Area of Expertise

Islet Cell Transplantation
Type 1 diabetes is a chronic debilitating disease that affects more than one million individuals in the United States - the overwhelming majority of whom are diagnosed in childhood. In addition to requiring self-administration of insulin many times a day, patients typically can suffer many complications in the course of their lifetime, including kidney failure, nerve damage, heart disease, and blindness. Although whole organ transplant is an effective treatment, it is associated with much higher perioperative risks. Islet transplantation, a minimally invasive procedure, is currently performed under local anesthesia as an out-patient procedure that typically takes less than an hour to complete.

The goal of islet cell transplantation is to give diabetics back the ability to produce insulin, the vital hormone that is needed to regulate blood sugar levels, by transplanting islet cells, the cells that actually produce insulin. These fragile clusters of cells comprise only one to two percent of the total pancreas and are scattered throughout the organ. Islet cell separation technologies allow these cell clusters to be culled from a donor cadaveric pancreas and transplanted into a recipient with diabetes at minimal risk to the patient so he or she can produce insulin once again.

The islet cell transplant takes place in an interventional radiology suite and the islets are infused in a way similar to the way an intravenous (IV) drip is administered. After the patient receives local anesthesia and a light sedation, a small catheter is inserted just under the patient’s lower rib into the portal vein that leads to the liver. The islets then drip into the liver where they reside and begin to produce insulin. As with any transplant, recipients must take life-long immunosuppression, or anti-rejection, drugs to prevent rejection of the donor cells.

Though still experimental, islet cell transplantation offers a number of advantages

• No major surgery is required, and thus there is less risk to the patient and a much shorter recovery time. Patients typically leave the hospital in three to four days.
• Transplanting only the islet cells avoids the double load of digestive enzymes. In whole organ transplants, the patient’s failing pancreas is not removed and continues to perform its digestive functions although it can no longer produce insulin.
• Islet cells can be treated and/or manipulated in the lab prior to transplantation.

Scientists at the Diabetes Research Institute (DRI) have already shown that islet cells can function for more than 11 years once transplanted -- the longest functioning transplants to date. The patients in this particular study require small amounts of insulin together with immunosuppressive drugs to prevent rejection, and they continue to maintain normalized blood sugar levels. These results support the notion that islet replacement, even when partially successful, is associated with very significant benefits. In particular, the normalization of HbA1c levels and absence of hypoglycemic episodes that would require medical assistance is a clear advantage over intensive insulin regimens, offering an improved quality of life and reduced risk and severity of complications.

The Ricordi Method for Isolation of Islet Cells
The Ricordi Method, an automated procedure for isolating of pancreatic islet cells, was developed in 1986 by the Diabetes Research Institute’s scientific director Camillo Ricordi, M.D., while working in the laboratory of Paul Lacy, M.D., at Washington University in St. Louis. The method, which includes the use of the Ricordi Chamber, helped earn Dr. Ricordi the Nessim Habif World Prize in Surgery from the University of Geneva in 2001. The prize is given for the invention of a machine or apparatus that has made it possible to achieve significant progress in a field of surgery.

Dr. Ricordi’s invention of the automated method of islet isolation made it possible for scientists to obtain larger numbers of islets from a human pancreas. Further improvements on the Ricordi Method have made it possible to isolate enough islets from one pancreas to transplant one patient. Until recently, as many as five and six organs were needed to carry out one transplant, making the advent of this automated method a major step forward in the field. The Ricordi Method continues to be the backbone of all islet cell isolation procedures.

Cellular Isolation and Preservation
Cellular isolation and preservation is one of the areas of research for which the Diabetes Research Institute is best known. The DRI is the first facility in the United States to demonstrate that islets processed at one center can be safely preserved, transported, and transplanted at another institution across the country. This technique allows donor organs from any state in the country to be processed in Miami and the resulting fragile cells preserved and successfully transplanted into a patient in another state. Therefore, patients with diabetes need no longer reside close to an islet isolation facility to be candidates for this procedure.

