplantation and overall safety will be available for presentation. Conclusions: The preliminary findings from this trial support the safety and efficacy of islet-alone transplantation, and indicate that the Edmonton Protocol may be successfully replicated across centers internationally. Standardization of islet processing between centers remains a major challenge, but it should not delay the development of successful clinical protocols in the field of islet transplantation.

Current status of clinical islet transplantation: advances and obstacles

Purpose of review Historically, the field of clinical islet transplantation began in earnest from 1974 to 1996. In these early attempts, generally less than 10% of Type 1 diabetic islet recipients ever achieved insulin independence. Thus, while the “proof of principle” had been demonstrated in these rare successes, a more consistently successful protocol was necessary for the field of islet transplantation to advance beyond its conceptual stages. Recent findings The dramatic breakthrough in 2000 with the ‘Edmonton protocol’ for successful solitary islet transplantation has restored optimism for the application of islet transplantation as a treatment for Type 1 diabetes. Due to recent successes, islet transplantation has evolved from a theoretical concept to its current status as a potential therapeutic option for patients with Type 1 diabetes. Summary This review focuses on the progress that has been made since this landmark transplantation trial and on important obstacles that continue to impede wider application of clinical islet transplantation.

NIH-Supported National Islet Transplantation Registry.

An estimated 300,000 to 500,000 cases of type 1 diabetes exist today in the United States. Despite strict monitoring and attempts at control, people with type 1 diabetes still face the prospect of diminished health and earlier death than the general population. Islet transplantation offers an alternative to insulin usage and a potential treatment for type 1 diabetes mellitus. There are more than 30 islet transplant centers in the world focusing their efforts on the challenges and methods of this procedure. As the field of islet transplantation matures and the number of islet transplants performed increases, detailed analyses on factors that predict patient and graft survival are needed. This increased amount of data will allow for a better understanding of the safety and efficacy of islet transplantation. In response to the need for more complete information in the field, the National Institute of Diabetes and Digestive and Kidney Diseases is sponsoring the North American Collaborative Islet Transplant Registry (CITR). The mission of CITR is to expedite progress and promote safety in islet/beta-cell transplantation through the collection, analysis, and communication of comprehensive and current data on all islet/beta-cell transplants performed in North America. Compiling and analyzing data from all transplant centers in North America will accelerate the identification of both critical risk factors and key determinants of success, and thereby guide transplant centers in developing and refining islet/beta-cell transplant protocols, leading to an advancement in the field of islet transplantation. Participation in CITR is voluntary, and more than 22 transplant centers have been invited to join. Seven centers are actively participating in CITR, with an additional 11 centers in the process of joining. Both an executive committee and a scientific advisory committee guide CITR. All islet transplants performed in North America since January 1, 1996, are captured by the CITR database. Through an electronic, Internet-based data capture system, quality control procedures, and minimization of duplicate efforts at the transplant center, the most relevant and succinct information are entered. From these data a comprehensive report will be published annually. In addition, special analyses will be performed and published periodically.

Genetic engineering of insulin expression in nonislet cells: implications for beta-cell replacement therapy for insulin-dependent diabetes mellitus.

Insulin-dependent diabetes mellitus (IDDM) occurs as a consequence of autoimmune destruction of the insulin-producing pancreatic beta-cells. Although progress has been made in the field of islet transplantation, an appealing alternative strategy for beta-cell replacement therapy for IDDM is to target insulin expression to non-islet cells. We have recently generated transgenic nonobese diabetic (NOD) mice in which insulin gene expression was targeted to proopiomelanocortin (POMC)-expressing cells of the intermediate lobe (IL) of the pituitary. We have shown that POMC-expressing IL pituitary cells secreted large amounts of mature insulin, similar to islet beta-cells. However, in contrast to the insulin-producing islet beta-cells, the insulin-producing IL pituitary cells were not attacked by the immune system. Remarkably, transplantation of small amounts of the transgenic IL tissues into diabetic NOD mice resulted in the restoration of near-normogylcemia and the complete reversal of diabetic symptoms. In separate experiments, IL allografts showed enhanced viability and were highly vascularized, compared with similarly transplanted islet allografts. These features are highly advantageous in the transplantation setting and demonstrate the considerable potential of these non-islet cell types for insulin-gene delivery in IDDM.

Future prospects in diabetes management

New ways of treating insulin-dependent diabetes mellitis (IDDM) may help to prevent the insurgence of late diabetic complications associated with this condition. One approach involves immunointervention at the time of clinical diagnosis, with the aim of maintaining some residual β cell function. Research is also progressing in the field of islet transplantation, following significant developments in animal models.