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JDF’s Mission Is to Find a Cure for Diabetes and Its Complications through the Support of Research
Melton and Son
Doug Melton, Ph.D., one of the world-renowned researchers who have joined the new center, turns his expertise to helping his seven-year-old son, Sam, who has diabetes.

New Multimillion-Dollar Center to Create a Fast Track for Diabetes Cure Focused on Islet Cell Transplantation
Diabetes Research Initiative Funds 32 Scientists at Harvard

Boston, Mass.; Sept. 10, 1998—Hoping to put a cure for Type 1 diabetes on a fast track, the Juvenile Diabetes Foundation International (JDF) and Harvard Medical School have focused an unprecedented combination of experts in diabetes and many other scientific fields on finding a cure for diabetes. 

    The new JDF Center for Islet Cell Transplantation at Harvard Medical School will launch an ambitious multidisciplinary attack on one of diabetes’s most tantalizing yet frustrating fields of research—replacing the body’s natural insulin-producing cells, which have been destroyed in people with Type 1 diabetes. The Foundation will provide approximately $20 million over the next five years to the researchers, which include Harvard faculty from seven affiliated institutions. 

    “We at JDF are proud to see our dream of successful islet cell transplantation without immunosuppression put on the fast track,” said JDF Chairman of the Board John J. McDonough. “As someone who has had Type 1 diabetes for 56 years and as the parent of a daughter with Type 1, I want to assure her, and all those who suffer from diabetes, that we are doing everything possible to find the cure.” 

    “For 28 years the tireless support of our volunteers has helped advance diabetes research worldwide. Now, thanks to the Florence DeGeorge Islet Research Challenge Grant, which provided initial funding for this Center, we are able to fund this highly collaborative, goal-oriented approach, which we hope will act as a model for all of our research programs,” added McDonough. 

    The new Center is made possible through a $5-million pledge named the Florence A. DeGeorge Islet Research Challenge Grant. The DeGeorge family foundation has provided these funds to help find a cure for diabetes and its complications through the support of research. “Our concern has always been to accelerate a cure for this devastating disease through islet cell research. We believe that the initiative with the Harvard Medical School and associated researchers points the way in accelerating islet cell research and transplantation as a potential way of accomplishing our goal,” said Lawrence DeGeorge. “My wife, Florence, and our whole family are pleased to be able to make this contribution to this important and innovative Center.” 

    Diabetes kills one American every three minutes and reduces life expectancy by as much as one third. It consumes one out of every eight U.S. health-care dollars. Millions of people with diabetes—including many infants—depend on several insulin injections every day to stay alive, while facing a future of severe disability and premature death. 

    The new Center’s goal is a cure. The 32 researchers at the JDF Center for Islet Cell Transplantation at Harvard, will work collaboratively to discover how to transplant insulin-producing islet cells without the recipients’ needing a lifetime of immunosuppressants, which can have even more devastating long-term effects than the disease itself. 

    Many of these world-renowned researchers had not previously applied their expertise directly to diabetes. “My entire career has been focused on basic developmental biology, until now,” says Doug Melton, professor of molecular and cellular biology, Harvard University and Howard Hughes Medical Institute, and one of the Center’s lead researchers. “My seven-year-old son, Sam, has diabetes, and I think the new Center provides us with the chance to extensively and collectively study—and hopefully find a cure for—this chronic and complex disease.” 

    The Center will follow a business-oriented model to tackle the major obstacles that still block safe, workable islet cell transplants. Researchers, their projects, and the Center will receive annual performance reviews; funding is contingent upon progress achieved towards the Center’s goals; and attendance at monthly think-tank–style meetings is required to identify promising approaches and ensure continued coordination. Collaboration means individual work will be guided by both positive and negative outcomes of others. 

    “The most interesting and productive science today is multidisciplinary,” said Harvard Medical School Dean Joseph B. Martin. “The level of detailed knowledge in most fields is now so vast that the next advances will come through intertwining knowledge from diverse fields. This work in Type 1 diabetes is a great example of the opportunities for multidisciplinary science when the broad Harvard medical community collaborates.” 

    Key gaps in diabetes research knowledge were identified last year when a JDF task force mapped out what was known about the disease, the current state of diabetes-related research, and its founders’ main goal of a cure in their children’s lifetime. Center scientists will focus on major strategies to close knowledge gaps in four high-priority areas identified in the JDF maps, specifically: islet transplantation, tolerance induction, autoimmunity, and expansion of islet cell supply. 

    To cure Type 1 diabetes via islet cell transplantation, researchers have to figure out how to conquer two different types of immune problems: autoimmunity and tolerance. They must turn off the autoimmune response that destroyed the patient’s original islet cells so that the new ones are not also attacked. They also have to create tolerance to the new cells, which may be destroyed by a different part of the immune system, just like a transplanted organ. Then, they have to find a plentiful source of replacement islet cells, from tissue culture, animals, or genetic manipulation. 

    Most of the Center’s 32 researchers are Harvard faculty at the University, School of Medicine, School of Public Health, and Harvard-affiliated Boston medical institutions, such as Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Dana–Farber Cancer Institute, Joslin Diabetes Center, and Massachusetts General Hospital. Additional expertise was recruited from Charlestown, Mass.–based Diacrin Inc., Massachusetts Institute of Technology, and the University of Minnesota. 