Bone Marrow Isolation Pre-Clinical Studies
The DRI’s pre-clinical program serves as a bridge for translating key findings made in the basic sciences into clinical application. Ongoing DRI studies have two primary objectives

• to enhance islet graft survival and, ultimately, induce donor specific tolerance
• to assess the immunological alterations that occur in pre-clinical recipients of islet transplants

The emphasis of this program is placed on defining the mechanisms that are involved in islet acceptance and long-term survival. Currently, the DRI’s multifaceted approach to tolerance induction is centered on first determining the effect of donor bone marrow infusions and chimerism on the survival of islet transplants and, secondly, on identifying and testing novel immunointervention strategies to improve islet transplant success.

Stem Cell Research
Multiple research projects involving stem cells are conducted at the DRI, including a recently implemented program under Daniel H. Mintz, visiting professor, Helena Edlund, Ph.D., a leader in the field of pancreatic cell development. Edlund has contributed seminal observations on pancreatic ontogeny, defining developmentally regulated genes that are fundamental in the ontogeny of the endocrine pancreas.

The main goal of this line of research is to gain profound knowledge about the sequence of events and triggers that affect the development of the endocrine pancreas. The long- term strategy is to be able to repeat the fundamental developmental stages and re-create beta cells from selected cell precursors for the production of insulin. There is growing evidence that several populations of multi-potent stem cells can be driven to acquire beta cell form and function. Understanding the critical steps that normally guide stem cells toward developing into functioning pancreas cells capable of producing insulin will allow us to refine strategies to generate beta cells in the laboratory. Success in this approach would solve one current and pressing problem: the shortage of insulin-producing tissue for transplantation in relation to the huge number of patients who could benefit from the procedure.

Immune Tolerance Network (ITN)
The DRI is part of a $142 million, seven-year initiative called the Collaborative Network for Clinical Research on Immune Tolerance. This ambitious project aims to unite the efforts of leading researchers in order to accelerate clinical trials under the auspices of the National Institute of Allergy and Infectious Diseases, a branch of the National Institutes of Health.

Dr. Ricordi heads the clinical islet sub group of the network, the division charged with developing “tolerogenic approaches” for use in clinical islet transplant trials for patients with Type 1 diabetes.

The network involves nearly 40 research institutions and hopes to result in improvements for the management of not only Type 1 diabetes, but also other immune system disorders such as lupus, arthritis, and asthma. This project constitutes one of the largest National Institutes of Health awards for clinical research and is the first such program for cross-disciplinary research on immune tolerance. The first clinical trial is already under way at the University of Miami and other participating centers.

Islet Cell Resource Center
The objective of the Islet Cell Resource (ICR) Center is to continue and further expand the mission of the existing cGMP Islet Cell Processing Facility at the University of Miami’s Diabetes Research Institute by participating in the network of ICR centers.

The specific aims of this collaborative effort are

• to optimize isolation procedures to obtain high yields of functional islet cells
• to provide well-characterized islet cells for transplantation into patients with Type 1 diabetes
• to distribute islet cells to investigators for clinical research or eligible research applications
• to develop isolation, preservation, and shipment procedures that result in maximum islet cell function upon transplantation

Human Islet Isolation and Transplantation Techniques Annual Training Workshop
The Diabetes Research Institute was host to the first Human Islet Isolation and Transplantation Techniques Annual Training Workshop, a three-day training workshop on human pancreatic islet isolation, purification, and culture techniques, covering manufacturing and production, FDA regulations, cGMP/cGTP requirements, and clinical transplantation protocols.

This workshop was hosted by leading scientists in islet transplantation and endorsed by the Cell Transplant Society and the International Pancreas and Islet Transplantation Association. More than 70 participants attended the highly interactive conference in Miami, and plans for the following workshop are under way for the fall. Approximately two training sessions per year will be given on a rotational basis, ensuring participants the latest information on islet cell processing technology and methodology.