Michael J. Friedlander Professor of Medicine, Professor of Microbiology & Immunology and Surgical Sciences
Director, Columbia Center for Translational Immunology
Director of Research, Transplant Initiative
Director, Bone Marrow Transplantation Research, Division of Hematology/Oncology
As a young girl growing up in Canada, Megan Sykes developed an interest in science and decided to study medicine as a student at the University of Toronto. “I realized the limitations of our knowledge and felt that I had something to contribute,” Dr. Sykes recalled. After 19 years at Harvard University, Dr. Sykes arrived at Columbia University in April 2010 to establish and direct the Columbia Center for Translational Immunology (CCTI), a strategic research partner of the Naomi Berrie Diabetes Center (NBDC).
A key objective of the research conducted by Dr. Sykes and her colleagues is to successfully reverse the overactive immune response of people with type 1 diabetes (T1D), and to prevent this immune response from recurring. To do so, they will apply a technique devised for organ transplantation to produce a state called “mixed chimerism” - an immune system that blends elements of both the donor and recipient. This process tricks the immune system of a transplant recipient into regarding a donor organ as “self,” protecting the transplanted tissue rather than rejecting it. The ability to achieve a state of durable, or lasting, mixed chimerism in people with T1D who receive islet cell transplants is essential to Dr. Sykes’ strategy to cure T1D.
In recent studies of T1D, Dr. Sykes and her colleagues have actually been able to reverse autoimmunity in a mouse model that closely resembles human diabetes, and get the mice to tolerate donated, functional islet cells - effectively curing T1D in these mice.
The ultimate goal of Dr. Sykes’ work is to apply this strategy to humans: to transplant functioning islet beta cells to a person with T1D, while preventing the recipient’s immune system from mounting a rejection response or autoimmune attack. This would allow the person to live a diabetes-free life, without immunosuppressive drugs that can lead to infections or increased risk for cancer.
The CCTI research team has made a number of major discoveries related to T1D. Dr. Sykes recently answered our questions about her work:
Tell us about your efforts to “educate” the immune system for successful transplant outcomes.
We accomplished the reversal of T1D in diabetic mice by using a strategy I originally helped develop for organ transplantation, to decrease the likelihood that the immune system of a person who has a transplant will reject a donor organ. This strategy, referred to as “education” of the immune system, involves first clearing the T-cells from a recipient’s immune system, so as to “wipe the slate clean.” Then some of the donor’s bone marrow is transplanted into the recipient, along with the organ. This tricks the immune system into regarding the new organ as “self,” and leads the body to accept and protect the donor organ, rather than reject it.
With this method, we pioneered the achievement of “mixed chimerism,” in which an immune system blends elements of both the recipient and the donor. This was a tremendous advance in preventing organ rejection, and it paved the way for a breakthrough in kidney transplantation: the first-ever transplants in which recipients were able to discontinue immunosuppressive drugs after surgery or accept their organs for years thereafter.
How have you applied “immune education” to cure T1D in mouse models?
Using this technique in a mouse model that closely resembles human T1D, we have actually been able to reverse autoimmunity and cure T1D in these mice. By using bone marrow transplantation with non-toxic methods in pre-diabetic and diabetic mice, we have been able to reverse the autoimmune T-cell response, thus preventing the development and recurrence of T1D; and induce tolerance toward transplanted donor islets from non-diabetic mice.
We are now focusing on exploring the abnormalities in T-cell development that occur in people with T1D. Incredibly, we can now replicate a person’s immune system in a live mouse, which allows individualized analysis of the person’s immune system and testing of immune therapies. This will help advance investigations at Columbia toward clinical trials of pancreatic-cell transplantation in humans—with the goal of achieving a successful and permanent cure for the disease.
Tell us more about the “personalized immune” mouse.
As my research team reported in March 2012, the “personalized immune” mouse recreates the robust and diverse characteristics of an individual human’s immune system. This innovative mouse model offers an unprecedented tool for analyzing the abnormalities that contribute to T1D and other autoimmune diseases. It could also help predict how a person with T1D will respond to existing drugs or immunotherapies.
The personalized immune mouse will provide an unprecedented window into the fundamental difference between the immune system of a person with T1D compared to someone who lacks the genes that predispose to the disease. Studies based on this new mouse model will shed valuable light on the genetics of T1D. A number of HLA-associated genes have been linked to T1D. About a third of the population has one or more of these genes. But a much smaller percentage of the population actually develops the disease. What this means is the HLA genes are necessary, but not sufficient, to cause T1D. Using the personalized immune mouse, we expect to learn much more about the role that non-HLA genes play in the disease.
How can tolerance be induced in people with T1D in preparation for islet cell transplantation?
An essential component of our strategy to reverse diabetes autoimmunity is to successfully transplant functioning islet beta cells to a person with T1D. To do so, it will be necessary to induce lasting tolerance for the transplanted tissue. We are testing a new tolerance induction strategy that involves a special “regulatory” cell type that comes from the transplant recipient. These regulatory cells are used in combination with bone marrow transplantation and a mild form of conditioning, which prepares the recipient to receive the donor bone marrow. The preliminary data in studies of non-human primates are very exciting, demonstrating a more durable form of chimerism and the most robust tolerance that has ever been seen.
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