News & Research

University of Miami Miami, Florida

T regulatory cell therapy for type 1 diabetes

General Research Subject: Type 1 Diabetes

Focus: Immunology, Other, Transplantation

Type of Grant: Junior Faculty

Project Start Date: January 1, 2010

Project End Date: December 31, 2012

Research Description

The immune system focuses on attacking and destroying foreign materials and avoids attacking self tissues. But this process can fail leading the immune system to attack self tissues leading to autoimmune diseases and in the context of type 1 diabetes (T1D) the insulin-producing â cells are destroyed. Islet cell transplantation is recognized as an approved treatment for T1D. A significant complication of such transplantation is that life-long immune suppression is required which is toxic, not always successful, and impairs normal immune response to infectious microorganisms. One mechanism that immune system employs to keep these self-reacting cells in check is through a population of regulatory T cells that function by blocking the destruction of self tissues. These regulatory T cells can also block immune responses to transplanted tissues, thereby preventing their destruction.

However, the use of these regulatory T cells in therapy is hindered by the lack of sufficient numbers of these cells required to inhibit the desired immune response(s) and survivability of the donor regulatory T cells. Mice that are genetically deficient in these regulatory T cells exhibit rapid lethal autoimmunity. In this unique animal model we have shown when regulatory T cells are given autoimmunity is prevented and mice live a normal disease-free lifespan. Importantly, tolerance to transplanted tissue is also achieved with regulatory T cells treatment.

These findings suggest a potential use of Treg cells as therapy for the treatment of T1D. We have also shown that when these regulatory T cells are given to normal mice these cells fail to survive. Therefore, the overall goal of this proposal is to elucidate the mechanisms by which successful 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 of the mice in order to create space for the donor Treg cells to survive long-term and that these donor regulatory T cells will become bias towards the transplanted tissue. These proposed studies will ultimately play a part in determining whether donor Treg cells can be used successfully for the treatment of T1D.

Reseacher Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes? 

My work with T regulatory cells in mouse models of autoimmunity shows great promise in establishing adoptive T regulatory cell therapy as a successful treatment for achieving both self and transplant tolerance. This work has provided some clues as to the biological environment required in order to achieve successful therapy.  Some investigators are taking the approach of expanding T regulatory cells which would allow a larger number of T regulatory cells to be used for adoptive immunotherapy. However, our laboratory has shown that under the right biological conditions, adoptively transfer of a small number of T regulatory cells is a very effective method to prevent autoimmunity and induce tolerance to transplanted tissue which is accompanied by long-term survival of the adoptive transferred T regulatory cells. The study of the mechanisms by which successful T regulatory cell therapy can be achieved is the heart of this proposal.

These proposed studies are aimed at defining the critical requirements for T regulatory cell therapy in diabetes relevant mouse models and will lay the groundwork for future research that would focus on how to safely translate a similar approach to the clinical arena. I hope that my work outlined in this research project will lead to the design of novel therapies for tolerance induction with the ultimate goal of achieving both self and transplantation tolerance for the treatment of type 1 diabetes patients.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond? 

There is a lot of interest in using T regulatory cells for immunotherapy for the treatment of type 1 diabetes. However, currently their use is hindered by the lack of sufficient numbers of these cells required to inhibit the desired immune response(s) and survivability of the donor regulatory T cells. Our previous work has demonstrated that under the right biological conditions, adoptive therapy with a small number of T regulatory cells can be an effective strategy for treatment of autoimmune diseases and organ transplantation rejection, but manipulation of the recipient's immune system appears necessary to achieve long-term engraftment and therapeutic efficacy. The proposed studies are aimed at defining the critical requirements for successful T regulatory cell immunotherapy and will ultimately play a part in determining whether donor T regulatory cells can be used successfully for the treatment of type1 diabetes. Importantly, these studies could greatly impact the development of a novel, non-toxic approach to tolerance induction with the ultimate goal of achieving both self and transplantation tolerance.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts? 

My passion for science has always been part of my academic life. Since my time as graduate student I have had a strong interest in doing research that had potential for clinical setting. I am interested in understanding the basic immunobiology of T regulatory cells and applying that knowledge for future clinical translational applications. I am very excited about this research proposal and what makes this research so motivating is the fact that the data generated will be of vital importance for the development of a novel adoptive T regulatory cell therapy for the treatment of patients with type 1 diabetes, which is so desperately needed. I have learned and incorporated a great deal of knowledge and techniques that enable me to obtain significant new results in my current field of work on the immunobiology of T regulatory cells and the translational potential for the treatment of autoimmune diseases and tolerance induction. My short-term goal is to actively pursue the work proposed.

This Junior Faculty award from the ADA will provide me with the means to incorporate a broad range of techniques and procedures that are vitally important to the continuation of my research. Here at the University of Miami where I am junior faculty, my department chair and the scientific director of the Diabetes Research Institute, are both committed to my career development and will allow 100% of my time to be devoted to research without demanding teaching responsibilities for me during this critical transition time.

This award will also enable me to achieve my long-term goal, which is to become a productive independent scientist in the field of immunology focusing on the immunobiology of T regulatory cells and autoimmune diabetes. Importantly, this award would generate enough original data in order to successfully apply for a traditional research support grant (R01) as a new investigator from the NIH and be considered for promotion to Associate Professor. I am motivated and passionate about my research and I do believe that my most creative and productive years still lie ahead.

In what direction do you see the future of diabetes research going? 

Type 1 diabetes is an autoimmune disease resulting in the destruction of insulin-producing, pancreatic ß-cells and in turn lifelong dependence of patients on insulin injections. Patients with type 1 diabetes are also at risk of developing both acute and chronic complications, which severely affect health, quality of life and can become life-threatening. Pancreas and islet transplantation can restore insulin secretion, but require chronic immunosuppression, and grafts are still susceptible to chronic rejection and recurrence of autoimmunity.

Diabetes is a complex disease and achieving both self and transplantation tolerance is the ultimate goal we must accomplish to be able to cure diabetes through transplantation. The future of diabetes research will require a multidisciplinary approach including all levels of research from basic science in small rodents and preclinical animal studies in non-human primates to clinical application. My basic science research along with many other scientists will ultimately lead to a cure for type 1 diabetes.