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Under the Microscope

 

Under the Microscope with Allison Bayer, Ph.D.

As we continue to develop the DRI BioHub, overcoming the challenges posed by the immune system will play an essential role in our ability to discover a biological cure for type 1 diabetes (T1D).  Reversing autoimmunity and preventing the rejection of transplanted cells – and doing so without the need for harmful immunosuppressive drugs – are top priorities at the DRI.
 
Much has been learned about the immune system in recent years, which has led our researchers to develop new strategies using the cells of our own body, rather than toxic agents, to address these critical immune-related issues. Dr. Allison Bayer is a member of the DRI team studying a particular population of immune cells, known as regulatory T cells (Tregs), which are found throughout the body and protect “self” cells from being destroyed. Research has shown that in people with T1D, alterations in Tregs may be responsible for this autoimmune attack on the insulin-producing cells.
 
Dr. Bayer, Research Assistant Professor in Department of Microbiology and Immunology, is investigating methods to utilize these cells through a process known as adoptive Treg therapy. In the interview below, she explains more about her research and the status of this work. 

What is a Regulatory T cell (Treg) and why is it important for the study of type 1 diabetes?

The immune system focuses on attacking and destroying foreign materials and avoids attacking “self” tissues. But this process can fail, causing the immune system to destroy its own tissues, which is known as autoimmunity. In type 1 diabetes (T1D), the insulin-producing beta cells are destroyed. One mechanism that the immune system employs to keep these self-reacting cells in check is through a population of Tregs that block the destruction of self tissues. These Treg cells can also block immune responses to transplanted tissues, thereby preventing rejection. Mice that are genetically deficient in regulatory T cells exhibit rapid, lethal autoimmunity. Using this unique experimental model, we have shown that when additional Tregs are given to these recipient mice (adoptive Treg therapy), autoimmunity is prevented and the mice live a normal, disease-free life. Importantly, tolerance to transplanted tissue is also achieved with this type of Treg treatment. These findings suggest a potential use of Tregs as therapy for the treatment of T1D. 

Can you further explain Adoptive Treg Therapy?

In the context of type 1 diabetes, adoptive Treg therapy means correcting for the deficiency of these cells by giving Tregs from one’s self or from another individual in order to reset the natural regulatory function of the immune system and prevent the attack on the insulin-producing beta cells. When we give the “new” or donor Tregs to the patient, these cells will have to compete with the patient’s own Tregs. Imagine that you have a full house, but you need to let new people into the house. In order to make room for the new tenants, you would have to first “evict” some of the existing residents. Creating space for the new tenants also avoids depleting critical resources for all the people living in the house. The same idea holds true for the “new” Tregs. We need to make space and limit competition for resources in order for the new Tregs and the patient’s own Tregs to grow, survive and function.

What is the focus of your research?

I am investigating the mechanisms by which successful adoptive Treg therapy can be achieved for the reversal of autoimmune diabetes or to suppress islet transplant rejection. We anticipate that we will need to manipulate the immune system in order to recreate the biological environment for donor Tregs to survive long-term and induce tolerance toward the transplanted tissue. Through studies in experimental mouse models, we have been able to identify critical factors for successful adoptive Treg therapy, and these include making adequate space, minimizing competition, and adding agents, namely interleukin-2 (IL-2), to promote their growth, survival, and function. Also, since Tregs regulate many different types of immune cells, we need to direct that regulation specifically to resetting the autoimmune response, while leaving the rest of the immune system intact. 

What have been your latest results?

Recently, we have focused on developing adoptive Treg therapy in a mouse model of spontaneous autoimmune diabetes, which closely resembles T1D in humans. Keeping in mind the critical factors our previous work defined in designing a clinically relevant strategy, we have demonstrated that adoptive Treg therapy can reverse the disease in this experimental model when we recreate the Treg supportive environment with a small number of Tregs. In fact, we are able to use a 20-fold less quantity of Tregs to observe therapeutic benefit when compared to non-manipulated mice.

How does your research with Tregs differ from what other groups are working on?

Many other groups are working on developing adoptive Treg therapy. Because Tregs are a rare population, many groups are expanding Tregs to generate large numbers of these cells prior to giving the Tregs for therapy.  However, work from our lab has demonstrated that, under the right biological environment, a small number of non-expanded Tregs can efficiently control autoimmunity and induce tolerance to transplanted tissue. Therefore, by recreating this supportive environment at the time when “new” Tregs are given, we have shown that a small number of Tregs result in a therapeutic benefit. Currently, clinical adoptive Treg therapy requires several rounds of expansion before Tregs can be given to patients. This is cost inefficient, and there is the risk of amplifying “bad” cells that could destroy beta cells. Safety trials with expanded Tregs are ongoing in T1D patients. Our approach to understand and recreate a supportive environment for donor Tregs to grow and survive may circumvent or lessen the need for this large-scale Treg expansion prior to adoptive transfer to patients.

What are the next steps of your research?

Although we have had success with adoptive Treg therapy in experimental mouse models, we still have unanswered questions about recreating the supportive Treg environment, effects on other immune responses, and how those responses will impact Treg growth, survival, and function. With that said, we have specifically designed the experimental studies to be more easily applied to patients by using clinically-approved agents with a known safety profile. The studies in my lab will ultimately play a part in determining whether donor Tregs can be used successfully for the treatment of T1D in the clinical setting. My lab is also collaborating with Drs. Chris Fraker, Luca Inverardi, and Giacomo Lanzoni to understand the role of Natural Killer (NK) cells in autoimmune diabetes. These cells act as a first-line of defense against viral infections and respond to cancer cells. Understanding these cells and the interplay of these cells with Tregs will aid in developing better strategies to treat T1D.

How did you become interested in type 1 diabetes research?

I have always had a passion for science and wanted to engage in research that could have positive effects on people’s lives. I am interested in understanding the basic immunobiology of Tregs and applying that knowledge for future clinical applications. My basic science research using experimental mouse models allows me to design experiments that answer complex questions which could otherwise not be easily addressed with the patients themselves. What makes this research so motivating is the fact that it may provide a basis for designing novel therapies that can impact those with T1D.

Why did you come to the DRI? 

I was a fellow in Dr. Thomas Malek’s lab and I had an interest in applying our findings on immunobiology of Tregs in a lethal systemic autoimmunity mouse model to autoimmune diabetes. Specifically, I wanted to forge my own research in my own laboratory and the DRI was the perfect place to do this. I am motivated and passionate about my research and I do believe that my most creative and productive years still lie ahead.



In vivo environment for Treg immunotherapy

Restoring immune system balance in those with autoimmune diseases will require treatment with immune cell-depleting agents prior to the infusion of new Treg cells.  The use of these agents temporarily reduces the numbers of selected immune cell populations. By doing so, this reduction will create "space" for the infusion of newly introduced cells, while the host Treg cells survive and regenerate. The use of low-dose IL-2 will promote the growth and survival of both recipient and donor Tregs while reducing inflammation.

 

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