ISLET CELL
TRANSPLANTATION UNIT (ICTU)
Tel: (02) 6778021
Introduction
Type 1 diabetes mellitus (DM) is caused by the autoimmune destruction of insulin secreting cells in the pancreas. The lack of insulin results in elevated levels of blood sugar (hyperglycemia). Untreated DM can lead to diabetic ketoacidosis in the short-term and long-term complications such as kidney failure, blindness, and severe heart disease.
Conventional treatment of type 1DM is based on the provision of exogenous insulin. Although this therapy has been the mainstay of DM management for the past 80 years, it is not optimal. Even under the best care, blood sugar levels do not return to normal, and individuals receiving exogenous insulin are susceptible to low blood sugar reactions (hypoglycemia) that are often life threatening.
During the past twenty years, significant efforts have been directed towards developing an alternative approach to the treatment of DM.
One general approach has been to develop improved insulin delivery systems ("artificial pancreas") in which an insulin infusion pump is regulated by an internal glucose sensor. While great progress has been made in these systems, they have certain drawbacks including the fact that they are mechanical and subject to failure.
A second approach has been to transplant pancreatic islet cells from human or animal sources to replace destroyed native islet cells. The challenge of the latter approach is that the transplanted material undergoes autoimmune attack just as the original insulin producing cells. In addition, the transplanted islet cells, being foreign tissue, are subject to tissue rejection by the recipient. To overcome these problems, special medications (with significant side effects) designed to suppress the body's immune response and special preparations of the islet cells are required for the transplants to succeed.
Alternative approaches to islet cell transplantation are also being developed including islet cell microencapsulation, immune modification of islet cells, and the substitution of animal islets or fetal islets in place of mature human islet cells.
Despite the challenges, there has been incremental improvement in the success rate of islet cell transplantation. Approximately 30 centers worldwide perform islet cell transplants, and in the past ten years, approximately 400 transplants have been performed (figures from the International Islet Transplant Registry, Newsletter #9, 2000). Recent improvements in harvesting techniques and modified immunosuppressive regimens have lead to prolonged graft survival. The most impressive results have recently been reported by a team from the University of Alberta in Edmonton. Using a glucocorticoid-free immunosuppressive regimen, this group was able to maintain graft viability for an average follow-up period of one year (Shapiro, et al. NEJM 343:230-8, 2000). The results from this and other centers is very encouraging, implying that before long, islet cell transplantation will reach the stage in which it can be a recommended procedure for all individuals with type 1 DM.
The Hadassah Medical Organization, as part of its long-term strategic plan, will expand its efforts in the fight against diabetes. The Hadassah Diabetes Center (HDC), combining top basic and clinical expert in diabetes-related areas, will utilize multiple approaches to reduce the incidence of DM and its complications. One of the programs under development will be the Islet Cell Transplantation Unit (ICTU). The ICTU will include both clinical and basic science research components. The human islet cell transplantation center will be established, with the initial goal of performing 10-20 transplantations/yr. during the first 3 years of operation.
The Islet Cell Transplantation Program will focus on improved islet cell harvesting and preservation, the use of xenografts (i.e. non-human sources of islet cells), developing new strategies for islet cell transplantation (e.g., transplantation into protected sites, modification of islet cells), and on the improvement of anti-rejection pharmacological protocols. The ICTU will exploit the resources (both human and technical) already present at HMO, and recruit additional physicians, scientists, and support staff who are experts in the field of islet cell transplantation. To facilitate the ICTU, HMO will build state of the art basic science and clinical islet cell transplantation facilities.
Ensuring the success of the ICTU
To be successful, the ICTU will need to confront the following issues that are a challenge to all islet cell transplant programs:
§ Development of a human islet cell procurement program. The program must be designed so that optimal and rapid procurement of pancreas from donor can be accomplished to ensure that viability of islet cells is maintained.
§ Improving islet cell harvesting and preservation to allow maximal flexibility in transplanting procedures.
§ Maximizing the yield of islet cells from each pancreas so as to avoid the need for multiple transplants.
