News & Research

    University of Minnesota, Minneapolis, Minnesota

Real time in vivo imaging of diabetes: the role of programmed death-1

General Research Subject: Type 1 Diabetes

Focus: Immunology

Type of Grant: Junior Faculty

Project Start Date: July 1, 2009

Project End Date: June 30, 2012

Research Description

Type 1 diabetes (T1D) results from the T cell mediated destruction of insulin producing beta cells within the pancreas. The goal for treating diabetes is to selectively target only destructive T cells, without disabling the body's ability to fight foreign invaders. The purpose of this grant is to understand how these autoreactive T cells can be inhibited using negative regulatory receptors, namely Programmed Death Ligand-1 (PD-L1). The grant focuses on the where, when, and who required for PD-L1 expression, a critical molecule for T1D prevention. To accomplish this, a novel animal model will be imaged, in real time to visualize the earliest effects on diabetes development. This system shares several characteristics with human diabetes.

In addition, a powerful treatment protocol to selectively target the autoreactive T cells has been developed. Using this type of approach allows us to 're-educate' the immune system to selectively silence destructive immune responses. Thus in effect, restore a state of self-tolerance for diabetes treatment to prevent further tissue destruction. This model system will help facilitate the testing of immune based therapeutics to selectively target diabetogenic T cells and enhance PD-L1 mediated suppression for prevention and treatment of T1D. The goals of this grant are to 1) define the role of PD-L1 and inflammation during the pathogenesis of T1D, and 2) understand the fundamental mechanisms of how immune cells can be selectively silenced. The insights gained through this research will provide a rational basis for the development of PD-L1-specific therapies for the treatment of T1D patients.

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? 

Our research efforts are focused on understanding the fundamental mechanisms that regulate T lymphocytes during Type 1 diabetes (T1D) and developing treatment strategies to limit their destructive nature. T1D is an autoimmune disorder resulting from the T cell mediated destruction of the insulin producing beta cells within the pancreas. T lymphocytes are at the center of this disease process and orchestrate this selective attack of self tissue.  At the root of autoimmunity lies perhaps the most important aspect of immune regulation, the ability to discriminate between self and non-self. This highly selective response is characterized by a complicated set of mechanisms which regulate T lymphocyte activity. Autoimmunity results when these mechanisms fail. Recently, we have generated a powerful treatment protocol to selectively target autoreactive cells.

Using this type of approach allows us to re-educate the immune system to selectively silence destructive T lymphocytes while maintaining an intact immune system to fight off pathogens and infections. This re-education restores a state of self-tolerance and prevents further tissue destruction. This therapeutic approach is extremely effective at preventing diabetes in susceptible mice.  In fact, using animal models we prevented diabetes in treated mice and identified a key regulatory pathway called Programmed Death-1 (PD-1) to promote tolerance.  PD-1 is an inhibitory receptor expressed on the surface of T and B lymphocytes, and interacts with two ligands, Programmed Death Ligands (PDL)-1 and 2, which are expressed on tissue derived cells. 

We have shown that PD-1 controls diabetes and promotes long term islet function. This grant will investigate the mechanism of PD-1 biology and how it influences T cell migration and dynamic interactions with other key cell types of the immune system during the breakdown of tolerance and induction of diabetes.  Together, these studies will determine the specific role PD-1 and PD-L1 expression have as the last line of defense against diabetes. Lastly, this project will test the biological role of PD-L1 as a therapeutic target to cure diabetes. 

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

The purpose of this project is to improve our understanding of the mechanisms involved in the immune regulation of self-destructive T cells using regulatory receptors.  Our work will determine the contribution of the PD-1 pathway during the pathogenesis of diabetes and the therapeutic potential as a novel target for diabetes treatment.  The successful completion of this project will lead to a better understanding of negative regulatory receptors during diabetes, and provide a rational basis for the development of therapeutic targets to cure diabetes. 

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

My interests in studying autoimmune diabetes stem from early childhood. Although I didn't know or appreciate the complexity of this disease when I was young, I was interested in learning more because it had affected our family.  Diabetes is so prevalent that it is difficult to find someone who is not directly affected or related to someone afflicted with this disease. Although injecting insulin daily has been an effective therapy and life saving treatment, it is not a cure.  This treatment strategy does not address the underlying problem of autoimmunity, and therefore it is clear that research aimed at developing therapies for the prevention and treatment of this debilitating autoimmune disease is necessary. 

This award will significantly impact my professional development as an independent investigator and help provide necessary funding for our research efforts.  My career goal has been to pursue immunological research in an academic setting to better understand autoimmunity and develop treatments that will improve human health.  I believe that strong basic research will provide the necessary insight into this complex clinical disease and help to identify targets for therapeutic opportunities.  Receiving this grant from the ADA will ensure the financial support that will allow me to continue my research on immunological tolerance.

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

The future of diabetes research will include three major areas: early disease diagnosis and detection, islet replacement or regeneration, and specific immune modulation aimed at induction of immunological tolerance.  Successful early diagnosis is important for several reasons.  If patients are properly diagnosed at early stages, treatments targeting beta cell survival can be implemented to prolong islet function and limit damage.  Similarly, as part of the cure for diabetes, islet cell mass and islet cell function must be restored (or replaced through transplantation) to achieve insulin independence.  Stem cell research holds tremendous opportunity in this regard. Each of these topics are important and critical for the long term treatment of diabetes, however, without addressing the underlying autoimmune condition, islet beta cells will continue to be targeted and destroyed. 

Therefore, I believe future work to develop an effective cure for T1D should also address this problem.  The goal for our research is to selectively target only the destructive T cells without disabling the remaining immune cells, thereby allowing the body to fight foreign invaders.  One of the more promising concepts to achieve this goal is the use of antigen specific tolerance.  We have recently demonstrated that selectively targeting the insulin reactive T cells is an effective therapeutic strategy for treating diabetes.  Using this approach or similar approaches to restore immunological tolerance combined with the replacement or restoration of islet cell function holds great promise for curing diabetes.