    Scientists are optimistic about the progress possible with this mission-oriented Center, but they remain cautious about building-up false hope in patients. “Diabetes presents a set of problems that are large and complex,” says Center director Hugh Auchincloss, Jr., associate professor of surgery at Harvard Medical School and transplant surgeon at Massachusetts General Hospital. “But, huge progress has been made in the last five years, and there’s every reason to believe that the rate of progress will continue and accelerate.” 

    Because other diseases share some of these underlying problems, advances toward a cure for diabetes may also help people with arthritis, lupus, and multiple sclerosis. 

    JDF is the leading nonprofit, nongovernmental funding source for diabetes research in the world. “JDF was founded by the parents of children with diabetes who promised to find a cure in their children’s lifetime,” says McDonough. “We will keep that promise.” 


* Diabetes is a chronic, genetically determined, debilitating disease affecting every organ system. Insulin is not a cure, but merely life support. Type 1 diabetes is caused by the autoimmune destruction of the insulin-producing cells of the pancreas and is usually, though not always, diagnosed in childhood. [back.] 
 

 

 
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JDF’s Mission Is to Find a Cure for Diabetes and Its Complications through the Support of Research

 

Juvenile Diabetes Foundation Center for Islet Cell Transplantation at Harvard Medical School

How Is the Center Unique?

  • The goal of the new Juvenile Diabetes Foundation Center at Harvard is to cure Type 1 diabetes by pancreatic islet cell replacement. More specifically, the goal is to achieve successful islet transplantation for people with Type 1 diabetes without the need for long-term immunosuppression, which can have complications worse than the disease. 
  • The Center is organized as a collaborative, coordinated effort. It is science with a mission. This approach can only be pursued if the funding mechanisms and administrative structure are established to promote interaction and collaboration between investigators. Only this drives research toward a well-defined goal. 
  • The Center is broadly multidisciplinary, pulling together researchers with many different perspectives on the disease. 
  • Until now, many of the 32 world-renowned researchers, who include Harvard faculty from nine institutions, have not applied their expertise directly to diabetes. 
  • The Center is organized on a business-world model: 
    • All long-term research goals are defined by the Center, rather than by the individual researchers. 
    • Researchers will receive annual performance reviews. 
    • Funding is contingent on progress achieved toward solving targeted problems related to islet cell transplantation. 
    • Attendance at monthly think-tank–style meetings is required to identify promising approaches and ensure coordinated research. 
    • An outside panel of internationally recognized diabetes experts, working with JDF volunteer leaders, will conduct critical reviews of the Center’s work. A different outside expert will address the researchers each quarter.
What Will the Center Do?

The Center will address four main obstacles that must be overcome to restore normal blood sugar levels in people with Type 1 diabetes, through islet replacement which are: 

  1. Islet Transplantation 

  2. Replacement of islet tissue will not ultimately involve whole organ pancreas transplantation, which is too cumbersome, too invasive, and is associated with too many complications. Further progress in refining the optimum technical approach to islet cell transplantation is an essential step along this path to a cure for people with Type 1 diabetes. 
  3. Tolerance Induction 

  4. Even if technical problems of islet transplantation are overcome, it will still not be appropriate therapy for most people with Type 1 diabetes. This is because the immunosuppressive drugs currently needed for transplant survival can themselves be quite toxic and is associated with potentially devastating long-term side effects and complications. Thus, achieving tolerance to donor tissue without the need for toxic immunosuppression is key. 
  5. Autoimmunity 

  6. Even if transplantation of foreign tissues could be achieved without immunosuppressive drugs, evidence strongly suggests that the transplanted islets will still be destroyed--causing a recurrence of diabetes--unless treatment of the underlying autoimmunity is provided. People with Type 1 diabetes have previously developed an immune response to islet cells. This response must be blocked if new islets are to survive in these people. 
  7. Expansion of Islet Supplies 

  8. Islet transplantation for large numbers of people with Type 1 diabetes will require the use of cells obtained from a variety of sources or from islets cells grown in culture since the number of potential human donors is not sufficient. Thus, finding a cure requires more progress in developing alternative islet cell resources and/or growing islet cells in culture.

        Some Center laboratories will serve as a world-wide resource for other researchers working toward a cure. They will supply islet cells, a unique mouse model for diabetes, vectors for getting new genes into cells, and techniques for identifying key immune system genes. 
     
     

How Does the Center Fit into JDF’s Overall Research Plans?

The Juvenile Diabetes Foundation Center at Harvard is a model for future JDF centers. Since JDF’s founding in 1970, our volunteers have focused on ways to achieve successful islet transplantation as a potential cure. It is only with the progress made from its intense investment of time and resources over the years that JDF is now able to fund such a large mission-oriented Center. The Center also directly responds to JDF’s call for a bold, new plan to speed research advances to people with diabetes.

This cutting-edge effort at Harvard is a direct outcome of JDF’s innovative mapping of diabetes completed by its Research Task Force in 1998. This task force received input from leading scientists worldwide, and pro-bono guidance from McKinsey & Co. The maps spotlighted gaps in research knowledge. The objective of JDF sponsored research is to close gaps in high-priority areas and accelerate progress down the many potential paths to a cure. The new $20 million Center at Harvard, has been designed to bridge gaps along one of these paths. Based on the mapping and results of the Research Task Force, JDF intends to fund additional centers worldwide to focus on similar and other priority areas.
 