§ Techniques of transplantation that allow for maximal survival of islet cells with a minimum of procedural side-effects.
§ Anti-rejection protocols that prevent rejection of islet cells as foreign tissue and prevent autoimmune destruction of the transplanted cells. Protocols will utilize drugs that maximize islet cell function (avoidance of corticosteroids and islet cell toxins) and have minimal side effects on overall immunity.
§ Post-operative metabolic management of transplant recipients.
To confront these challenges, the ICTU at Hadassah will be designed as a multi-disciplinary program encompassing diabetologists, transplant surgeons, immunologists, invasive radiologists, experts in islet cell culture and preparation, and support staff. The ICTU will develop the following programmatic aspects that will enable it to deal with the issues listed above.
1. Development of a national islet cell recruitment program. The program will be designed to increase physicians' awareness of islet cell transplant, develop the means of transporting potential donors to HMO or performing surgical removal of pancreas at other institutions, and organ preservation during the initial harvesting phase. Participants in the program will also have the responsibility for identifying and preparing potential recipients.
2. Islet cell preparation unit. . The unit will have round-the-clock staff who will be prepared to isolate islet cells from the pancreas as soon as these are available. The Unit will also have the equipment to maintain and test islet cells and cell function.
3. Transplant team. The team will consist of a surgeon, diabetologist, invasive radiologist, immunologists, and ICTU nurse. The responsibility of the team will be to prepare the recipient, perform the transplant, manage the diabetes during the initial operative phase, and provide care during the immediate post-operative phase.
4. Post-transplantation care. ICTU staff including diabetologist, immunologist, and ICTU nurses will monitor and treat rejection episodes of the islet cells. The function of the islet cells will be frequently assessed, and if necessary, appropriate treatment for residual diabetes will be instituted.
An important feature of the ICTU will be the islet laboratory. This will be an ultra-modern, sterile facility with state of the art equipment for isolating and preparing human islet cells. Technicians in the facility will be responsible for isolating islet cells from fresh pancreas removed from donors post-mortem. To maintain maximal viability of cells, the procedure for isolation will require a large-scale apheresis system that facilitates rapid separation of islet cells from other cellular components. Exposure to low temperatures which damages islet cells will be minimized. In addition, all isolation procedures will be done using human blood products rather than animal to avoid the possibility of contamination. The facility will also have the necessary equipment for assaying the number of islet cells, for culturing cells, and for testing their functional capacity. Technicians at the facility will maintain an on-call schedule so that islet cell preparations can be done at any time.
ICTU- the clinical program
1. Organ procurement - The number of islet cells per pancreas is limited, and the goal is to maximize islets harvested per pancreas. This involves both optimal isolation techniques and maintaining islet viability. Criteria for selection of donor pancreas must be extremely stringent as factors such as age, body mass index, and duration of intensive care prior to harvest. Surgical techniques employed in harvesting the pancreas are critical since the time of warm and cold ischemia affects cell viability.
2. Islet isolation - Progress has been made on increasing the yield of viable islet cells harvested per gram of pancreatic tissue. The Edmonton group, which has been very successful, advocates the use of media free of animal proteins to prevent the possibility of immune sensitization. Cells are continuously maintained in optimal conditions to avoid ischemic changes. Fresh cells are also used for transplantation to ensure maximal cell survival.
3. Quantification and functional testing - A key to the success of a given transplant is the number of viable, functional cells transplanted. As part of the preparation of islet cells for transplant, isolated islet cells will be tested for viability and the ability to appropriately secrete insulin. The assays used will be designed for rapid turn around so that results will be available immediately after islet cell harvest. This will provide information to the transplant team as to whether adequate cells are available for transplant.
4. Transplantation - The ICTU will focus on developing the least invasive methods for transplantation that ensure maximal survival of islet cells. The liver being the primary target for insulin action, the preferred approach will be a percutaneous trans-hepatic approach in which islet cells are injected into the portal vein under fluoroscopic guidance.
