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Joslin's Islet Cell Transplantation Program - Fall, 2001

Joslin Diabetes Center's ultimate goal is a world without diabetes. Toward that end, we are currently engaged in three major approaches to combating, and ultimately eradicating, this devastating and debilitating disease that currently afflicts some 16 million Americans.

One approach is restoring insulin production in people with type 1 diabetes. Our most promising and exciting undertaking to achieve that goal is transplantation of the islets of Langerhans cells, which have been destroyed causing type 1 diabetes. The goal of this research is to transplant healthy insulin-producing cells into a person with diabetes to return them to a non-diabetic state, and to protect the transplanted islets from the immune system attack that caused diabetes in the first place. The pace of our advances has given us increasing confidence that islet cell transplantation will be a successful and practical treatment for diabetes, and a close equivalent to an actual cure,

Progress to Date

Gordon C. Weir, M.D., Director of the Joslin Islet Transplantation Laboratory and holder of a chair from the Diabetes Research and Wellness Foundation, and his research team are focusing their efforts on finding a satisfactory source of insulin-producing tissue and methods for preventing this tissue from being destroyed by immune rejection and autoimmunity.

Important progress has been made in three vital areas:

1. Finding a source of insulin-producing cells for transplantation

A major obstacle to providing islet transplantation to those in need is the lack of insulinproducing cells, as these can only be obtained from cadaver donors. Only 3,000 donor pancreases become available in the U. S. per year, which means that about 1,000 patients per year could be rendered free of insulin as the transplants require several pancreases. This does not come close to helping the 35,000 new cases of type 1 diabetes that develop each year or the thousands of persons with existing type 1 or those with type 2 diabetes some of whom could benefit also.

Human cells versus pig cells as a source of islet tissue. For the past several years we have focused on the use of neonatal pig tissue as a source for xenotransplants (transplanting animal cells into humans). We have learned a great deal about islet cell clusters from these pigs and how to transplant them. Once the pig-to-human immune reaction is controlled, this source of tissue might be of considerable value.

However, in the past few years there has been remarkable progress fulfilling the goal of expanding the supply of human ß-cells to meet the needs of those who need islet transplants. Two exciting advances have been:

Human pancreatic duct cells can make new islets. Joslin's Dr. Susan Bonner-Weir and her group have succeeded in making new islets. Precursor cells from the ducts of human pancreases that would normally be thrown away after the isolation of islets have been developed into new islet cells. These cells are called cultivaled human islet buds (CHIBs) and contain insulin-producing cell s. Further efforts are being devoted to find ways to fürther expand these cells so that sufficient numbers will be available for transplantation.

Embryonic stem cells are a promising source. Stem cells are the other new and exciting possible source of insulin-producing cells. The concept of a stem cell is somewhat complex. For example, the duct cells used by Dr. Bonner-Weir can be considered a type of adult stem cell. Embryonic stem cells (ES cells) also seem to hold particular promise. These are a different kind of stem cell, obtained frorn fertilized eggs used for in-vitro fertilization. The fertilized eggs are kept frozen and once pregnancy is achieved, many eggs will not be utilized. Investigators in Spain published a study showing that mouse embryonic stem cells, which seem to have an unlimited capacity for growth, can be turned into insulin-producing cells that can normalize blood sugar in mice. One can be optimistic to think that human embryonic stem cells can be cultured in a similar fashion to produce cells that can be used for human transplants.

Joslin's Islet Transplantation Laboratory, which has much experience working with islet cells, is now well positioned to make important progress. Dr. Weir and his group are currently working with mouse and monkey embryonic stem cells and intend to work with human embryonic stem cells as soon as they become available. This means that the possibilities of finding a new source of human ß-cells is very promising and the more difficult path of using pig cells may not have to be taken. In spite of this promise, work will continue with neonatal and adult pig cells in case the human cell work does not progress fast enough.

2. Protection of islets from immune destruction:

After about 5 years of work on this obstacle, Dr. Weir and his team have made a major advance with providing protection with an immunobarrier membrane. After trying a variety of membranes, they turned to the 20 year old technique of microencapsulation, using a gel called alginate, obtained from seaweed. Using a droplet generator, it is possible to place islets in a tiny gel bead. This gel covering then protects the islet cells from being killed by the immune system. Thousands of these encapsulated cells can be placed into the peritoneal cavity of diabetic animals and eventually humans. Using new reagents and a new approach, unprecedented results were obtained proving complete protection against autoimmunity and transplant rejection in mice. Moreover, with no immunosuppression, the islets survive for over 300 days in these mice and appear to release insulin fast enough to be useful for human transplants.