 More Information:

The new Center at Harvard complements other JDF research efforts. JDF is the leading nonprofit, nongovernmental funder of diabetes research in the world. The Foundation has targeted several pathways to find a cure for Type 1 diabetes and its complications. The new Center at Harvard was designed to accelerate progress down one of those paths. Additional high priority areas of JDF research support include: 

  • Prevention of Type 1 diabetes through a vaccine given at birth, at the time a child is diagnosed, or later in the course of disease. 
  • Bioengineering of insulin-producing cells. 
  • Autoimmunity not related to islet transplantation. 
  • Preventing or reversing the complications of diabetes. 

  • Biomechanical approaches to restoration of normal blood sugar. 
 
 


 
 

Go to JDF Main Page
Go to JDF Main Page.
JDF’s Mission Is to Find a Cure for Diabetes and Its Complications through the Support of Research

 

Juvenile Diabetes Foundation Center for Islet Cell Transplantation at Harvard Medical School

The Scientists and the Science

An unusually broad and intense collaboration of more than 30 investigators from Harvard Medical School, affiliated Boston institutions and other experts will focus on a single mission: To cure Type 1, or juvenile, diabetes through islet cell transplantation without the need for long-term immunosuppression.

    The Center’s research program is organized in sections that will address the four major obstacles to moving islet transplantation successfully from the research bench to the patient’s bedside; a fifth section will provide core resources. The four obstacles are overcoming autoimmunity, inducing tolerance, expanding islet cell sources, and overcoming specific problems associated with islet cell transplantation. The core resources section will provide specialized support for researchers in all four sections. The world-renowned researchers chairing each section will integrate results across all sections, while also being responsible for progress toward specific section goals. Required attendance at monthly meetings and annual evaluations of results are designed to foster active collaboration among all researchers and accelerate progress toward a cure.

  1. Pre-existing Autoimmunity

  2. Of all of the Center’s research areas, the problem of pre-existing autoimmunity remains perhaps the largest hurdle to successful islet transplantation. This pre-existing autoimmunity in people with Type 1 makes islet cell transplantation very different from all other types of organ and tissue transplants.

        In Type 1 diabetes, the cells of a person’s own immune system destroy the insulin-producing cells of the pancreas, which are located in island-like clusters called the “Islets of Langerhans.” Without these islet cells and the insulin they secrete, people with Type 1 diabetes are unable to process the sugars in food, leading to coma and death unless regular insulin injections are taken. These aberrant islet-cell killing immune cells can also destroy transplanted islet tissue, creating a major obstacle to the use of islet transplantation as a cure for Type 1 diabetes.

        Scientists know that some combination of environmental and genetic factors turns on the immune cells, while another set of events determines whether the immune cells will promote or prevent diabetes. The same molecular pathway that creates the islet-killing T helper immune cells, known as T helper 1, also can create beneficial T helpers, known as T helper 2, which actually appear to protect against Type 1 diabetes and other autoimmune diseases.

        Autoimmunity researchers in the Center will study defining moments that determine the nature of these T helper cells with the hope of eventually interfering with the process. They will also study the molecular mechanisms that may make it possible to reprogram an activated immune cell to generate a protective T helper 2 cell rather than a destructive T helper 1 cell in children with Type 1 diabetes.

        One of the important differences between these two types of immune cells is that T helper 2 cells secrete a chemical messenger called interleukin-4, which appears to prevent the development of many types of autoimmune disease, including Type 1 diabetes. These unusual subpopulations of immune cells have been shown to play an important role in controlling interleukin-4 levels.

        In many cases, investigators in this section have not previously focused on diabetes. However, they are known as leading scientists in the more general fields of autoimmunity and T cell regulation. Taken together, the projects they propose offer hope of translating basic research into new strategies to eliminate the pre-existing autoimmune response in people with Type 1 diabetes, overcoming one obstacle to islet cell transplantation.

    Harvey Cantor, MD
    Chair, Autoimmunity Section, JDF Center at Harvard Medical School
    Immunologist
    Professor of Pathology and Chair, Program in Immunology, Harvard Medical School
    Chair, Department of Cancer Immunology and AIDS, Dana–Farber Cancer Institute
    (617) 632-3348, alison_angel@dfci.harvard.edu

    Cantor’s research helps define the development and function of T cells that control the immune response. He aims to design a vaccination strategy to inhibit the onset and progression of Type 1 diabetes. The precise mechanism by which vaccination with autoreactive T cells may treat or cure autoimmune disease is unknown. The overriding goal of these studies is to use a combination of molecular, genetic and cellular approaches to design appropriate T cell vaccines to inhibit this autoimmune process, first in mice and then on human islet-specific T cells.

    Abul K. Abbas, MD
    Cellular immunologist
    Professor of Pathology, Harvard Medical School and Brigham and Women’s Hospital
    (617) 732-6523, aabbas@rics.bwh.harvard.edu

    Abbas’s research into the cellular and genetic basis of immunological tolerance and into the glitches that cause autoimmune diseases addresses fundamental questions about autoimmune reactions against islet tissues and the genetic control of these responses. Using a mouse model for his Center-funded project, his group will focus on two aspects of the human disease. First, they will express a model protein antigen in the islets of mice, and examine responses of antigen-specific T cells to these islets. Second, Abbas will transplant antigen-expressing islets into healthy and diabetic mice and test strategies for preventing rejection of the transplanted islets.