5. Patient pre-op and post-op management - Pre-operative management will focus on preventing the transmission of infectious diseases (especially cytomegalovirus and other DNA viruses) via transplanted cells. Patients will also be started on an immunosuppressive regimen that will be initiated pre-operatively and continued throughout the post-operative period. As mentioned above, it appears that corticosteroids, which has been a cornerstone of immunosuppressive therapy, is best avoided in islet cell transplants. Therefore, newer, less toxic immunosuppressive agents will be utilized.
6. Long-term post transplantation management - Endocrine and diabetes specialists will follow patients in terms of their metabolic management. Patients will be periodically assessed to determine their insulin reserve and whether they are experiencing episodes of either hyper- or hypoglycemia. If necessary, exogenous insulin will be provided. The team will also decide whether an additional transplant procedure is necessary. The immunologists participating in the ICTU will manage the immunosuppressive regimen and monitor patients for acute and chronic rejection episodes. They will also determine whether the transplanted islet cells are undergoing autoimmune attack.
7. Quality of life analysis - One of the main issues of islet cell transplantation is cost-benefit. The procedure is costly and patients must receive expensive and potentially toxic agents to prevent rejection. A cost benefit analysis, performed by specialist, will determine whether the tangible and intangible benefits associated with islet cell transplantation outweigh the costs.
ICTU - The experimental program
1. Xenografts - One of the limitations of an islet cell transplant program is the availability of human islet cells. An alternative to human islets is islets from animal sources. One excellent source is pig islets because porcine insulin is nearly identical to human insulin. A goal of the ICTU will be to perfect porcine islet harvest and long-term cryostorage. One strategy to prevent islet cell rejection is microencapsulation of islet cells. In this approach, islet cells are coated with a protective membrane that allows for the secretion of insulin, but protects the cell against antibodies and other cytokines involved in rejection.
2. Alternative sites for transplantation - One of the problems of transplantation is to find an ideal site for placement of transplanted islet cells. Ideally, islet cells should be implanted in sites proximal to the portal circulation, as this resembles physiologic conditions. However, alternative sites may afford greater protection against rejection. The ICTU researchers will attempt transplantation at other sites including the bone marrow in animal models to determine whether there is an advantage to other sites in terms of both immune-protection and preservation of islet cells.
3. Immune-protection - The ultimate success of islet cell transplantation depends on preventing islet cell rejection and a resumption of the autoimmune attack directed towards the transplanted islet cells. Despite poor results in the past, recent progress in encapsulating material promises exciting development in this area in the near future. With the use of animal models, ICTU immunologists will attempt to develop improved immunosuppressive regimens that maximize synergy between different immunosuppressive agents. Immunosuppressive protocols will be initially done in animals which will allow for examination of transplanted islet cells and other organs to determine the degree of immune-suppression and side effects.
4. Function of transplanted islet cells - A major issue is whether transplanted islets offer advantages over conventional therapy in terms of improved metabolic control and prevention of long-term complications. Animal models will be used to determine whether glucose control is restored to normal in transplanted diabetic animals, and whether long-term complications are prevented. The data from these experiments will help in determining whether islet cell transplants is cost-effective and a viable alternative to conventional therapy.
MEMBERS OF THE ICTU
Itamar Raz
- Professor Raz is the Director of the Islet Cell Transplant Center. Professor Raz is the director of the Hadassah Diabetes Unit and the Center for Prevention of Diabetes and its Complications. As part of his responsibilities, he has overseen the pancreas transplant program at Hadassah. Professor Raz serves as the president of the Israeli Diabetes Association and is the Director of the Israeli Diabetes Research Group, a consortium of 15 large diabetes clinical centers working together on clinical research projects. Professor Raz is involved in basic science and clinical research dealing with prevention of type 1 DM, improved insulin delivery systems, and the prevention of diabetic complications.
Rafael Nesher - Dr. Nesher, the acting director of the Endocrine Laboratory Service, is an expert in islet-cell physiology and in the mechanism of insulin release. Dr. Nesher has extensive expertise in studying b-cell defects in animal models of diabetes and has supervised diabetes-related clinical studies. Dr. Nesher is expected to supervise the clinical transplantation laboratory.
