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Our immune system performs perhaps the most complex task in our body – it protects us against innumerable infectious agents that can cause us harm. To function properly, the multitude of cells that make up our immune system must work with, not against, each other and in perfect balance. B cells, for instance, produce antibodies to kill microbes. T cells not only help B cells with antibody production, but also kill “bugs” by their own means. Typically, any T cells and B cells that cannot do their jobs are vetted and eliminated by the immune system to avoid potential harm.
Nonetheless, mistakes can happen in the process of generating the billions of cells that make the immune system work. Rogue T cells can sneak through the learning process and cause damage to our body’s own tissues and cells, such as the pancreatic islets. This self-destruction is known as an autoimmune attack.
The immune system has several mechanisms to safeguard against autoimmunity. Understanding how these mechanisms work is one of the critical steps to finding a cure for type 1 diabetes.
Zhibin Chen, M.D., Ph.D., an Assistant Professor in the Department of Microbiology and Immunology and at the Diabetes Research Institute at the University of Miami Miller School of Medicine, is looking into how one of these natural safeguards, called regulatory T cells, or Treg cells, works to regulate overall immune function.
Treg cells are the mediators of the immune system, working with other protective factors to make sure it is in robust condition to fight infection but not out of control to cause harm to the body’s own cells.
It is a delicate balance. A loss of Treg cells can cause several autoimmune diseases, including type 1 diabetes. Scientists believe Treg cell replacement is essential in these cases. In fact, scientists have shown that Treg cell therapy in animal models can be beneficial even in recipients that do not have an apparent Treg cell deficiency.
Dr. Chen and his team are working on ways to boost the patient’s own Treg cells to encourage long-term survival of transplanted islets, as well as to inhibit the onset of diabetes in the first place.
As a young medical doctor, Dr. Chen initially treated patients for lupus in his native China. He changed his focus to type 1 diabetes while studying and doing research at the Joslin Diabetes Center and Harvard Medical School, where he obtained his postdoctoral training.
What brought you to the DRI?
I had a strong desire to find an institute where my training and research successes could be quickly put to clinical use. I was impressed with the well-established translational research core facility.
The DRI is well known for its leadership in type 1diabetes research and its sincerity in focusing this research solely on finding a cure. Dr. Ricordi’s vision in this endeavor is well respected throughout the world. With comprehensive training in both medicine and science, and broad research experience in both basic immunology and its application to autoimmune diseases, particularly type 1 diabetes, I feel my research will contribute to this vision. This was a huge attraction for me, and I feel very lucky to be able to join the team.
How have you applied your earlier findings and achievements to developing cure-focused strategies here at the DRI?
One of our advantages is that we have a variety of animal models that spontaneously develop type 1 diabetes very quickly – within a few weeks. The benefits of this model were initially published in the Proceedings of the National Academy Science of USA, 2006. We are using these models to investigate ways to boost the patients’ own Treg cells with a combination of immune modulation drugs that are already FDA-approved. These models will enable us to quickly assess which combinations work to promote Treg cells and inhibit diabetes. We can then test promising regimes on the standard islet transplantation model, which is much more expensive and time-consuming.
Is there also an advantage to using FDA-approved drugs?
By using FDA-approved drugs that are already proven safe and have shown potential to treat similar diseases, we will be able to accelerate our research findings to clinical islet transplantation trials. We anticipate making an impact in the clinical arena in the near future by developing an effective regime of immunological treatments that can promote long-term survival of islet transplants using drugs that already exist.
Can you tell us of any challenges you face in your efforts to develop effective immunological treatments?
A typical hurdle for all successful organ transplants to overcome is the inability of the immune system to accept the transplant due to alloimmunity – a state caused by immunological incompatibility between the donor and recipient. Type 1 diabetes presents an even more difficult challenge, since the autoimmunity that mistakenly destroyed the patient’s own beta cells in the first place is also at play to destroy the transplanted beta cells. This process of rejection is known as recurrent autoimmunity.
We are developing Treg cell therapies with cells that are prepared and manipulated exogenously. Clinical trials in this area are underway or have been planned. Despite the great interest, however, there are still a lot of unknowns, like what kind of Treg cells would be most effective. Taking a cue from our previous studies, my lab is investigating if autologous Treg cells that are specifically directed toward beta cells can protect islet transplants in preclinical models.
How might transplant patients benefit from Treg cell therapies over the long term?
Treg cells may be able to promote the survival of islet grafts by at least two different mechanisms. First, they may directly suppress the function of destructive T cells – like good cops arresting bad guys. Second, Treg cells may also inhibit the inflammatory damage to the graft – like firefighters doing damage control.
The potential benefits of Treg cell therapies could have a great impact on the DRI’s integrated and sequential approach to finding a cure for type 1 diabetes. For example, the restoration of Treg cells could open up the possibility for islet regeneration, for establishing immune tolerance and for several approaches to cell replacement.
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