    Laurie H. Glimcher, MD
    Immunologist
    Irene Heinz Given Professor of Immunology, Harvard School of Public Health; Professor of Medicine, Harvard Medical School
    (617) 432-0622, lglimche@hsph.harvard.edu

    Glimcher’s group focuses on molecular immunology with a special interest in the gene regulation of the immune response and how it relates to controlling autoimmune diseases. Originally interested in rheumatoid arthritis, she has discovered key factors that regulate the production of interleukin-4, increased levels of which may dampen the heightened immune response to islet cells in patients with Type I diabetes. For the Center, she will concentrate on several factors that dramatically augment interleukin-4 production and play a critical role in whether T helper cells become harmful or beneficial.

    Michael Grusby, PhD
    Molecular immunologist
    Associate Professor of Molecular Immunology, Harvard School of Public 
    Associate Professor of Medicine, Harvard Medical School
    (617) 432-1240, grusby@mbcrr.harvard.edu

    Grusby is an authority on how certain proteins known as STATs recognize and turn on certain genes that regulate the differentiation of T helper cell subsets. He hopes to manipulate the process to treat diseases such as diabetes. Working with mice that are genetically deficient in the transcription factor STAT4 and do not develop T helper 1 cells, Grusby’s group has found preliminary evidence that they are protected from developing diabetes. He now wants to develop a mouse model in which STAT4 function can be controlled at will to test the hypothesis that the transcription factor may be a therapeutic target for treatment of this disease.

    David A. Hafler, MD
    Cellular immunologist, clinician
    Director, Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women’s Hospital
    Associate Professor, Harvard Medical School
    (617) 525-5330, hafler@cnd.bwh.harvard.edu

    Hafler’s research team directly examines tissue from patients with autoimmune disease to learn how autoreactive T helper 1 cells recognize the self antigens that trigger them to destroy their own tissue and how the cells are regulated. Hafler’s group recently identified a kind of T cell that produces interleukin-4, a small hormonelike molecule also made by T helper 2 immune cells. There are fewer of these cells in the blood of patients with Type 1 diabetes, and the cells do not secrete interleukin-4. But in the blood of their high-risk siblings, the same specialized T cells do produce interleukin-4, which seems to halt progression of the disease in otherwise genetically predisposed people. Hafler aims to find out what protects family members who are at high risk for developing diabetes, but do not.

    I-Cheng Ho, MD, PhD
    Rheumatologist, molecular immunologist
    Assistant professor of medicine, Harvard School of Public Health
    (617) 432-0697, ho@mbcrr.harvard.edu

    A complicated genetic program causes the abnormal immune response of Type 1 diabetes. Ho wants to learn more about the regulation of the genes that control expression of interleukin-4. He then hopes to alter the genetic program and subsequently turn the abnormal response into a protective response for diabetes.

    Terri Laufer, MD
    Immunologist
    Assistant Professor of Medicine, University of Pennsylvania

    In a special diabetic mouse model, Laufer will examine the genetically determined molecules, or antigens, on the surface of islet cells that turn on the immune system’s anti-islet response. These studies should show how islet cells trigger an autoimmune reaction, rather than being tolerated by the immune system.

    Myra A. Lipes, MD
    Molecular biologist
    Investigator, Joslin Diabetes Center
    Assistant Professor of Medicine, Harvard Medical School
    (617) 264-2701

    Lipes’s expertise is in molecular biology and in using transgenic technology to create animal models to study diabetes. She studies how beta cells, which are the specific type of islet cells that produce insulin, are destroyed in Type 1 diabetes. Lipes’s group has discovered that certain cells in the pituitary, a small gland below the brain, can be engineered to secrete large amounts of insulin, sufficient to cure diabetes when implanted into diabetic mice. Yet, the insulin-producing pituitary cells are not attacked by the immune cells that destroy beta cells in Type 1 diabetes. Her research group has also found that these cells are also resistant to rejection in other mice. Taken together, these finding suggest that these cells may be “immunologically privileged.” Lipes hopes to identify the specific mechanisms involved which enable these cells to escape destruction by the immune system, which may lead to new strategies to bioengineer immune-resistant beta cells for transplants.
     

  3. Tolerance Induction

  4. People with diabetes who receive replacement islet cells will have to overcome the same rejection problems as other transplant patients. Immunosuppressive therapy can be difficult for everyone receiving a transplant, but at present young people with Type 1 diabetes would face fewer problems on a lifetime of insulin injections than they would on chronic immunosuppressive therapy, the side effects of which can include serious opportunistic infections and malignancies. In order to avoid a cure that could be worse than the disease, researchers need to find ways to transplant islet cells without the need for traditional immunosuppression. Researchers are attempting to induce tolerance to antigens that alert the immune system to reject islet tissue grafts from the same species (allografts) and from a different species, such as a pig (xenografts). They also aim to identify certain islet cell antigens important in autoimmunity.

        During the past two years, at least five different laboratories around the world have reported new strategies for tolerance induction that have achieved survival of organ transplants in monkeys for greater than one year without the ongoing use of conventional immunosuppressive drugs. Also, a number of new molecules have been discovered during the past several years (such as CTLA-4, CD40, Fas, and their respective ligands) which can be used to help induce tolerance. Many of these molecules help activate the unwanted rejection immune response to transplanted tissue by providing “costimulation.” After the receptors on T cells first recognize foreign antigens, these costimulatory signals act as a second signal necessary to switch on the immune system’s rejection response. In the absence of costimulatory signals, T cells tend to become inactivated or tolerant to foreign antigens.