Recently, the Weir team has begun to focus on research on encapsulated cells in monkeys. It is too early to draw firm conclusions but the initial results are encouraging. The capsules protect monkey islets in recipient monkeys, and there was no inflammatory reaction at 5 weeks. The goal is for transplantation of a sufficient number of encapsulated monkey islets to be successful in normalizing the glucose levels of diabetic monkeys without the need for immunosuppression.

Once success is achieved in monkeys, the next step will be to use these capsules to protect transplanted human islets, which means that it might be possible to transplant islets in humans without immunosuppression. Although it is expected that these islets will work in human-to-human transplants, fürther alterations in the capsules to provide protection of pig islets in humans will need to be made. Because the prospect for obtaining new human islet cells from embryonic stem cell is promising, the capsules developed in the Joslin Islet Laboratory are potentially of great value.

3. The Clinical Islet Transplantation Prograin:

In 1998, the Juvenile Diabetes Research Foundation Center for Islet Transplantation at Harvard Medical School was established. This Center now supports over 35 investigators working on multiple facets of islet transplantation. The Center is directed by Dr. Hugh Auchincloss, a transplant surgeon at Massachusetts General Hospital. Drs. Gordon Weir, Susan Bonner-Weir, and Arun Sharma of our Section on Islet Transplantation and Cell Biology at Joslin are actively involved in the activities of the JDRF Center. Dr. Weir is an Associate Director of the Center, and Director of the Islet Core Laboratory, which isolates islets for the scientists of the Center.

The Core laboratory is based at Joslin, with its "clean-room" built with funds provided by Joslin donors. Joslin was selected as one of the Edmonton replication sites after scientists in Edmonton Canada had encouraging success with human islet transplants by removing steroids from the immune suppressive regimen. Islets have already been isolated from over 50 human pancreases obtained from the New England Organ Bank. Islet transplants in human patients using two protocols are expected to start in the fall of 2001 and will hopefully include ten transplants in the next year. This program is important to learn more about the best approaches for transplantation in anticipation of a new source of ß-cells.

An exciting benefit of the Center is that collaboration is being facilitated. Drs. Bonner-Weir, Weir, and Sharma are working closely with others involved in stem cell research, including Drs. Joel Habener, Melissa Thomas, and Dennis Sgroi, Massachusetts General Hospital, and Douglas Melton, Harvard University. Dr. Aldo Rossini of the University of Massachusetts in Worcester is collaborating in human islet transplantation and Dr. Clark Colton of MIT is finding novel ways to assess the quality of islets prior to transplantation. Visiting scientists have included, Drs. James Shapiro from Edmonton, Canada, David Harland from the Islet Transplant Group at the National Institutes of Health, and Bernhard Hering from the University of Minnesota.

The Next Steps for Joslin's Transplantation Program

The most important project for the Joslin transplantation group is to continue to develop a new source of insulin-producing cells. The work of Dr. Susan Bonner-Weir and her tearn with the CHIBS represents a major break-through and continues to flourish. It is necessary now to separate out the different kinds of duct cells to identify a population that may be more efficient in making islets than other duct cells. It will also be important to find more efficient ways to expand these duct cells so that we can greatly increase our yield of islets.

Plans are already underway to expand the embryonic stem cell program. For the first stage, a team is being assembled as the stem cell project is becoming a major priority. While work is currently focused on mouse and monkey stem cells, it will soon be possible to work with human embryonic stem cells now that the Bush administration has developed a workable plan. The second stage will be dependent on securing additional laboratory space and recruiting additional senior staff.

Work will continue on encapsulation of islets and researchers anticipate obtaining definitive information about exactly how encapsulated monkey islets can perform in diabetic monkeys. lf this work is successful, Dr. Weir's team could progress directly to humans, using human islets isolated frorn cadaver donors, which could then be eneapsulated and transplanted into recipients with diabetes, without the need for immunosuppression.

The Joslin islet team also plans to continue work with gene therapy. As the viral vectors that are used to transfer genes into cells become more effective, it is expected that the potential to use this approach for clinical purposes will increase. The current focus is on the small molecules CTLA4 and TGF beta, which can inhibit the invading white blood cells that normally destroy transplanted islets.

Finally, Dr. Weir and his research team continue to work actively with the clinical islet transplantation program of the JDRF Center for Islet Transplantation at Harvard.

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Impressum © Stephan A. Schreiber 2011