Research

One of the newest and most quickly evolving fields of bioengineered medicine involves nanoparticles, synthetic materials that are microscopic in size. Scientists at the DRI are studying whether these microscopic particles can be used to help diabetes patients tolerate transplanted cells. Work is underway to test if these particles can be loaded with anti-rejection drugs and, because they are so small, sent precisely to cells in the body that regulate the immune system’s response. By accurately targeting delivery of the drug to a specific cell, we can potentially reduce the immune response that would be triggered by the introduction of foreign tissue and allow diabetes patients to better accept transplanted insulin-producing cells. DRI scientists are also seeking new surgical sites of implantation for transplanted cells, be they encapsulated cells or cells loaded into biohybrid devices. Each and every day, members of the Division of Cellular Transplantation apply new technologies to existing scientific challenges so that research in the field of transplantation advances quickly, and clinical outcomes improve.

The DRI’s unique translational structure serves as a bridge for bringing key findings made in the lab into clinical application quickly and efficiently. Ongoing DRI studies have two primary objectives:

• To enhance islet graft survival and, ultimately, induce donor specific tolerance for patients receiving islet cell transplants
• To assess the immunological alterations that occur in recipients of islet transplants

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

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 insulin producing cells (called islets) can be processed at one center, and then safely transported and transplanted at another institution across the country. This successful 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. Now, patients with diabetes need no longer reside close to an islet isolation facility to be candidates for this life-changing procedure.

The DRI scientific team currently processes a multitude of cell types for research including but not limited to hematopoetic cells and cell subtypes (CD4+), mesenchymal stem cells, NK cells, natural expanded T-Reg cells, Schwann cells, adipose-derived cells , and several types of cell-based vaccines.

The objective of the Islet Cell Resource (ICR) Center is to continue and further expand the mission of the existing cGMP 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.

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 many years once transplanted. 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 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.

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.