    David H. Sachs, MD,
    Chair, Tolerance Section, JDF Center at Harvard Medical School
    Transplantation immunologist
    Professor of Surgery (Immunology), Harvard Medical School;
    Director, Transplantation Biology Research Center, Massachusetts General Hospital
    (617) 726-4065, sachs@helix.mgh.harvard.edu

    Working at the interface of basic research and clinical applications, Sachs studies transplantation tolerance, xenotransplantation and immunogenetics of the major histocompatibility complex, the major genetic barrier to transplantation. In the past 25 years, he has also developed a partially inbred line of miniature swine, which may be the ideal donor for eventual xenotransplantation of islets. Sachs hopes to adapt a new transplant-within-a-transplant technique that successfully induced tolerance to a donor kidney in an animal model. In a donor pig, Sachs transplanted thymus tissue into the kidney and let it heal. Later, the thymo-kidney was transplanted into another pig, where it performed the functions of both organs, even in a mismatched recipient. Sachs thinks similar “islet kidneys” or “thymo-islet kidneys” would help islet cells engraft more quickly with less chance of rejection, first for transplants in the same species and then for transplants between species.

    Sandy Feng, MD, PhD
    Transplant and general surgeon, molecular biologist
    Transplant surgeon, Massachusetts General Hospital
    Assistant Professor of Surgery, Harvard Medical School
    (617) 724-3730, feng@helix.mgh.harvard.edu

    Feng seeks to selectively alter the immune response to transplanted islets and avoid the consequences of generalized suppression of the recipient’s immune system. Using the techniques of gene transfer, she will place into islet cells genes that can turn down or turn off the immune response, such as those that block costimulation. Feng hopes the expression of these genes by the islet cells will produce local and graft specific immunosuppression without systemic immunosuppression. In some experiments, she will be testing various genes, both individually and in combination, for their ability locally to turn down or turn off the immune response and prolong graft survival. In other experiments, she will test the best way to transfer genes to various sources of islet tissue using viral vector systems. Together, the experiments will guide the design of large animal trials to evaluate potential future human applications.

    Mohamed H. Sayegh, MD
    Transplant nephrologist and immunologist
    Associate Professor of Medicine, Harvard Medical School
    Research Director, Laboratory of Immunogenetics and Transplantation, Brigham and Women’s Hospital
    (617) 732-5259, sayegh@bustoff.bwh.harvard.edu

    Sayegh studies how the immune system recognizes tissue transplanted from the same species (allorecognition) and how to use a better understanding of those mechanisms to generate new strategies for tolerance induction. He aims to develop strategies to block costimulatory activation to induce tolerance to islet transplants. He will be using a mouse model to study an indirect pathway of allorecognition, which is thought to be important in islet destruction and allograft rejection.

    Megan Sykes, MD
    Transplant immunologist
    Head, Bone Marrow Transplantation Section, Transplantation Biology Research Center Massachusetts General Hospital
    Associate Professor of Surgery and Medicine (Immunology), Harvard Medical School
    617-726-4070, sykes@helix.mgh.harvard.edu

    An expert in the area of bone marrow transplantation biology, Sykes uses bone marrow transplantation within and between species to induce immunological tolerance. Bone marrow–derived cells are responsible for telling T cells whether tissue should be tolerated as “self” and or should be destroyed as “nonself.” Sykes has developed a way to induce tolerance for another difficult transplant, skin grafts. Sykes uses temporary immunosuppression (a type called costimulatory blockade) to inactivate part of the immune system so that the donor marrow has a chance to engraft and subsequently educate newly developing T cells to accept transplanted tissue from a fully mismatched donor. In her project for the Center, her research team will evaluate and apply this method to donor islet transplantation in a diabetic mouse. Other studies have shown bone marrow transplantation can cure diabetes in mice, but in ways that would be too toxic for people. This new approach to bone marrow transplantation is expected to be far less toxic, and therefore has the potential to treat diabetes in humans.
     

  5. Islet Cell Sources

  6. For transplants to be successful, researchers need to find new sources of insulin-producing islet cells, or beta cells. Sufficient quantities of beta cells might come from a variety of sources: by bioengineering human cell lines; by obtaining islets from other species, such as pigs; by replicating beta cells from humans or other species; or by manipulating other kinds of cells to become beta cells. For example, evidence from animal models suggests that epithelial cells remaining in the pancreatic ducts of adults retain the ability to form new pancreatic cells of all types. This process of becoming a more specialized cell type is called differentiation.

        While a number of new genes and molecules that control the growth and development of the pancreas and of islet cells have been identified, scientists have yet to be able to expand islets in culture and maintain insulin production by those cells.

        Researchers working in this area will extend the understanding of the molecular mechanisms and genes involved in the replenishment and expansion of beta cells. There is potential for providing a better source of islet tissue for transplantation and for providing ways to regenerate new islets in people with Type 1 diabetes. Although the center is focused on transplantation, successful islet regeneration, coupled with induction of selfantigen tolerance, would represent the kind of crossproject alternative “cure path” the center was designed to encourage through its mechanisms of collaboration and cooperation among the sections.

