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.
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Pre-existing
Autoimmunity
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.
-
Tolerance
Induction
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.
-
Islet
Cell Sources
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.
-
Islet
Cell Transplantation
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.
-
Core
Resources
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.