Nurit Kaiser - Professor Kaiser is an expert in islet-cell physiology and the mechanism of islet-cell destruction. Like Dr. Nesher, Professor Kaiser has extensive expertise in studying b-cell defects in animal models of diabetes and has recently entered the area of islet transplantation into animal models of diabetes. Prof. Kaiser is expected to supervise the islet research laboratory.
Achmed Eid - Professor Eid is a transplant surgeon at Hadassah with extensive experience in liver, kidney and pancreas transplant. He has published many articles on detailing methods for avoiding complications associated with transplants. Professor Eid will be in charge of organ procurement and will work with Dr. Talia Sasson in performing the islet cell transplants.
Talia Sasson - Dr. Sasson is an intensive radiologist at the Institute of Radiology at Hadassah-Ein Kerem. She has expertise in diagnostic and therapeutic procedures involving percutaneous approaches. She will work with Dr. Eid in performing islet cell transplants.
Rueven Or - Professor Or is a renown expert in the field of bone marrow transplantation. He has written extensively on problems associated with transplantation and rejection. He will work with Professor Naparstek in developing anti-rejection protocols and monitoring episodes of rejection or other problems associated with transplants.
Ben Glaser - Professor Glaser is an international expert in the field of genetics and diabetes. He has identified genes related to type 2 DM and islet cell dysplasia. Professor Glaser has extensive experience in treating diabetes and performing clinical research among diabetic patients.
Ehud Ziv - Professor Ziv is an expert in experimental models of diabetes. He has significant experience in analyzing pancreatic and hepatic function in animals with DM. He will be an active participant in the islet cell basic science research program.
Isaiah D. Wexler - Dr. Wexler is a pediatric endocrinologist with an expertise in the area of metabolic disease associated with carbohydrate regulation. He has extensive clinical experience in the treatment of type 1 DM. Dr. Wexler is the secretary for the Israel Diabetes Research Group. He will serve as the coordinator of the ICTU with responsibilities for overseeing the clinical and scientific activities of the ICTU under the direction of Professor Raz.
David J. Gross - Professor Gross is an expert in the field of immune-modulation as means of prevention and treatment of type 1 DM. Professor Gross has also extensive experience in management of diabetic patients. Professor Gross will participate in both clinical aspects of care and prevention as well as in studying innovative models for immune modulation of transplanted patients.
Eythan Galun - Dr. Galun is the director of HMO Gene Therapy Center and an expert in targeted immune modulation. Dr. Galun has a large group of young investigators involved in studies directed to optimize islet transplantation in animal and will supervise the experimental part of islet transplantation into animal models.
Gil Leibovitch - Dr. Leibovitch has extensive experience in clinical management of diabetic patients and is an experience islet-cell molecular biologist. Dr. Leibovitch has recently began colborative studies with Professor Kaiser on the developmental role of beta-cell transcriptional factors and on mean of beta-cell expansion. Dr. Leibovitch will be involved in teaching, care and manegment of diabetic patients as well as in studies aimed at inovative sourse of
Reinhard G. Bretzel - Professor Bretzel, Professor of Medicine at the Justus-Liebig University in Giessen, Germany, will serve as both a consultant and collaborator at the ICTU. Professor Bretzel is a world leader in islet cell transplantation and is the Director of the International Islet Transplant Registry which is an umbrella organization, tabulating the results of islet cell transplants world-wide. Professor Bretzel has chaired many conferences on the topic of islet cell transplantation as a means of treating type 1 diabetes.
Erol Cerasi - Professor Cerasi, the retiring Chief of Endocrinology and Metabolism at the Hadassah Medical Center, is a world leading authority in diabetes. Several important breakthrough findings and hypothesis in the area of islet cell function and glucose metabolism are credited to Professor Cerasi, resulting in awarding him numerous national and international awards in the area of diabetes. Professor Cerasi plans to continue to maintain a research laboratory at Hadassah and will serve as consultant to the ICTU.