    Ron Kahn, MD
    Chair, Islet Cell Sources Section, JDF Center at Harvard Medical School
    Director, Joslin Diabetes Center
    (617) 732-2635, kahnr@joslab.harvard.edu

    Kahn will determine the factors that are responsible for the growth of beta cells in a mouse model of insulin resistance. This unusual mouse provides a way of looking at beta cell growth and development in a living adult animal. Initial transplantation experiments will focus on whether this rapid cell replication is stimulated by generally circulating factors or local mediators, as well as on the genetic background of the activity.

    Susan Bonner-Weir, PhD
    Cell biologist focusing on islets
    Senior Investigator, Joslin Diabetes Center
    Associate Professor of Medicine, Harvard Medical School
    (617) 732-2581, bonners@joslab.harvard.edu

    Bonner-Weir, an expert in islet growth, will work in collaboration with Arun Sharma PhD, an instructor at Joslin and an expert in the molecular biology of insulin gene expression. They will be identifying genes and environmental factors involved in making new beta cells. They have just developed two cell lines that produce a green fluorescent protein as the cells start to make insulin. Those living cells that are becoming insulin-producing beta cells look green under a special fluorescent microscope, providing a simple and quick system to screen for environmental factors and genes that influence this process. Additionally these same cells will be used to screen a cDNA library generated from regenerating pancreas for novel genes that are involved in making new beta cells. Both approaches should lead to better understanding of how to stimulate the growth and differentiation of beta cells and eventually lead to new therapies.

    Dariush Elahi, PhD
    Clinical physiologist, Massachusetts General Hospital
    Associate Professor, Harvard Medical School (pending)
    (617) 724-0955, elahi.dariush@mgh.harvard.edu

    Joel Habener, MD
    Professor of Medicine, Harvard Medical School
    Howard Hughes Medical Institute Investigator, Massachusetts General Hospital

    Elahi and Habener have shown that naturally occurring peptides known as GLP-1 have growth-inducing properties. GLP-1 can induce conversion of ductal cells into insulin-secreting cells. GLP-1 may also have insulinlike properties of its own. Another similarly structured peptide is known as extendin-4, which lasts much longer in the body than GLP-1. These Center studies aim to evaluate how these two peptides convert cells to insulin-secreting cells in diabetic mice as well as directly regulate blood glucose levels. They plan to extend these studies to humans.

    Christiane Ferran, MD, PhD
    Transplant nephrologist, immunologist, molecular biologist
    Assistant Professor, Harvard Medical School
    Immunobiology Research Center, Beth Israel Deaconess Medical Center
    (617) 632 0840, cferran@bidmc.harvard.edu

    Beta cell susceptibility to death may be the major underlying variable influencing the occurrence of Type 1 diabetes. Triggered by immune or nonimmune mechanisms, this death usually occurs by apoptosis or programmed cell death. Very little is known about the defense mechanisms of beta cells in general and their role in diabetes. Ferran aims to determine the function and physiological implications of several known antiapoptotic genes in islet defense, to overexpress one of these protective genes (A20), and to study the impact of this overexpression on the occurrence of experimental diabetes. The ultimate target is the genetic manipulation of islets to express these ‘protective’ genes to preserve beta cells after the onset of diabetes to protect them from further autoimmune destruction and halt the progress of diabetes.
     

  7. Islet Cell Transplantation

  8. Unlike short-term organ transplant success rates approaching 90 percent, the one-year success rate for islet transplants hovers at about 5 percent. Center researchers hope to improve the outcome of islet transplants by testing new ideas emerging from the other Center activities—first in animal models and then in human clinical trials. Although a half-dozen clinical islet transplants have been performed at Massachusetts General Hospital over the past 20 years, neither the hospital nor any other Harvard institution has an active clinical islet transplant program at this time. One of the world’s foremost experts in clinical islet transplantation, Bernhard Hering MD, of the University of Minnesota, will help Center investigators develop their clinical program, which is projected to begin human clinical trials as early as a year from now.

        Even where islet transplantation is being performed, results in people with diabetes have been disappointing, both because of the need for ongoing immunosuppression and because even this immunosuppression does not seem to be adequate to prevent the recurrence of autoimmune diabetes in most cases.

        Results have been improving, however. Recent clinical trials of islet transplantation have shown that as many as 30 percent of recipients can maintain some islet function (although rarely without any supplemental insulin) for prolonged periods of time. Also, other trials have created insulin independence in people who do not have Type 1 diabetes but have had their pancreas surgically removed and then received autologous (from themselves) or allogeneic (from other people) islet transplants.

        In xenotransplantation, or transplants between different species, genetic engineering can now prevent at least one type of rejection that is especially important when donors from different species are used for transplantation. And in several recent cases, pig islet cells transplanted into human patients have survived for several months after transplantation.

        Center projects in this area will test strategies to prevent islet rejection and to induce tolerance, will apply new technology to study the microscopic mechanisms of islet destruction, and will develop earlier tests for detecting islet rejection.

    Hugh Auchincloss, Jr., MD
    Chair, Transplantation Section and Director, JDF Center at Harvard Medical School
    Transplant surgeon and transplantation immunologist
    Surgical Director of Pancreas Transplantation, Massachusetts General Hospital
    Acting Surgical Director of Kidney Transplantation, Brigham and Women’s Hospital
    (617) 726-8418, auchincl@helix.mgh.harvard.edu

    Auchincloss studies the mechanisms of graft rejection, especially focusing on how the rejection of organs and tissues from donors of another species (xenotransplantation) differs from the rejection of tissues from members of the same species (allotransplantation). His project will involve preclinical trials of islet transplantation in monkeys. It will provide the testing ground for new strategies that have been developed by other investigators in the Center. His project will test possible new strategies to avoid immunosuppression and to prevent recurrent autoimmuniity so that clinical trials of these strategies can begin.

