Cell-intrinsic immunopathology of type 1 diabetes in a humanized mouse model
General Research Subject: Type 1 Diabetes
Focus: Genetics\Type 1 Diabetes, Immunology, Transplantation
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2011
Project End Date: June 30, 2015
Type 1 diabetes results when the immune system attacks and destroys the insulin-producing beta cells in the pancreas. In a normal immune system this autoimmune attack is either prevented by elimination of self-reactive immune cells during development, or controlled by the action of immunoregulatory cells. Observations from Type 1 diabetic patients and a mouse model of diabetes suggest that genetic predisposition to diabetes correlates with many functional abnormalities in immunoregulatory cells. Since these data are collected after diabetes develops, it is difficult to distinguish whether any particular immunoregulatory abnormality directly causes disease or results as a symptom of diabetes progression and treatment. Research in this proposal focuses on determining which immunoregulatory defects are caused by a genetic predisposition to Type 1 diabetes. This is accomplished by generating a human immune system in a mouse. The laboratory has developed a humanized mouse model or 'Mini Me' mouse that allows robust immune reconstitution from immune stem cells of adult T1DM and normal volunteer donors. The Mini Me mouse permits comparison of the development and the evolution of immunoregulatory function in control and T1DM prone immune systems in the absence of diabetes. This research aims to determine which immunoregulatory populations are inherently dysfunctional in the T1DM immune system and use these insights to more effectively target therapeutic strategies to treat or cure Type 1 diabetes.
Mentor: Sykes, Megan, MD Postdoctoral Fellow: Danzl, Nichole
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
My project addresses the genetically-determined immunological abnormalities that promote development of type one diabetes. We have developed a model in which robust, complete human immune systems can be generated de novo in immunodeficient mice using bone marrow stem cells from adult volunteer donors. We have shown that mice can be reconstituted from bone marrow of type one diabetes patients and from healthy control volunteers who share the same diabetes-associated HLA alleles but do not have the disease. This model will allow us to analyze immune development, function and regulation and to identify abnormalities associated with type one diabetes without the complications involved in analyzing lymphocytes from immune systems of adults who already have disease. In our model, the immune system develops de novo in parallel cohorts of mice from stem cells of type 1 diabetic and control volunteers, allowing a disease-free platform with which to identify fundamental abnormalities in immunoregulation and correlate them with individual genetic information on known diabetes susceptibility and protective alleles. The understanding to be gained from this project will ultimately lead to new immunological approaches that could be used to prevent diabetes when signature functional immunologic abnormalities are identified in a genetically predisposed individual.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I came into the type one diabetes field from the vantage point of a transplantation immunologist. I began by developing an approach to inducing immune tolerance to islet transplants so that these grafts could be accepted without immunosuppression in the NOD mouse model. In the course of this work, I discovered that the same manipulation that we were using to induce tolerance to the islet grafts also reversed the autoimmune process that caused diabetes in NOD mice. This work, combined with interactions in my role as an investigator in the Harvard JDRF Center, got me interested in the immunology of human type 1 diabetes and in particular in developing this approach to cure the disease. The model we have developed will ultimately be useful in evaluating this curative approach in the context of specific, genetically-determined immunologic abnormalities that we identify in newly-generated immune systems from individuals with type one diabetes.
In what direction do you see the future of diabetes research going?
An in-depth understanding of immunological abnormalities predisposing to type 1 diabetes and the mechanisms by which genetic polymorphisms cause these abnormalities is now within reach due to the development of improved tools for human immune analysis and because of new information provided by recent GWAS studies. Islet replacement, initially through induction of tolerance to allografts and xenografts and eventually through the generation of new islets from stem cells, is an important direction that will change the standard of care for diabetes in the future.
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