Reijonen, Helena Kristiina, PhD
Characterization of autoreactive memory T cells in T1D
General Research Subject: Type 1 Diabetes
Type of Grant: Basic Science
Project Start Date: July 1, 2009
Project End Date: June 30, 2012
Type 1 diabetes (T1D) is an autoimmune disease characterized by beta-cell destruction mediated by islet targeting T lymphocytes. These cells have been identified in T1D patients but their characteristics are still incompletely understood. Islet-targeting T lymphocytes were investigated using tetrameric compounds that bind to these T cells in a specific manner. This study was performed using blood samples from patients with recent-onset type 1 diabetes and also in patients who have received simultaneous pancreas-kidney transplant (SPK) but years later show signs of recurrence of diabetes (T1DR), despite immunosuppression that prevented rejection of the transplants. Monitoring of islet-targeting T cells in these patients revealed changes associated with the clinical course.
However, the features of these cells allowing persistence in the body decades after the onset of diabetes leading to recurrence of islet destruction are still largely unknown. In the proposed study we aim to run comparative studies on the T cells in patients with T1DR and with recent onset T1D or pre-diabetes. The hypothesis is that the T cells targeting distinct islet structures in patients with recent onset T1D and pre-diabetic subjects compared to patients with T1DR will be overlapping, but the key features may differ. The aims of the study are identification of distinct islet specificities of the T cells in blood and characterization of the signature of these cells. This project will generate novel information about dynamics of the disease progression with direct relevance to understanding and prevention of spontaneous disease development and recurrent diabetes in transplant patients.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Our project is focused on the cell mediated immunity of type 1 diabetes. Destruction of insulin producing beta cells in T1D is primarily mediated by CD4 and CD8 T lymphocytes that target islet proteins. In part because of the rarity of these autoreactive T cells in the circulation and limitations of T cell assays, many of the key phenotypic and functional properties of these cells have remained incompletely characterized. We have been collaborating for the past few years with investigators at the University of Miami in studying recurrence of type 1 diabetes (T1DR) in recipients of simultaneous pancreas-kidney (SPK) transplants. In this collaboration we are aiming at an extensive characterization of autoreactive T cells and their phenotypic/functional features using tetramer technology.
We will also perform comparative studies in patients with recent onset T1D and autoantibody-positive, at-risk first degree relatives (prediabetic). By comparing these two patient populations we will investigate whether recurrent islet autoimmunity in pancreas transplant patients is associated with fewer and selected T cell specificities compared to prediabetic subjects and recent onset T1D patients. We will also examine whether these autoreactive T cells display different key phenotypic features in these two patient populations. Finally, we are interested in how these autoreactive T cells become persistent memory T cells that can recognize their target decades after the disease onset and destruction of the original islet tissue in patients who have received pancreas transplant. This project will generate new information about key features and the population dynamics of T cells associated with islet autoimmunity in the context of spontaneous disease development as well as recurrence of autoimmunity after transplantation which will facilitate the design of prevention therapies in both settings.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Using novel approaches and reagents to interrogate islet specific T cells, this project will help us to a better understanding of the characteristics of CD4 and CD8 T cells associated with islet autoimmunity in the context of spontaneous disease development, recurrence of autoimmunity and designing immunosuppressive regimen after transplantation. Also, in clinical trials aiming at intervention or prevention of T1D more knowledge of the nature and dynamics of the T cell mediated cellular response is needed for the design of new and safer immunomodulatory therapies targeted specifically to eliminate the disease causing T cell population and for the evaluation of their therapeutic effect.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I entered the field of diabetes research when I started my PhD studies in Finland. I had a specific interest in type 1 diabetes since Finland has the highest incidence of T1D in the world. The focus of my project was to determine the genetic predisposition to T1D. It was a very exciting project and lead a way to the nation-wide screening of newborns for diabetes risk in one of the largest diabetes prevention trials in the world (DIPP-Diabetes Intervention and Prevention Study).
After I received my PhD at the University of Turku, I came to USA and joined Dr Nepom's group at Benaroya Research Institute in Seattle, first as a post-doctoral fellow and later as an independent investigator. I wanted to broaden my knowledge in diabetes immunology and extend my research interests from the immunogenetics of T1D more towards mechanistic studies focusing on the function of the MHC class II molecules in the autoimmune response leading to T1D. I am grateful for ADA giving me the opportunity to continue these projects. This award from ADA is a crucial part of the funding for my research team. This support gives an opportunity to explore these important questions that would help us to a better understanding of the natural history of T1D leading to a more specific and individual design of immunotherapies, and eventually a cure.
In what direction do you see the future of diabetes research going?
We need to understand the basic mechanisms in the immune system that trigger and drive the progression of organ-specific autoimmunity. Target proteins that are recognized by autoreactive T cells, the phenotype and activation pattern of T lymphocytes and the regulation of autoimmunity are all fundamental questions that form basis for the intervention therapies in T1D. There are several promising clinical trials going on but we still have to wait for the antigen-specific therapies due to the lack of knowledge of the mechanisms underlying the autoimmune process leading to diabetes. It is essential to learn which T population is prerequisite for the disease outcome and sufficient/necessary for the clinical disease.
Only then we would be able to predict which individuals at a high genetic risk would progress to diabetes and be the target group for intervention or prevention therapies. Other important areas of diabetes research are islet-transplantation and beta cell regeneration. Gained knowledge on the key features of persistence of the autoreactive T cells and potential resistance to immunosuppression will have a significant impact on the design of post-transplant treatment regimen to avoid organ rejection and/or recurrence of autoimmunity. These approaches can dramatically improve the quality of life in individuals who already have had diabetes for years and therefore cannot benefit from the intervention trials.
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