    Clark K. Colton, PhD
    Biomedical engineer
    Professor of Chemical Engineering, Massachusetts Institute of Technology
    (617) 253-4585, ckcolton@mit.edu

    A leading researcher in the field of bioartificial organs, Colton wants to use encapsulation as a way to aid transplants of tissue from other species, such as islet cells from pigs. The idea is to encapsulate the tissue inside a semipermeable barrier, so that small insulin molecules can escape, but large immune cells and their protein products cannot penetrate inside to attack the tissue. One of the problems with the technique is that blood vessels also cannot pass through to deliver life-sustaining oxygen to the tissue. Colton will work on new ways to deliver oxygen to the transplanted tissue, investigate whether the technique works, and understand how it can prevent rejection.

    Robert B. Colvin, MD
    Immunopathologist
    Chief, Pathology, Massachusetts General Hospital
    Benjamin Castleman Professor of Pathology, Harvard Medical School
    (617) 726-2966

    Dennis Sgroi, MD
    Surgical and molecular pathologist
    Assistant Professor of Pathology, Harvard Medical School
    Assistant Pathologist, Massachusetts General Hospital
    (617) 726-5697, sgroi@helix.mgh.harvard.edu

    Considered the world’s foremost authority on kidney transplantation pathology in humans and experimental animals, Colvin studies the mechanisms of allograft and xenograft rejection and develops new immunosuppressive approaches. The marriage of two technologies, laser capture microdissection and high density cDNA arrays, now enable the routine identification of potentially thousands of molecular mediators of graft destruction and autoimmune injury in microscopically selected cells in animal models. Working with Colvin, Sgroi aims to combine his expertise with that of experts in animal models of diabetes to rapidly identify new genes that may have a significant role in the development of diabetes. Now that they can procure target cells from disease tissues and can run a rapid genetic profile of these cells, they hope to identify the key genes expressed during islet destruction by immunological mechanisms during autoimmune diabetes or during transplant rejection to generate new therapies to treat or cure diabetes.

    A. Benedict Cosimi, MD
    Chief, Transplantation Unit, Massachusetts General Hospital
    Claude E. Welch Professor of Surgery, Harvard Medical School
    (617) 726-8256, padykc@a1.mgh.harvard.edu

    Dicken S. C. Ko, MD
    Transplant Surgeon, Massachusetts General Hospital
    Instructor in Surgery, Harvard Medical School
    (617) 724-3730, ko.dicken@mgh.harvard.edu

    Cosimi has been researching more selective approaches to immunosuppression, particularly using polyclonal and monoclonal antibody therapy. Recently, new conditioning regimens that produce tolerance to allografts or xenografts in nonhuman primate recipients prevented rejection of kidney or heart transplants in monkeys, even after all immunosuppressive treatment was discontinued after 30 days. Working with Cosimi, Ko aims to develop a preclinical trial for inducing transplantation tolerance in monkeys by bone marrow chimerism—the concept developed by David Sachs and Megan Sykes (see Tolerance). Specifically, he wants to develop a model for inducing islet cell tolerance in transplantation so that a recipient of an islet allograft will be able to maintain those tissues without any immunosuppressive medications. His study will extend a successful tolerance induction protocol used in kidney allografts to islet cell transplantation, which would be a new approach to islet cell transplantation without using any immunosuppression.

    John Iacomini, PhD,
    Molecular biologist specializing in immunology
    Assistant Immunologist, Massachusetts General Hospital
    Instructor in Surgery, Harvard Medical School
    (617) 724 9846, iacomini@helix.mgh.harvard.edu

    Iacomini uses a new mouse model to study how human immune cells mediate rejection of pig islets and to develop methods to overcome rejection. Ultimately, this work may contribute to the cure of juvenile diabetes by making it possible to successfully transplant pig islets into diabetic individuals. Using immunodeficient mice, his group has developed a model to study human antipig cellular responses leading to the rejection of transplanted pig islets. He will use this model to determine the mechanism of rejection, and test ways to overcome rejection mediated by immune cells from people with diabetes. The studies represent the development of a practical small animal model to expedite transplantation trials of basic research, and will serve as a useful tool for other investigators in the Center to expedite clinical application of basic research findings.

    Terry B. Strom, MD
    Immunologist, nephrologist
    Professor of Medicine, Harvard Medical School
    Director, Division of Immunology, Beth Israel Deaconess Medical Center
    (617) 632-0150, tstrom@bidmc.harvard.edu

    A leading expert in how the T cell responds to transplanted tissue, Strom hopes to develop a more sensitive early-warning system to determine whether recipients are mounting a destructive or protective response to islet transplants. Following transplantation with foreign tissues, the recipient’s immune system mounts an active response to the transplant—usually rejection, but sometimes the response can be protective and lead to tolerance. Scientists can now detect the presence of certain highly select genes that are switched on in immune cells before clinically evident rejection is present in circulating blood cells in mouse islet and human kidney transplant recipients. Strom hopes to apply such monitoring to human islet transplant recipients. So far, protective immune responses are more difficult to detect. Strom also aims to develop a convenient road map to chart a given recipient’s progress toward achieving tolerance and permanent drugfree islet transplant survival.
     

  9. Core Resources

  10. More than six other laboratories in the Center will support work of all Center scientists. One lab will produce islet cells for animal studies and human transplants. Two labs will analyze the tissues from experiments performed by Center investigators before and after transplantation. Another group will produce a special kind of mouse, which so far represents the only animal model for Type 1 diabetes. Another lab will design and test specialized “vectors” derived from animal viruses that will make it possible to genetically modify islet cells to prevent their rejection after transplantation into patients. Another lab will use powerful new techniques to identify genes critical for in the development of islet cells and in islet transplant acceptance in the body.

    Gordon C. Weir, MD
    Chair, Core Resources Section, JDF Center at Harvard Medical School
    Islet cell biologist, endocrinologist
    Joslin Diabetes Center
    Professor of Medicine, Harvard Medical School
    (617) 732-2581, weirg@joslab.harvard.edu

    Weir chairs the core resources section. A leading authority on pig and rodent islet cells, Weir will run the islet core laboratory, a fundamental part of the Center. Without such a facility, it would be impossible to start preclinical studies with nonhuman primates and human islet allograft program. This laboratory will supply human, pig, monkey, rat and mouse islets to investigators of the Center as they are needed. A high priority is to start a human islet allograft transplant program. With the goal of using pig islet cells as a source for eventual human transplants, Weir will also develop neonatal islets as a source for transplantation and collaborate with Mulligan (see below) on gene transfer methods to help these cells resist rejection.

    Albert Edge, PhD
    Molecular and cellular biologist, immunologist
    Senior Director, Molecular and Cellular Biology, Diacrin, Inc.
    (617) 242-9100, aedge@diacrin.com

    At the Charleston, Mass.–based company Diacrin, Edge has been studying cellular transplantation as a therapy for disease. His company has transplanted a number of cell types into humans for the treatment of intractable diseases in FDA-approved clinical trials. He will direct the pig islet isolation and transplantation core. The research group at Diacrin has developed ways to isolate large numbers of healthy pig islet cells. They have shown that these islets function in animal models and are hoping to apply these results to successful transplantation in humans. They will supply islets isolated from adult pigs to other investigators and work on procedures for preventing immune rejection of transplanted islets.

    Myra A. Lipes, MD
    Michael Grusby, PhD
    (see earlier descriptions)

    Using their special expertise, Lipes and Gusby will produce and maintain mice colonies, including diabetic mice, needed for their projects and other Center research efforts.

    Douglas Melton, PhD
    Developmental biologist
    Professor of Molecular and Cellular Biology, Harvard University
    Howard Hughes Medical Institute Investigator
    (617) 495-1812

    Melton is an associate director of the Center. A leading expert on embryonic development, Melton has recently turned his attention to the discovery of genes that control islet cells and pancreas development. He will direct the Center’s cDNA Library Core Facility. The new technology known as cDNA microarray or DNA chip analysis can display thousands of individual genes on small filters. The filters are then used to examine gene expression patterns in samples of RNA from any tissue or cell source. The large quantities of information are analyzed with sophisticated computer software. In this core, Melton will produce arrayed filters that display thousands of genes present in islet cells. The filters can be used, for example, to identify patterns of gene expression in developing islet cells, in islet cells from early versus later stage diabetes, or in instances of tissue rejection. This type of survey provides insights into genes controlling pancreatic development and disease pathology, allowing for disease intervention by appropriate drug development or gene therapy. It may also help scientists grow islet cells in culture.

    Richard C. Mulligan, PhD
    Mallinckrodt Professor of Genetics, Harvard Medical School
    Howard Hughes Medical Institute Investigator, The Children’s Hospital
    Director, Harvard Gene Therapy Initiative
    (617) 355-8541, mulligan@rascal.med.harvard.edu

    Mulligan is an internationally recognized leader in the development of new technologies for transferring genes into mammalian cells. Scientists use the specialized tools created in his laboratory to unravel basic questions about human development and to devise new therapies for the treatment of inherited and acquired diseases. Mulligan will direct a Mammalian Gene Transfer/Vector Core that will provide a centralized service for the production and characterization of gene transfer reagents necessary for each of the individual projects comprising the Center’s activities. Such a Core will be continuously fueled by the ongoing efforts in Mulligan’s laboratory to develop more effective gene transfer ‘vectors’ (the vehicles used to ferry new genes into cells) and therefore will provide state of the art technology in this area.

    Neal Smith, MD
    Instructor, Department of Pathology, Massachusetts General Hospital
    (617) 726-1835, smith.rex@mgh.harvard.edu

    In collaboration with Colvin (see above) and immunologist Frederic Preffer PhD, assistant professor at Harvard Medical School, Smith will work with the Immunopathology and Molecular Biology Core. Tissue analysis from both patients and from experimental animals will help explain how islet graft are destroyed and how islets are lost as diabetes develops. This core will provide Center investigators with morphological analysis of the immune responses in these tissues. In parallel, Bonner-Weir, an expert in islet morphology and pathology, will be running a related core, the Islet Histology Core for analysis of the islet cells themselves. Both cores will provide numerous techniques to identify the cell type and whether the cells are dying or differentiating. In addition to the tissue analysis, interpretation and collaboration will be given as needed. 


 


 
 
 
 

 

 

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